ORCID Profile
0000-0001-8718-6175
Current Organisations
Monash University
,
Royal Melbourne Hospital
,
Royal Australasian College of Physicians
,
University of Melbourne
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Publisher: Elsevier BV
Date: 08-1998
DOI: 10.1016/S0198-8859(98)00040-8
Abstract: Pancreatic islet beta cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is believed to be mediated by a T-helper 1 (T(H)1) lymphocyte response to islet antigens. In the mouse, T(H)1 (IL-2, IFN-gamma) and T(H)2 (IL-4, -5, -6, -10) responses are associated with the generation of IgG2a and IgG1 subclasses, respectively. The equivalent human subclasses have not been defined. Because the IgG subclass response to an antigen may be a potentially useful marker of T(H)1/T(H)2 immune balance we measured IgG subclass antibodies to glutamic acid decarboxylase (GAD), a major islet autoantigen in IDDM, in 34 newly-diagnosed IDDM patients and in 28 at-risk, first-degree relatives of people with IDDM. In the newly-diagnosed patients, total IgG antibodies to GAD were detected in 74% (25/34) IgG1 and/or IgG3 were significantly more frequent than IgG4 or IgG4/IgG2 (14/34 versus 5/34, p = 0.01). GAD antibody-negative patients were significantly younger (p = 0.01). In 15 at-risk relatives who had not progressed to clinical diabetes after a median of 4.5 years, 10 had IgG2 and/or IgG4 antibodies compared to only 3/13 progressors (p = 0.02). Total IgG and IgG2 antibodies were higher in non-progressors. Non-progressors were older than progressors (p = 0.01), and relatives with IgG2 and/or IgG4 responses were also older (p = 0.01). These results suggest that IgG subclass antibodies to GAD may contribute to diabetes risk assessment in islet antibody relatives.
Publisher: American Diabetes Association
Date: 31-08-2017
DOI: 10.2337/DC17-0916
Abstract: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 & .00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were ided into those with (DYS/IND+) and without (DYS/IND−) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were ided into those with (IND/DYS+) and without (IND/DYS−) concomitant dysglycemia. The cumulative incidence for type 1 diabetes was greater after IND/DYS− than after DYS/IND− (P & 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND− (P & 0.001), whereas within the Index60 & .00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS− did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS− than for DYS/IND− (P & 0.001). Hazard ratios (HRs) of DYS/IND− with age and 30- to 0-min C-peptide were positive (P & 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P & 0.001 for both). In contrast, HRs of IND/DYS− and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P & 0.01 for all]). The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.
Publisher: Wiley
Date: 06-2010
Publisher: American Diabetes Association
Date: 09-03-2010
DOI: 10.2337/DC09-1481
Abstract: To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)–treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM). Sixty CSII-treated type 1 diabetic participants (aged 13–70 years, including adult and adolescent subgroups, with A1C ≤9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4–10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (≤3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16–32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks. In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7–8.2to 7.6% [7.2–8.0] P & 0.03) in group A but not in group B (7.8% [7.5–8.1] to 7.7 [7.3–8.0] NS) with no difference between groups. More subjects in group A achieved A1C ≤7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28 P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm. Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C ≤7%. Upon RT-CGM cessation, A1C returned to baseline.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.DIABRES.2014.08.030
Abstract: Vitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes. Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n=26) or placebo (n=24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR). In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (-0.08) was not different (P=0.112). However, change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups. Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.
Publisher: Wiley
Date: 05-1994
DOI: 10.1111/J.1365-2265.1994.TB03017.X
Abstract: Most bioassays used to measure thyroid stimulating antibodies (TSAb) rely on the ability of patient sera to generate cAMP in cultured cells of non-human origin. The cell line most commonly used has been the rat thyroid cell line, FRTL-5. Recently, a new cell line (JPO9) possessing a transfected human TSH receptor has been developed. The aim of this study was to evaluate the JPO9 cells by comparing them with the widely used FRTL-5 cells, using the method of 3H-adenine incorporation for the direct measurement of intracellular cAMP. The ability of patient sera to generate cAMP production in JPO9 and FRTL-5 cells was used as the index of thyroid stimulation. The specificity of the assay was determined using sera from patients with autoimmune thyroid and non-thyroid autoimmune diseases. We studied sera from 28 patients with newly diagnosed Graves' disease, 72 patients with Graves' disease at various stages of treatment, 8 patients with Hashimoto's thyroiditis, 40 patients with a variety of non-thyroid autoimmune disease and 42 control subjects. The intracellular 3H-cAMP generated in JPO9 cells following preincubation with 3H-adenine and subsequent incubation with patient or control sera, was used as a measure for TSAb. The results obtained with these cells were compared to those obtained with the widely used FRTL-5 cells and they were also correlated with the measurement of TSH binding inhibitory immunoglobulins by a conventional radioreceptor assay. JPO9 cells were more sensitive and had a wider range of response to bovine TSH (bTSH) than had FRTL-5 cells (10(-7)-10(-2) U/ml compared to 10(-5)-10(-3) U/ml respectively). Unlike FRTL-5 cells, JPO9 cells respond well to unmodified serum and grow constitutively in the absence of TSH, thereby not requiring TSH deprivation prior to assay. The TSAb values obtained with both cell lines correlated well (r = 0.87). The JPO9 cells responded specifically to Graves' sera (23 out of 28 newly diagnosed patients were positive), whereas no patients with Hashimoto's thyroiditis and only 4 of 40 patients with non-thyroid autoimmune diseases gave low positive results for the presence of TSAb. The JPO9 cells provide similar diagnostic information to FRTL-5 cells in patients with autoimmune thyroid disease. However, because they are more sensitive, grow faster, have less fastidious growth requirements and respond to unextracted sera, compared to FRTL-5 cells, we conclude that the JPO9 cells are preferable for the measurement of TSAb.
Publisher: American Medical Association (AMA)
Date: 21-11-2017
Publisher: Elsevier BV
Date: 05-2009
Publisher: Wiley
Date: 14-08-2007
Publisher: Mary Ann Liebert Inc
Date: 02-2011
Abstract: This study evaluated the impact on quality of life (QoL) of an algorithm guiding the responses of continuous subcutaneous insulin infusion (CSII)-treated type 1 diabetes (T1D) patients using real-time (RT)-continuous glucose monitoring (CGM). Sixty CSII-treated T1D participants (13-70 years old, glycosylated hemoglobin [HbA1c] ≤ 9.5%), including adult and adolescent subgroups, were randomized in age-, gender-, and HbA1c-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial Group A received CSII/RT-CGM with the algorithm, and Group B received CSII/RT-CGM without algorithm. Phase 2 was the 16-32-week follow-up study Group A returned to usual care (CSII without RT-CGM), and Group B was provided with algorithm at 16 weeks. QoL was assessed by DQOL (adults) and DQOLY (adolescents) questionnaires at baseline, 16 weeks, and 32 weeks. Higher scores (range 1-5) indicate poorer QoL. Analysis was by analysis of variance (between group for baseline-16 weeks) and paired two-tailed t tests (within group for baseline and 32 weeks) with significance at P < 0.05. Withdrawals left 28 of 30 patients in Group A and 27 of 30 patients in Group B at 32 weeks. In Phase 1, QoL in Group A (2.16 [0.44] baseline to 1.86 [0.40] at 16 weeks) improved compared with Group B (2.03 [0.47] to 2.03 [0.50]) (P = 0.002). Change in QoL correlated with changes in HbA1c (R = 0.36 P = 0.007). In Phase 2, Group A QoL was better at 32 weeks compared with baseline (2.16 [0.44] vs. 2.02 [0.43]) (P = 0.04) but was not in Group B (2.03 [0.47] vs. 1.99 [0.51]) (P = not significant). An algorithm guiding CSII-treated T1D responses to RT-CGM improved QoL, which persisted post-RT-CGM withdrawal. Algorithm provision at RT-CGM initiation was required to benefit QoL.
Publisher: Hindawi Limited
Date: 07-01-2020
DOI: 10.1111/PEDI.12952
Abstract: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of s les and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.
Publisher: Springer US
Date: 1988
DOI: 10.1007/978-1-4684-5616-5_8
Abstract: We report the results of fifteen cases of Sprengel's deformity treated surgically by initial subperiosteal resection of the middle third of the clavicle in conjunction with surgical release of all attachments of the scapula to the spine, excision of any omovertebral bone and resection of prominent supraspinous process of scapula. The patients included ten female and three male patients (age range at the time of operation, 3.3-10 years mean: 6.11 years). The deformity involved the left shoulder in eight patients, the right shoulder in three and two were bilateral. All patients were followed for an average of 5.9 years (range 4-11 years). Preoperatively, the arc of total abduction (glenohumeral and scapulothoracic) ranged from 80 to 140°, and the average was 110°. The shoulders were level, and the range of motion was dramatically improved with an average range of abduction of 166.5° (range 140-180°). The age of the patients and the presence of an omovertebral bone did not influence the results. All patients and their parents expressed satisfaction with the operative results. We feel that our procedure is a simple one, which helps to improve the degree of correction, avoid neurovascular complications and has the advantage of complete regeneration of the clavicle. The technique provides an easy, safe method of repositioning the scapula at its normal level.
Publisher: Mary Ann Liebert Inc
Date: 07-2017
Abstract: This qualitative study explored trial participants' experiences of four nights of in-home closed loop. Sixteen adults with type 1 diabetes, who completed a randomized crossover trial, were interviewed after four consecutive nights of closed-loop. Interviews were audio recorded, transcribed, and analyzed with a coding framework developed to identify the main themes. Participants had a mean age of 42 ± 10 years, nine were women mean diabetes duration was 27 ± 7 years, and all were using insulin pumps. Overall, first impressions were positive. Participants found closed-loop easy to use and understand. Most experienced more stable overnight glucose levels, although for some these were similar to usual care or higher than they expected. Compared with their usual treatment, they noticed the proactive nature of the closed-loop, being able to predict trends and deliver micro amounts of insulin. Most reported technical glitches or inconveniences during one or more nights, such as transmission problems, problematic connectivity between devices, ongoing alarms despite addressing low glucose levels, and sensor inaccuracy. Remote monitoring by the trial team and their own hypoglycemic awareness contributed to feelings of trust and safety. Although rare, safety concerns were raised, related to feeling unsure whether the system would respond in time to falling glucose levels. This study provides relevant insights for implementation of closed-loop in the real world. For people with diabetes who are less familiar with technology, remote monitoring for the first few days may provide reassurance, strengthen their trust/skills, and make closed-loop an acceptable option for more people with type 1 diabetes.
Publisher: American Diabetes Association
Date: 08-1987
Abstract: A major problem in standardization of the islet cell cytoplasmic antibody (ICA) assay is variation in sensitivity of the different human pancreas substrates used in in idual laboratories. To circumvent this problem, we have developed an assay that utilizes Wistar-Furth rat pancreas as substrate, an anti-islet monoclonal antibody (A2B5) to identify islets and fluorescein-conjugated protein A to identify patient autoantibodies. Sera from 85 control subjects, 27 type I diabetics, and 17 subjects at high risk for developing type I diabetes were assayed in parallel with our standard ICA assay on human pancreas substrate and with Wistar-Furth rat pancreas as substrate. Two sera from control subjects (2 of 85) were ICA positive with rat pancreas compared to 1 of 85 with human pancreas substrate. Sera from 11 of 27 type I diabetics and 15 of 17 sera from high-risk subjects were ICA positive with either rat or human pancreas substrate. A correlation between the specific islet fluorescence readings on human and rat pancreas sections was found with sera from high-risk and control subjects. Furthermore, end-point titers of an ICA-positive serum were identical with both assays. Finally, incubation of an ICA-positive serum with glycolipids, extracted from either human or Wistar-Furth rat pancreas, blocked subsequent ICA binding. These findings suggest that Wistar-Furth rat pancreas expresses an identical or similar autoantigen to human pancreas.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1992
Publisher: Wiley
Date: 23-06-2019
DOI: 10.5694/MJA2.50247
Abstract: To assess glucometric outcomes and to estimate the incidence of hypo- and hyperglycaemia among non-critical care inpatients in a major Australian hospital. A prospective 10-week observational study (7 March - 22 May 2016) of consecutive inpatients with diabetes or newly detected hyperglycaemia admitted to eight medical and surgical wards at the Royal Melbourne Hospital. Point-of-care blood glucose (BG) data were collected with networked glucose meters. Glycaemic control, as assessed with three glucometric models (by population, by patient, by patient-day) incidence of adverse glycaemic days (AGDs patient-days with BG levels below 4 mmol/L or above 15 mmol/L). During the study period, there were 465 consecutive admissions of 441 patients with diabetes or newly detected hyperglycaemia, and 9817 BG measurements over 2953 patient-days. The mean patient-day BG level was 9.5 mmol/L (SD, 3.3 mmol/L). The incidence of hyperglycaemia was higher than for a United States hospital benchmark (patient-days with mean BG level above 10 mmol/L, 37% v 32), and that of hypoglycaemia lower (proportion of patient-days with mean BG level below 3.9 mmol/L, 4.1% v 6.1%). There were 260 (95% CI, 245-277) AGDs per 1000 patient-days the incidence was higher in medical than surgical ward patients (290 [CI, 270-310] v 206 [CI, 181-230] per 1000 patient-days). 604 AGDs (79%) were linked with 116 patients (25%). Episodes of hyperglycaemia (BG above 15 mmol/L) were more frequent before lunch, dinner, and bedtime 94 of 187 episodes of hypoglycaemia (BG below 4 mmol/L) occurred between 11 pm and 8 am. Glucometric analysis supported by networked glucose meter technology provides detailed inpatient data that could enable local benchmarking for promoting safe diabetes care in Australian hospitals.
Publisher: Wiley
Date: 11-07-2008
DOI: 10.1111/J.1365-2265.2007.02995.X
Abstract: Most pituitary surgery centres prescribe perioperative glucocorticoids to subjects undergoing transsphenoidal pituitary adenomectomy (TSA), despite reports suggesting this may be unnecessary. Evidence-based guidelines for glucocorticoid use in TSA have recently been published but there are no prospective studies of their utility. To implement and assess a protocol for reduced glucocorticoid replacement for subjects undergoing TSA. Prospective and retrospective cohort study in an Australian pituitary surgery centre. Clinical and biochemical data for 56 TSAs performed for non-ACTH-secreting tumours between March 2004 and April 2006 were prospectively collected and compared with data for 47 TSAs performed between October 2001 and November 2003, before implementation of the protocol. In the prospective cohort, a postoperative days 1-3 morning serum cortisol threshold of 250 nmol/l (91 microg/dl) was used to guide long-term glucocorticoid requirement. Implementation of the protocol was associated with significant reductions in dose and duration of glucocorticoid treatment post TSA in 44 'low-risk' cases (no preoperative glucocorticoid use or evidence of pituitary apoplexy). In two low-risk cases, long-term glucocorticoid replacement was required despite postoperative cortisol greater than 250 nmol/l. Following the remaining 42 low-risk operations, glucocorticoid was not prescribed on hospital discharge on the basis of morning serum cortisol > 250 nmol/l and no clinical evidence of hypocortisolism. None of these 42 cases required glucocorticoid treatment for hypocortisolism following surgery. Short synacthen tests were performed in 35 of these subjects a minimum of 6 months after surgery and were normal. Use of the protocol was not associated with differences in postoperative complications. Reduced glucocorticoid replacement in TSA is safe and reduces patient exposure to glucocorticoids and their potential adverse events. The occurrence of hypocortisolism in two low-risk subjects with serum cortisol > 250 nmol/l highlights the importance of daily clinical assessment when using this protocol.
Publisher: Wiley
Date: 06-08-2007
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-1996
DOI: 10.1126/SCIENCE.272.5269.1811
Abstract: Insulin-dependent diabetes mellitus (IDDM) is a multigenic autoimmune disease. An IDDM susceptibility gene was mapped to chromosome 2q34. This gene may act early in diabetogenesis, because "preclinical" in iduals also showed linkage. Human leukocyte antigen (HLA)-disparate, but not HLA-identical, sibs showed linkage, which was even stronger in families with affected females. The genes encoding insulin-like growth factor-binding proteins 2 and 5 were mapped to a 4-megabase pair interval near this locus. These results indicate the existence of a gene that acts at an early stage in IDDM development, screening for which may identify a specific subset of at-risk in iduals.
Publisher: Wiley
Date: 27-03-2007
Publisher: Wiley
Date: 11-2003
Abstract: The Melbourne Prediabetes Family Study, a prospective study of first-degree relatives of people with type 1 diabetes (T1D), provided an opportunity to examine late-onset autoimmune diabetes within the context of a family history of T1D. We compared genetic, immunologic, and clinical features in relatives of people with T1D, who developed early- versus late-onset diabetes.
Publisher: Elsevier BV
Date: 11-2007
Publisher: Hindawi Limited
Date: 20-05-2019
DOI: 10.1111/PEDI.12865
Abstract: To investigate the longitudinal relationship between the gut microbiome, circulating short chain fatty acids (SCFAs) and intestinal permeability in children with islet autoimmunity or type 1 diabetes and controls. We analyzed the gut bacterial microbiome, plasma SCFAs, small intestinal permeability and dietary intake in 47 children with islet autoimmunity or recent-onset type 1 diabetes and in 41 unrelated or sibling controls over a median (range) of 13 (2-34) months follow-up. Children with multiple islet autoantibodies (≥2 IA) or type 1 diabetes had gut microbiome dysbiosis. Anti-inflammatory Prevotella and Butyricimonas genera were less abundant and these changes were not explained by differences in diet. Small intestinal permeability measured by blood lactulose:rhamnose ratio was higher in type 1 diabetes. Children with ≥2 IA who progressed to type 1 diabetes (progressors), compared to those who did not progress, had higher intestinal permeability (mean [SE] difference +5.14 [2.0], 95% confidence interval [CI] 1.21, 9.07, P = .006), lower within-s le (alpha) microbial ersity (31.3 [11.2], 95% CI 9.3, 53.3, P = .005), and lower abundance of SCFA-producing bacteria. Alpha ersity (observed richness) correlated with plasma acetate levels in all groups combined (regression coefficient [SE] 0.57 [0.21], 95% CI 0.15, 0.99 P = .008). Children with ≥2 IA who progress to diabetes, like those with recent-onset diabetes, have gut microbiome dysbiosis associated with increased intestinal permeability. Interventions that expand gut microbial ersity, in particular SCFA-producing bacteria, may have a role to decrease progression to diabetes in children at-risk.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Informa UK Limited
Date: 12-04-2023
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.DIABRES.2011.09.026
Abstract: We document the first reported case of fulminant diabetes, without evidence of pancreatic islet autoimmunity, in Australia in a woman of Chinese Vietnamese background. Fulminant diabetes occurs primarily in Asia, particularly in Japan, but with widespread population migration clinicians need to be aware of this form of diabetes.
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/AH090671
Abstract: We aimed to evaluate service model configuration, service capacity and accessibility of diabetes-related footcare in an Australian community health setting. Eighty-eight community-based podiatry clinics were surveyed using the self-administered Footcare Provider Survey. Survey domains included communication, resources, service coordination and barriers to service provision. Sixty-nine from a possible 88 Victorian community podiatry clinics (78%) responded. Sixty-one (88%) provided ongoing care to in iduals with diabetes-related foot disorders. Communication with vascular and orthopaedic specialists was reported to be readily available in 37% and 27% of cases respectively. Overall, communication with general practitioners was deemed readily available in 62% of cases. Just 39% of podiatrists statewide agreed overall resources were sufficient, with 26% agreeing staffing levels were adequate. Thirty-nine percent of community podiatrists used clinical care pathways, and onsite collaboration was deemed appropriate in just 30% of cases. Perceived barriers to provision of care included inadequate staffing and resources, lack of confidence from other health professionals in the podiatrists? ability to manage diabetes-related foot disorders, and lack of access to specialists.
Publisher: Elsevier BV
Date: 07-2021
Publisher: American Diabetes Association
Date: 06-1995
Abstract: There is increasing interest in the use of glutamic acid decarboxylase antibodies (GADAbs) for identification of subjects at increased risk of developing insulin-dependent diabetes mellitus (IDDM). However, considerable variation exists between laboratories in the reported frequency of GADAb in various clinical situations, and disease sensitivity and specificity have not yet been compared between assays. An international workshop was held in which 101 coded freeze-dried sera, including 39 from subjects with newly diagnosed IDDM, 32 from healthy control subjects, 4 from nondiabetic subjects with Graves' disease, and 4 from islet cell antibody–positive subjects, were analyzed in 52 assays (radiobinding assay [RBA], 26 enzyme-linked immunosorbent assay [ELISA], 19 and enzymatic immunoprecipitation assay [EIP], 7). The mean sensitivity for RBAs (76.2%) was higher than for ELISAs (36.5%) and EIPs (49.9%) (P & 0.01). The mean specificity was similar for each assay format (RBA, 89.4% ELISA. 89.4% and EIP, 92.3%). The lower sensitivities of the ELISA and EIP were predominantly due to the inability of these assays to detect low levels of GADAb in IDDM. To convert results to standard units, standard curves were constructed using duplicate dilutions of the anti–glutamic acid decarboxylase monoclonal antibody MICA 3 and serum from a patient with stiff-man syndrome (SMS). Curves could be derived in 28 assays using the MICA 3 serum and in 29 using the SMS serum. The mean coefficients of variation between assays for disease and control s les were 45% when results were converted to MICA units, 77% for SMS units, and 76% for SD scores. The relatively lower scatter observed using the MICA 3 serum as a standard indicates that this serum may be useful as an international reference. Because assays for GADAb with a high level of sensitivity and specificity are now available, prospective studies are now required to establish the role of GADAbin clinical applications such as preclinical screening for IDDM.
Publisher: Royal College of Psychiatrists
Date: 06-1996
Abstract: An age-related dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is well recognised in animals, but still remains controversial in humans. There is increasing interest that raised corticosteroid levels, due to activation of the HPA axis, may cause both depressive symptoms and cognitive impairments. Steroid effects on cognition may be via the hippoc us, a major site of corticosteroid action and an important structure involved in learning and memory. To investigate this further, we examined the relationship between the dexamethasone suppression test, cognitive function, depressive symptoms and hippoc al atrophy on magnetic resonance imaging (MRI) in 32 normal controls, 49 subjects with NINCDS/ADRDA Alzheimer's disease and 51 patients with DSM–III–R Major Depression. Controlling for differences in dexamethasone concentrations, post-dexamethasone cortisol levels were related to advancing age in controls and depressed subjects. However, among subjects with Alzheimer's disease, post-dexamethasone cortisol levels were independently associated with both minor depressive symptoms and hippoc al atrophy on MRI. An association between advancing age and increased HPA axis dysregulation is supported for controls and depressed subjects. In Alzheimer's disease, HPA axis changes were associated with depressive symptoms and hippoc al atrophy. Longitudinal studies are now needed to determine the causal direction of these associations.
Publisher: Wiley
Date: 13-05-2005
DOI: 10.1111/J.1445-5994.2005.00814.X
Abstract: The use of recreational drugs has become increasingly popular among young people. As a centre caring for a large group of young patients with type 1 diabetes, we have become concerned about the number of patients presenting with drug-related metabolic problems. We present a case series highlighting the issues of substance abuse in young patients with type 1 diabetes.
Publisher: Wiley
Date: 25-02-2005
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.ORCP.2013.03.007
Abstract: Excessive body weight is increasingly seen in type 1 diabetes but its impact is debated. To address this uncertainty, we aimed to determine the association between excess body weight and the macro- and microvascular complications of type 1 diabetes. We identified 501 adults with type 1 diabetes attending an Australian hospital clinic and extracted their clinical and biochemical data from our patient management database. In both men and women, obesity (BMI > 30 kg/m(2)) was the predominant risk factor for retinopathy and cardiovascular disease despite similar HbA1c and increased use of cardioprotective drugs compared to non-obese patients. Obesity was associated with albuminuria in women, but not renal impairment or neuropathy in either sex. We conclude that obesity in type 1 diabetes may promote retinopathy and macrovascular disease. Future trials to determine the effect of weight loss on type 1 diabetes in obese people are needed.
Publisher: Oxford University Press (OUP)
Date: 1996
Publisher: American Diabetes Association
Date: 04-1988
Abstract: Regulatory elements that control expression of specific genes during development have been shown in many cases to contain functionally-conserved modules that can be transferred between species and direct gene expression in a comparable developmental pattern. An ex le of such a module has been identified at the rat myosin light chain (MLC) 1/3 locus, which has been well characterised in transgenic mouse studies. This locus contains two promoters encoding two alternatively spliced isoforms of alkali myosin light chain. These promoters are differentially regulated during development through the activity of two enhancer elements. The MLC3 promoter alone has been shown to confer expression of a reporter gene in skeletal and cardiac muscle in transgenic mice and the addition of the downstream MLC enhancer increased expression levels in skeletal muscle. We asked whether this regulatory module, sufficient for striated muscle gene expression in the mouse, would drive expression in similar domains in the chicken. We have observed that a conserved downstream MLC enhancer is present in the chicken MLC locus. We found that the rat MLC1/3 regulatory elements were transcriptionally active in chick skeletal muscle primary cultures. We observed that a single copy lentiviral insert containing this regulatory cassette was able to drive expression of a lacZ reporter gene in the fast-fibres of skeletal muscle in chicken in three independent transgenic chicken lines in a pattern similar to the endogenous MLC locus. Reporter gene expression in cardiac muscle tissues was not observed for any of these lines. From these results we conclude that skeletal expression from this regulatory module is conserved in a genomic context between rodents and chickens. This transgenic module will be useful in future investigations of muscle development in avian species.
Publisher: American Diabetes Association
Date: 10-1992
DOI: 10.2337/DIACARE.15.10.1313
Abstract: To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. Postal questionnaires were delivered to 12 centers. Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg the dosage in adults was limited to a maximum of 25–50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 ± 10 s to 4 ± 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the + 1-min s le varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.
Publisher: Elsevier BV
Date: 02-1994
Abstract: Antibodies to glutamic decarboxylase (GADAb) are present in insulin-dependent diabetes (IDD) but their association with age and sex and their temporal profile in relation to disease onset have not been fully documented. We have examined the association between GADAb and islet cell antibodies (ICA), age and sex, and have cross-sectionally and longitudinally measured the levels of GADAb before and after diagnosis of IDD. GADAb were measured by allowing serum immunoglobulin prebound to protein A Sepharose to precipitate GAD enzymatic activity from a fetal pig brain extract. GADAb levels were above the normal range (mean + 3SD of healthy controls, 460 nU/ml) in 19/44 (43%) at-risk subjects (ICA positive first degree relatives of persons with IDD), 35/108 (32%) recent-onset IDD subjects and 22/46 (47%) established IDD subjects. When analysed according to age and sex, GADAb levels were significantly higher (P 20 in both first degree relatives (P < 0.001) and recent-onset subjects (P < 0.01) and GADAb were uncommon in the absence of ICA. Levels of GADAb were similar in at-risk, recent-onset and established IDD subjects and GADAb status remained stable in all but 2/41 at-risk subjects followed for 17 (mean, range 3-33) months. In conclusion, GADAb levels are strongly influenced by age, sex and ICA status, and generally remain stable in at-risk subjects and after the onset of clinical IDD.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.JOCN.2004.03.002
Abstract: Dopamine agonists are first line treatment for prolactinomas. This treatment can cause serious complications in patients with invasive macroprolactinomas. This study reviewed 195 patients attending the endocrine clinic and/or undergoing surgery for pituitary tumours at The Royal Melbourne Hospital in a seven-year period (1996-2002). Thirty three patients had macroprolactinoma (diameter >10 mm). Eleven of them were treated with dopamine agonist prior to surgery and four developed severe complications. This study suggests that the severe complications of dopamine agonist therapy may be higher than previously reported. All patients should be educated about these complications and their early recognition.
Publisher: American Diabetes Association
Date: 06-1989
Abstract: A double-blind controlled trial of azathioprine (2 mg · kg−1 · day−1) was conducted with 49 patients aged 2–20 yr (mean 10.8 yr) who had newly diagnosed type I (insulin-dependent) diabetes. Patients were randomly assigned to receive either azathioprine (n = 24) or placebo (n = 25) for 12 mo, beginning within the 20 day period after diagnosis. Baseline clinical and metabolic characteristics did not differ between the two groups. No patient experienced complete remission, defined as restoration of normal carbohydrate tolerance without other treatment. Partial remission, defined as good metabolic control (hemoglobin A1c ≤7.9%, preprandial blood glucose ≤8 mM with an insulin dose of & .5 U. kg−1 · day1), occurred in 10 placebo (40%) and 7 azathioprine (29%) patients at 6 mo and in 4 placebo (16%) and 4 azathioprine (17%) patients at 12 mo (differences not significant). Fasting plasma C-peptide was significantly greater in the azathioprine-treated group at 3 and 6 mo, but this difference was not sustained. C-peptide responses to a standard meal and the frequency of islet cell and insulin antibodies did not differ between the two groups over the 12-mo period. Azathioprine caused no significant side effects. We conclude that in the dosage used, and despite early effects on endogenous insulin secretion, azathioprine alone does not influence the remission phase in children with newly diagnosed type I diabetes.
Publisher: Mary Ann Liebert Inc
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 02-08-2021
DOI: 10.1007/S00125-021-05523-2
Abstract: Accurate prediction of disease progression in in iduals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood s les taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial–Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA 1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M 60 , M 90 and M 120 , based on s ling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood s les. In TEDDY, where only 120 min blood s ling had been performed, the M 120 AUC was 0.865. In Fr1da, the M 120 AUC of 0.742 was significantly greater than the M 60 AUC of 0.615. Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M 120 , its validity across different at-risk populations and the requirement for 120 min s ling to stage type 1 diabetes suggest M 120 could be readily applied to decrease the cost and complexity of risk stratification.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2009
DOI: 10.1007/S00125-009-1365-0
Abstract: The objective of this study was to assess the impact of patient-led sensor-guided pump management on glycaemic control, and compare the effect with that of standard insulin pump therapy. An open multicentre parallel randomised controlled trial was conducted at five tertiary diabetes centres. Participants aged 13.0-40.0 years with well-controlled type 1 diabetes were randomised 1:1 to either study group for 3 months. Randomisation was carried out using a central computer-generated schedule. Participants in the intervention group used sensor-guided pump management no instructive guidelines in interpreting real-time data were provided ('patient-led' use). Participants in the control group continued their original insulin pump regimen. Continuous glucose monitoring (CGM) and HbA(1c) level were used to assess outcomes. The primary outcome was the difference in the proportion of time in the target glycaemic range during the 3 month study period (derived from CGM, target range 4-10 mmol/l). Secondary outcomes were difference in HbA(1c), time in hypoglycaemic ( or =10.1 mmol/l) ranges and glycaemic variability. Sixty-two participants were recruited and randomised 5/31 and 2/31 withdrew from intervention and control groups, respectively, leaving 26/31 and 29/31 for the intention-to-treat analyses. When adjusted for baseline values, the mean end-of-study HbA(1c) was 0.43% lower in the intervention group compared with the control group (95% CI 0.19 to 0.75% p = 0.009). No difference was observed in CGM-derived time in target (measured difference 1.72 95% CI -5.37 to 8.81), hypoglycaemic (0.54 95% CI -3.48 to 4.55) or hyperglycaemic (-2.18 95% CI -10.0 to 5.69) range or in glycaemic variability (-0.29 95% CI -0.34 to 0.28). Within the intervention group, HbA(1c) was 0.51% lower in participants with sensor use > or =70% compared with participants with sensor use or =70%) was not universally acceptable. ACTRN12606000049572
Publisher: American Diabetes Association
Date: 05-2006
DOI: 10.2337/DC05-2101
Abstract: OBJECTIVE—Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS—Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA−) (aged 30–75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a “LADA clinical risk score,” based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS—In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset & years (P & 0.0001), 2) acute symptoms (P & 0.0001), 3) BMI & kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score ≥2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score ≤1 of 99%. CONCLUSIONS—At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.
Publisher: SAGE Publications
Date: 22-10-2015
Abstract: Current electrochemical glucose sensors use a single electrode. Multiple electrodes (redundancy) may enhance sensor performance. We evaluated an electrochemical redundant sensor (ERS) incorporating two working electrodes (WE1 and WE2) onto a single subcutaneous insertion platform with a processing algorithm providing a single real-time continuous glucose measure. Twenty-three adults with type 1 diabetes each wore two ERSs concurrently for 168 hours. Post-insertion a frequent s ling test (FST) was performed with ERS benchmarked against a glucose meter (Bayer Contour Link). Day 4 and 7 FSTs were performed with a standard meal and venous blood collected for reference glucose measurements (YSI and meter). Between visits, ERS was worn with capillary blood glucose testing ≥8 times/day. Sensor glucose data were processed prospectively. Mean absolute relative deviation (MARD) for ERS day 1-7 (3,297 paired points with glucose meter) was (mean [SD]) 10.1 [11.5]% versus 11.4 [11.9]% for WE1 and 12.0 [11.9]% for WE2 P .0001. ERS Clarke A and A+B were 90.2% and 99.8%, respectively. ERS day 4 plus day 7 MARD (1,237 pairs with YSI) was 9.4 [9.5]% versus 9.6 [9.7]% for WE1 and 9.9 [9.7]% for WE2 P = ns. ERS day 1-7 precision absolute relative deviation (PARD) was 9.9 [3.6]% versus 11.5 [6.2]% for WE1 and 10.1 [4.4]% for WE2 P = ns. ERS sensor display time was 97.8 [6.0]% versus 91.0 [22.3]% for WE1 and 94.1 [14.3]% for WE2 P .05. Electrochemical redundancy enhances glucose sensor accuracy and display time compared with each in idual sensing element alone. ERS performance compares favorably with ‘best-in-class’ of non-redundant sensors.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2000
Abstract: To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was s led every 6 months for IAA, GADAb and IA2Ab. We did not find any antibodies in 263 (73%) infants 50 (14%) were positive for a single antibody once, 19 (5%) for a single antibody more than once and 25 (7%) for two or more antibodies. Of the latter, 10 (2.8% overall) were persistently positive they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64% of infants with two or more antibodies. Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient 'self limited' islet autoimmunity in at risk infants.
Publisher: Elsevier BV
Date: 04-1988
DOI: 10.1016/0896-8411(88)90019-4
Abstract: A recent international workshop documented marked interlaboratory variation in end point titers of standard islet cell antibody (ICA) positive sera. End titers were lower using a modified assay which utilizes fluorescein labeled protein A (ICA-pA) rather than fluoresceinated anti-IgG (ICA-IgG) to detect antibody binding to islets. In this study we sought to compare directly two ICA assays with respect to future development of IDDM. Sera were obtained from 26 prospectively evaluated high risk subjects identified by family screening or history of transient hyperglycemia and 12 normal controls. As expected, end point titers for ICA positive sera were 10 times greater using the ICA-IgG assay than with the ICA-pA assay. However, despite higher end point titers, the ICA-IgG assay failed to detect more 'prediabetics' and showed a prozone effect. Fourteen subjects were positive at a 1:2 dilution using the ICA-pA assay. Only 10 of these 14 were positive at a 1:2 dilution using the ICA-IgG assay but all became positive at greater sera dilutions. No normal controls were positive using either assay. A similar prozone was observed with anti-islet monoclonal antibodies A2B5 and 4F2. Sera from 14 long-standing IDDM patients (where titers of ICA may have decreased relative to time of onset of diabetes) which were negative using ICA-pA were also assayed using ICA-IgG. Five sera positive for ICA-IgG but negative for ICA-pA were identified. In addition two sera in which a prozone effect was seen with ICA-pA were identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 11-1992
DOI: 10.1111/J.1532-5415.1992.TB01803.X
Abstract: To determine whether age-related bone loss is negatively associated with serum intact parathyroid hormone (PTH). Survey. University hospital outpatient department. 100 community-dwelling women, age 18 to 80, recruited as a convenience s le. Dependent variables--bone density at the spine and femoral neck by dual-energy X-ray absorptiometry. Independent variables--age, menopausal status (binary) and intact serum PTH by Allegro immunometric assay. Post-menopausal women had higher serum PTH and lower bone density of spine and femoral neck than premenopausal women. Bone density at the spine decreased with age, but this effect was accounted for by menopausal state. Bone density at the femoral neck decreased with age even after adjusting for menopause. Log PTH was negatively associated with bone density at the femoral neck but not significantly at the spine. Multiple regression analysis adjusting for age and menopause showed no significant association between intact PTH and bone density at the spine or the femoral neck. Although this study confirmed the rise in intact PTH with age, there is no evidence that this is the mediator of age-related bone loss.
Publisher: American Diabetes Association
Date: 14-10-2020
DOI: 10.2337/DC20-1447
Abstract: To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes). Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR 70–180 mg/dL) during the final 3 weeks. Participants were randomized to HCL (n = 61) or control (n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19] P & 0.0001). For HCL, HbA1c was lower (median [95% CI] difference −0.4% [−0.6, −0.2] −4 mmol/mol [−7, −2] P & 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9] P & 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively. In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA1c, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous.
Publisher: Elsevier BV
Date: 05-1993
DOI: 10.1016/0140-6736(93)90940-I
Abstract: Glutamic acid decarboxylase (GAD) in pancreatic beta cells is an autoantigen in insulin-dependent diabetes (IDD). We measured immunity to GAD in 31 first-degree relatives of IDD patients judged to be at risk of developing IDD themselves because of the presence of islet-cell antibodies. We found that in most of the subjects GAD autoimmunity was either predominantly humoral or predominantly cellular. High concentrations of circulating autoantibodies that precipitate native GAD activity were associated with low proliferation of peripheral-blood T cells to recombinant GAD conversely, low concentrations of autoantibody to GAD were associated with high T-cell proliferation to GAD. Although T-cell proliferation was measured in the presence of autologous serum, GAD autoantibodies did not have a blocking effect in vitro. This dichotomy of the immune response to GAD defined heterogeneity within at-risk relatives and could have prognostic importance. We postulate that, if GAD is a pathogenetic autoantigen, sensitisation to beta-cell GAD is more likely to lead to IDD when the immune response deviates towards the expansion of autoreactive T cells rather than towards generation of autoantibodies. This idea is consistent with evidence that beta-cell destruction is mediated by T cells and that high concentrations of GAD antibodies are associated with slower progression to clinical disease.
Publisher: Mary Ann Liebert Inc
Date: 06-1995
Abstract: Radioactive iodine (RAI)-induced changes in the levels of antibodies to the thyroid-stimulating hormone (TSH) receptor (TRAb) in patients undergoing treatment for autoimmune thyroid disease have been well documented. Previous studies have reported effects on the overall level of the antibodies present, TSH-binding inhibitory immunoglobulins (TBII), without detailed studies of specific effects on the levels of thyroid-stimulating (TSAb) or thyroid-blocking antibodies (TBAb). More detailed studies have been reported only in in idual cases. In this study, the values of TSAb, TBAb, and TBII were measured longitudinally in 33 patients (27 females and 6 males) who received RAI. The bioassays for TSAb and TBAb were performed in JPO9 cells. Following RAI, there were significant and immediate effects on the values of TBII in 70% of patients. TBII levels fell in 7 patients (20%) (Group 1), rose in 16 patients (48%) (Group 2) or remained unchanged but elevated in 10 patients (32%) (Group 3). In the Group 1 patients, only TSAb were detectable and none of these patients became hypothyroid after treatment. In the 16 patients in Group 2, increases in TBII were attributable to specific increases in TSAb in 7 (44%), in TBAb in 3 (19%), and in both TSAb and TBAb in 3 (19%). There were 3 patients (19%) in this group in whom there was no detectable TSAb or TBAb activity despite the increase in TBII. Six patients from this group became hypothyroid within 6 months of RAI treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Informa UK Limited
Date: 05-1987
DOI: 10.1080/00325481.1987.11699821
Abstract: Considerable advances in the understanding of the immune basis of type I diabetes have encouraged trials of a number of forms of immunotherapy. Preliminary evidence indicates that cyclosporin (Sandimmune) treatment can halt beta cell destruction in about 50% of patients with newly diagnosed type I diabetes. Further studies are necessary to define the toxicity of this and other protocols prior to clinical use. Efforts to define the target antigen in type I diabetes may lead to development of more specific forms of immunotherapy or, possibly, a vaccine.
Publisher: Informa UK Limited
Date: 1998
DOI: 10.3109/08916939808993841
Abstract: Insulin-dependent diabetes mellitus (IDDM) is preceded by the presence of antibodies against islet proteins including a protein tyrosine phosphatase (PTP) designated IA-2. Recently, we cloned a novel PTP named IAR which shares 43% sequence identity with IA-2 and is recognised by antibodies from a majority of patients with IDDM. The aim of the present study was to determine whether IAR antibodies (IAR Ab) or IA-2 antibodies (IA-2 Ab) are associated with progression to IDDM in first-degree relatives "at-risk" for IDDM (operationally defined as those with islet cell antibodies [ICA] > or = 20JDFU or insulin autoantibodies [IAA] > or = 100 nU/ml), and to examine combinations of IAR Ab and IA-2 Ab in these subjects. The sensitivity and specificity of these antibodies were also examined in patients with recent-onset IDDM. Using Cox's Proportional Hazards Model, the number of siblings with IDDM was associated with progression to IDDM in "at-risk" relatives, but other covariables (age, sex, number of affected offspring or parents) were not significantly associated. Using number of affected siblings as a covariable, both IAR and IA-2 antibodies were significantly associated with progression to IDDM (p < 0.005). Combinations of both antibodies, however, did not result in a significantly stronger association with progression to IDDM. The threshold of positivity for IAR Ab (0.5 units) and IA-2 Ab (3.0 units) assays was adjusted to give the same specificity (97.9%) for each assay in 144 healthy control subjects, to allow standardised comparisons. Levels of IAR Ab and IA-2 Ab were strongly correlated in 53 recent-onset IDDM patients (r = 0.70, p < 0.0001) but 11.3% had IAR Ab in the absence of IA-2 Ab and 16.9% had IA-2 Ab in the absence of IAR Ab. The sensitivity for IDDM (defined as the proportion of IDDM patients positive) was 56.6% for IAR Ab and 62.3% for IA-2 Ab. We conclude that there is considerable overlap in IA-2 Ab and IAR Ab positivity, although either antibody can occur independently in IDDM patients. Both IAR Ab and IA-2 antibodies are associated with progression to IDDM in first-degree relatives at-risk of IDDM, but the use of IAR and IA-2 antibodies in combination are not significantly more strongly associated with progression than single antibodies. IAR Ab may play an important role in the prediction of IDDM.
Publisher: Oxford University Press (OUP)
Date: 06-1994
DOI: 10.1093/AJH/7.6.562
Abstract: There is much interest in the relationship of hypertension to hyperinsulinemia. Six male volunteers received cortisol, 50 mg orally four times daily, for 5 days. Plasma insulin concentration increased from 11.8 +/- 3.0 mU/L to 16.1 +/- 4.0 mU/L (P = .034). Fasting glucose increased from 4.7 +/- 0.3 to 5.8 +/- 0.1 mmol/L (P = .001). The insulin-to-glucose ratio was unchanged. Octreotide has been reported to lower blood pressure in obese, hyperinsulinemic, hypertensive patients. The hypothesis that cortisol-induced hypertension might be secondary to steroid-induced hyperinsulinemia was examined by determining whether reversal of hyperinsulinemia by octreotide would reverse cortisol-induced hypertension. Five healthy men were given two subcutaneous injections of 0.05 mg of octreotide before and on the fifth day of cortisol administration. Cortisol increased blood pressure, weight, plasma glucose concentration, and white cell count, with decreases in plasma potassium concentration and packed cell volume. Plasma cortisol concentrations were unchanged following octreotide in the control period but decreased after cortisol treatment. Insulin concentrations were reduced profoundly after octreotide, both in the control period (12.5 +/- 3.7 mU/L, falling to 1.1 +/- 0.3 mU/L at 30 min) and on cortisol (22.3 +/- 4.5 to 2.3 +/- 0.5 mU/L at 30 min). Octreotide did not lower pressure before or after cortisol treatment. Thus, octreotide was effective in lowering plasma insulin concentrations but di not lower blood pressure in normal subjects with cortisol-induced hypertension. These data do not support the notion that steroid-induced hyperinsulinemia is responsible for steroid-induced hypertension.
Publisher: Wiley
Date: 07-08-2018
DOI: 10.1111/DME.13762
Abstract: In recent years, immune checkpoint blockade has become a standard therapy for a wide range of cancers. Adverse events including endocrinopathies result from the induction of autoimmunity. We report a case series of nine in iduals who presented with immunotherapy-induced type 1 diabetes between 2015-2017. Onset of diabetes occurred within 12 weeks of commencing therapy. Anti- GAD antibodies were present in six people. Retrospective testing of islet antibodies in pre-treatment s les was possible in two people and this revealed anti-GAD seroconversion in the first and high anti-GAD titres pre and post-treatment in the second person. Six people had high risk HLA haplotypes. Clinical and genetic factors are described and compared with previously published cases. This article is protected by copyright. All rights reserved.
Publisher: American Diabetes Association
Date: 05-1988
Abstract: With biochemical and enzymatic treatment of frozen sections of pancreas, we have previously shown that cytoplasmic islet cell antibodies (ICAs) react with carbohydrate determinants of islet cell glycoconjugates. As a first step toward purifying these glycoconjugates, human pancreas tissue was extracted in a mixture of chloroform and methanol, and the glycolipids were obtained by effecting a Folch partition. The protein pellet, lipid fraction, and glycolipid fraction so obtained were assessed for their ability to block the binding of ICAs to frozen sections of human pancreas, the effect being quantitated with a photometer. Only the glycolipid extract could block ICA binding, and blocking was dose dependent. Subfractionation of the glycolipid extract by hydrophobic interaction on C18 cartridges demonstrated that blocking activity resided in the fraction bound and eluted with methanol, consistent with the autoantigen being a glycolipid. Furthermore, the binding of an anti-islet cell ganglioside monoclonal antibody, 3G5, could be blocked with these extracts, whereas the binding of an anti-islet cell protein monoclonal antibody, 4F2, was unaffected. The major gangliosides of the pancreas were seen to be GM3 and GD3 by thin-layer chromatography (TLC). Fractions scraped and eluted from TLC plates were tested for their ability to block ICA binding to pancreatic sections. Neither GM3- nor GD3-containing fractions could block ICA binding however, a fraction containing minor pancreatic gangliosides (including GM2) of monosialoganglioside mobility was a potent inhibitor of ICA binding to pancreas sections. TLC of a chloroform-methanol extract of human islets demonstrated that islets differentially express monosialogangliosides (especially GM2). These findings suggest that the islet cell autoantigen in frozen sections is a glycolipid migrating with a mobility characteristic of a monosialoganglioside.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2009
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.CLIM.2010.09.002
Abstract: Insulin autoantibodies (IAA) precede type 1 diabetes, but not all IAA-positive children develop other islet autoantibodies and disease. Diabetes risk can be stratified by laborious IAA affinity measurement using competition with multiple ligand concentrations. Here, we identify a single competitor concentration that discriminates low- and high-affinity IAA. Discrimination was achieved among 122 IAA-positive sera using 7.0 nM competitor which is 54-fold that of the assay radioligand concentration. Relative-binding <60% at this competitor concentration identified all 85 sera with affinities ≥1.0×10⁸ L/mol and none with lower affinities (P<0.0001), and 45 (96%) of 47 multiple islet autoantibody-positive sera (P<0.0001). IAA competition was further tested in a second set of 119 IAA-positive sera. Of these, 99 fulfilled high-affinity competition criteria of <60% relative-binding at 7.0 nM competitor including 89 (94%) of 95 sera with multiple islet autoantibodies (P<0.0001). Thus, increased IAA specificity can be achieved with simple modification to existing assays.
Publisher: American Diabetes Association
Date: 12-1992
Abstract: The goal of the Fourth International Workshop for Standardization of ICA Measurements was to determine the specificity of ICA assays and their ability to distinguish between control sera (n = 57) and sera from IDDM-related in iduals—representing relatives of IDDM patients (n = 21), healthy in iduals who later developed IDDM (n = 8), or newly diagnosed IDDM patients (n = 23). Results from 28 laboratories were analyzed. The mean specificity (percentage of control sera reported as negative) among 27 laboratories was 91%, including 6 laboratories with 100% specificity. Nevertheless, 78% of laboratories found at least one control s le & JDF U. Among s les from first-degree relatives, the mean concordance was 86%, including three sera found negative (0 JDF U) by all laboratories. Among in iduals who later developed diabetes, the mean concordance was 93%, with two sera found positive by 100% of laboratories. In sera from newly diagnosed IDDM patients, the mean concordance was 82%. Three sera were found positive and one serum negative by all laboratories. The JDF U of the sera considered to be positive were significantly greater than each laboratory's average for the controls. In conclusion, the results from laboratories participating in the Fourth International ICA Workshop demonstrated excellent specificity, good concordance, and an ability to separate control sera from defined, IDDM-related subjects.
Publisher: Wiley
Date: 05-2004
Publisher: Wiley
Date: 06-2004
Publisher: AMPCo
Date: 11-2004
Publisher: Wiley
Date: 11-2020
DOI: 10.1111/IMJ.15059
Publisher: SAGE Publications
Date: 10-07-2016
Abstract: Australasia is a region with a high incidence of type 1 diabetes (T1D). There are approximately 140 000 in iduals with T1D, and of these 10 000 are children. Although the region covers a huge geographical area, most children with T1D are managed by tertiary academic centers in the major capital cities. Local longitudinal data collection has been in place for several decades in most of these centers, however ongoing national data collection had not been attempted. In 2012, with funding from the Juvenile Diabetes Research Foundation (JDRF) Australian Type 1 Clinical Research Network, a national collaboration was formed to provide ongoing longitudinal collection of T1D patient characteristics and outcomes. The initial phase of this collaboration, known as the Australasian Diabetes Data Network or ADDN, was led by the Australasian Paediatric Endocrine Group (APEG) and thus included only children and adolescents. The next phase, commenced in 2016, will see adult sites added through collaboration with the Australian Diabetes Society (ADS). As most of the initial centers had longitudinal data collection in place the model employed was to establish the transfer and collation of data already collected into a central database. This required the definition of a common data dictionary, ethics and governance procedures and the employment of technology to enable efficient and accurate information transfer and accessibility. The ADDN project received widespread support from the diabetes research community with study investigators representing 20 pediatric centers across the region. The first phase focused on the 5 largest centers and at the end of 2015 these centers were uploading patient data to the ADDN database on a quarterly basis resulting in 5271 patients with 83 506 diabetes visits.
Publisher: Mary Ann Liebert Inc
Date: 07-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
DOI: 10.1161/01.STR.0000133687.33868.71
Abstract: Background and Purpose— Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation. Methods— Diffusion-weighted MRI, glycosylated hemoglobin (HbA 1c ), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images. Results— Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L n=14) compared with those without (6.5 mmol/L n=17 P =0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level ( P =0.001), as was pre-existing diabetes mellitus ( P =0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels ( P =0.849). There was no association between HbA 1c and glucose level ( P =0.737). Conclusions— Despite the small s le size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.
Publisher: American Diabetes Association
Date: 12-1998
DOI: 10.2337/DIABETES.47.12.1857
Abstract: The aim of this workshop was to assess the ability of in idual autoantibody (ab) assays and their use in combination to discriminate between type 1 diabetic and control sera. Coded aliquots of sera were measured in a total of 119 assays by 49 participating laboratories in 17 countries. The sera were from 51 patients with new onset type 1 diabetes and 101 healthy control subjects with no family history of diabetes. In the final analysis, data on diabetic sera were restricted to 43 subjects younger than age 30 years. The laboratories were asked to report results for these sera using their currently available anti-islet autoantibody assays. In addition, they were asked to combine information from their assays to classify sera as having high, moderate, or low probability of originating from a patient with type 1 diabetes. Actual strategies for combining assays were determined by each laboratory. There were no significant differences in sensitivity among 19 radioimmunoassays (RIAs) for IA-2 autoantibodies (cytoplasmic islet cell antibody [ICA] 512) using different constructs that included the intracellular portion of the molecule (mean sensitivity 73%). However, an enzyme-linked immunosorbent assay (ELISA) using the extracellular portion of the IA-2 molecule did not discriminate between diabetic and control sera. Among GAD autoantibody assays that achieved sensitivity & %, 26 were RIAs and one was an ELISA. When the sera were ranked according to their autoantibody levels, the concordance for insulin autoantibodies (IAAs) in different laboratories was markedly less than for IA-2ab and GADab. Using a combination of autoantibody assays, several laboratories achieved excellent discrimination between diabetic and control sera (sensitivity up to 80% with false-positive rate of 0%). A variety of strategies for combining information from different assays were successful (e.g., those including and excluding ICA), and no one strategy emerged as clearly superior. In conclusion, IA-2/ICA512 autoantibodies are a marker of type 1 diabetes and can be measured consistently by most assays. Several different strategies for combining assays achieved high sensitivity with a low false-positive rate.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 03-2019
DOI: 10.1111/IMJ.14085
Abstract: Reports from resource-poor countries have associated thionamide- and para-aminosalicylate sodium (PAS)-based treatment of multi-drug-resistant tuberculosis (MDR-TB) with the development of hypothyroidism. To identify predictors and assess the cumulative proportions of hypothyroidism in patients treated for MDR-TB with these agents in Australia. Retrospective multicentre study of MDR-TB patients from five academic centres covering tuberculosis (TB) services in Victoria, Australia. Patients were identified using each centre's pharmacy department and cross checked with the Victorian Tuberculosis Program. Hypothyroidism was categorised as subclinical if the thyroid-stimulating hormone was elevated and as overt if free thyroxine (fT4) was additionally reduced on two separate occasions. Our main outcome measured was the cumulative proportion of hypothyroidism (at 5 years from treatment initiation). Of the 29 cases available for analysis, the cumulative proportion of hypothyroidism at 5 years was 37% (95% confidence interval (CI): 0-57.8%). Eight of the nine affected cases developed hypothyroidism within the first 12 months of treatment. Hypothyroidism was marginally (P = 0.06) associated with higher prothionamide/PAS dosing and was reversible with cessation of the anti-tuberculosis medication. Prothionamide/PAS treatment-associated hypothyroidism is common in MDR-TB patients in Australia, emphasising the importance of regular thyroid function monitoring during this treatment. Thyroid hormone replacement, if initiated, may not need to be continued after MDR-TB treatment is completed.
Publisher: American Diabetes Association
Date: 08-2008
DOI: 10.2337/DC08-0239
Abstract: OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades. RESEARCH DESIGN AND METHODS—Caucasoid subjects (n = 462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped. RESULTS—Mean ± SD age at diagnosis, 8.5 ± 4.5 years, did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest-risk DRB1 genotype DR3,4 (2000–2005, 28% vs. 1950–1969, 79% P & 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000–2005, 48% vs. 1950–1969, 20% P = 0.0002). The frequency of the DRX,X genotype was low (≤3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (P & 0.0001) and DR4,X (P & 0.0001) and DR3,X (P = 0.015) genotypes but not for DR3,4. CONCLUSIONS—The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.
Publisher: Elsevier BV
Date: 11-2002
Abstract: Diabetes mellitus is a complex metabolic syndrome with significant effects on the systemic and cerebral vasculature. The incidence and severity of ischaemic stroke are increased by the presence of diabetes, and outcome from stroke is poorer. More than one third of patients admitted with acute stroke are hyperglycaemic at presentation. Reasons for the altered prognosis in diabetes associated stroke are multifactorial. A direct influence of hyperglycaemia at the time of ischaemia is likely to be important. The use of novel methods to delineate stroke topography and pathophysiology such as MR spectroscopy, diffusion and perfusion weighted MRI appear helpful in delineating the effects of hyperglycaemia on stroke pathophysiology. Randomised clinical trials to determine optimal management for patients with hyperglycaemia following stroke are ongoing. Such trials will determine if aggressive control of acute hyperglycaemia following stroke has similar benefits to that observed following acute myocardial infarction. Clinicians responsible for stroke patients should be aware of the importance of adequate glycaemic control in both primary and secondary prevention of stroke.
Publisher: Springer Science and Business Media LLC
Date: 08-1992
DOI: 10.1007/BF00429105
Abstract: (1) To determine the prevalence of cough, wheeze, and breathlessness, both as single symptoms and in combination, in primary schoolchildren and their relation to doctor diagnosed asthma. (2) To identify in areas with different levels of dust pollution whether questionnaire reported 'cough alone' (without wheeze or breathlessness) had similar risk factors to the questionnaire reported triad of 'cough, wheeze, and breathlessness'. Two cross sectional community surveys of primary schoolchildren (5-11 years) were performed in 1991 and 1993. Parent completed questionnaires related to socioeconomic and respiratory factors were distributed through 15 schools in three areas of Merseyside, one of which had a relatively high level of dust pollution. Data were analysed to determine the prevalence of different respiratory symptom patterns. Univariate and multiple logistic regressions were used to investigate the associations between respiratory symptom profiles and potential risk factors. The proportions of completed questionnaires that were returned were similarly high in both surveys, 92% in 1991 (1872 of 2035) and 87% in 1993 (3746 of 4288). The proportions of children with different respiratory symptom patterns were similar in the two surveys: in 1991, asymptomatic children 70.1% (1109 of 1583), those with cough alone 8.9% (141 of 1583), and children with the symptom triad of cough, wheeze, and breathlessness 8.3% (132 of 1583) the figures for 1993 were 69.5% (2144 of 3083), 9.2% (284 of 3083), and 7.3% (224 of 3083) respectively. The prevalence of doctor diagnosed asthma increased from 17.4% in 1991 to 22.1% in 1993. The symptom of cough alone was associated with going to school in an area of increased air pollution. The symptom triad of cough, wheeze, and breathlessness was associated with reported allergies, familial history of atopy and preterm birth. In 1991, of children with the symptom of cough alone one in eight were diagnosed asthmatic twice as many doctors made the diagnosis on this basis in 1993. The respiratory symptom of cough alone and cough, wheeze, and breathlessness represent clinical responses to different specific risk factors. Cough alone was associated with the environmental factors of school in the dust exposed zone and d ness in the home, whereas cough, wheeze, and breathlessness related to allergic history and preterm birth, and may be the best surrogate of asthma. Diagnosis of asthma on the basis of cough alone partly explains the increased prevalence of doctor diagnosed asthma, especially in dust polluted areas.
Publisher: American Diabetes Association
Date: 12-1985
Abstract: Azathioprine (2 mg/kg) was given, in addition to routine insulin treatment, to alternate patients presenting with recent-onset type I diabetes. Treated (N = 13) and untreated (N = 11) patients did not differ significantly at diagnosis with respect to age, duration of symptoms, body weight, blood glucose, hemoglobin A1c, or presence of ketosis. Eight patients were treated for 12 mo, three elected to stop treatment at 6 mo, and treatment was stopped in two because of side effects. Seven treated patients had a remission compared with one untreated patient. At 12 mo these seven patients were distinguished by significantly higher basal and glucagon-stimulated levels of C-peptide (1.98 ± 0.52 and 3.88 ± 0.34 μg/L, respectively) compared with the other six treated patients (0.93 ± 0.52 and 1.32 ± 0.85 μg/L, respectively), and by the persistence of islet cell cytoplasmic antibodies. Remissions were not sustained in the 1–2 yr after treatment, although relapsed patients required less insulin for control. These results corroborate those from nonrandomized trials using cyclosporine1,2 and suggest that protracted treatment with nonspecific immunosuppressive drugs may be necessary to avert insulin dependence.
Publisher: AMPCo
Date: 07-1999
Publisher: Mary Ann Liebert Inc
Date: 05-2022
Abstract: There is limited evidence supporting the recommendation that drivers with insulin-treated diabetes need to start journeys with glucose >90 mg/dL. Glucose levels of drivers with type 1 diabetes were monitored for 3 weeks using masked continuous glucose monitoring (CGM). Eighteen drivers (median [IQR] age 40 [35, 51] years 11 men) undertook 475 trips (duration 15 [13, 21] min). Hypoglycemia did not occur in any trip starting with glucose >90 mg/dL (92%
Publisher: Wiley
Date: 1995
DOI: 10.1111/J.1365-2265.1995.TB02596.X
Abstract: The aim of this study was to develop an assay for the measurement of thyroid blocking antibodies (TBAb), based on the ability of patient serum to inhibit TSH stimulated 3H-cAMP production following incubation of FRTL-5 or JPO9 cells with 3H-adenine. The assay was then used to evaluate a child born with neonatal hypothyroidism. The levels of TBAb, TSAb (thyroid stimulating antibodies), TBII (TSH binding inhibitory antibodies), and the thyroid antibodies anti-thyroid peroxidase and thyroglobulin antibodies were measured in both mother and child over a 6-month post-natal period. The assay for TBAb was used to evaluate a child born with neonatal hypothyroidism whose mother had a history of hypothyroidism due to Hashimoto's thyroiditis. A 99mTc pertechnetate scan showed no evidence of functioning thyroid tissue. At 20 months of age an ultrasound verified a normally positioned thyroid. Initially, high levels of TBII and antithyroid antibodies were present in the serum of both mother and child. In both, the levels of TSAb were undetectable but there were significant levels of TBAb. The levels of TBAb decreased to control levels in the child within 2 months of birth but remained elevated in the mother's serum. This case of neonatal hypothyroidism associated with the passage of thyroid blocking antibodies demonstrates the utility of this new assay in the differential diagnosis of neonatal hypothyroidism.
Publisher: Oxford University Press (OUP)
Date: 16-01-2019
DOI: 10.1093/OFID/OFZ025
Abstract: The importance of gut bacteria in human physiology, immune regulation, and disease pathogenesis is well established. In contrast, the composition and dynamics of the gut virome are largely unknown particularly lacking are studies in pregnancy. We used comprehensive virome capture sequencing to characterize the gut virome of pregnant women with and without type 1 diabetes (T1D), longitudinally followed in the Environmental Determinants of Islet Autoimmunity study. In total, 61 pregnant women (35 with T1D and 26 without) from Australia were examined. Nucleic acid was extracted from serial fecal specimens obtained at prenatal visits, and viral genomes were sequenced by virome capture enrichment. The frequency, richness, and abundance of viruses were compared between women with and without T1D. Two viruses were more prevalent in pregnant women with T1D: picobirnaviruses (odds ratio [OR], 4.2 95% confidence interval [CI], 1.0–17.1 P = .046) and tobamoviruses (OR, 3.2 95% CI, 1.1–9.3 P = .037). The abundance of 77 viruses significantly differed between the 2 maternal groups (≥2-fold difference P & .02), including 8 Enterovirus B types present at a higher abundance in women with T1D. These findings provide novel insight into the composition of the gut virome during pregnancy and demonstrate a distinct profile of viruses in women with T1D.
Publisher: Wiley
Date: 27-02-2006
DOI: 10.1111/J.1445-5994.2006.01039.X
Abstract: Admission rates for diabetes-related foot complications to an Australian hospital were assessed by comparing the frequently used method of retrospectively identifying patients according to International Classification of Diseases (ICD) codes with that of prospectively identifying patients at the time of admission. The aim was to determine the true admission rate of diabetes-related foot complications and to assess the ability of ICD discharge codes to accurately represent the clinical severity of each identified admission. The retrospective study of ICD codes identified approximately one-third of the patients admitted during the prospective studies. Furthermore, ICD codes allocated in the prospective studies failed to accurately represent the clinical condition in 61% of cases and the corresponding Weighted Inlier Equivalent Separations weighting resulted in a $215,000/year deficit for admissions to a single hospital.
Publisher: Springer Science and Business Media LLC
Date: 07-1994
DOI: 10.1007/BF03347748
Publisher: Springer Science and Business Media LLC
Date: 07-1994
DOI: 10.1007/BF03347749
Publisher: Mary Ann Liebert Inc
Date: 09-2022
Abstract: Sleep-related effects of closed-loop therapy among older adults with type 1 diabetes have not been well established. In the OldeR Adult Closed-Loop (ORACL) randomized, crossover trial of first-generation closed-loop therapy (MiniMed 670G), participants wore actigraphy and completed sleep diaries for 14-day periods at stage end. During objectively measured sleep (actigraphy) with closed-loop versus sensor-augmented pump therapy, glucose time-in-range 70-180 mg/dL (3.9-10.0 mmol/L) was greater (90.3% vs. 78.7%, respectively difference 8.2 percentage points [95% confidence interval {CI} 1.5 to 13.0]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2003
DOI: 10.1161/01.STR.0000085087.41330.FF
Abstract: Background and Purpose— Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI. Methods— We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points. Results— Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI ( r ≥0.60, P .01), acute and outcome MRI ( r =0.56, P =0.01), outcome National Institutes of Health Stroke Scale (NIHSS r ≥0.53, P .02), and outcome modified Rankin Scale (mRS r ≥0.53, P =0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose ≥7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels ≥7 mmol/L were independently associated with increased final infarct volume change. Conclusions— Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.
Publisher: Oxford University Press (OUP)
Date: 05-09-2014
DOI: 10.1093/NDT/GFT377
Abstract: Prednisolone is a major risk factor for hyperglycaemia and new-onset diabetes after transplantation. Uncontrolled observational data suggest that ided dosing may reduce requirements for hypoglycaemic agents. This study aims to compare the glycaemic effects of ided twice daily (BD) and once daily (QD) prednisolone. Twenty-two kidney transplant recipients without diabetes were randomized to BD or QD prednisolone. Three weeks post-transplant, a continuous glucose monitor (iPro2(®) Medtronic) was applied for 5 days with subjects continuing their initial prednisolone regimen (Days 1-2) before crossover to the alternative regimen. Mean glucose, peak glucose, nadir glucose, exposure to hyperglycaemia (glucose ≥7.8 mmol/L) and glycaemic variability were assessed. The mean ± standard deviation (SD) age of subjects was 50 ± 10 years and 77% were male. Median (interquartile range) daily prednisolone dose was 25 (20, 25) mg. BD prednisolone was associated with decreased mean glucose (mean 7.9 ± 1.7 versus 8.1 ± 2.3 mmol/L, P < 0.001), peak glucose [median 10.4 (9.5, 11.4) versus 11.4 (10.3, 13.4) mmol/L, P< 0.001] and exposure to hyperglycaemia [median 25.5 (14.6, 30.3) versus 40.4 (33.2, 51.2) mmol/L/h, P = 0.003]. Median glucose peaked between 14:55-15.05 h with BD and 15:25-15:30 h with QD. Median glycaemic variability scores were decreased with BD: SD (1.1 versus 1.9, P < 0.001), mean litude of glycaemic excursion (1.5 versus 2.2, P = 0.001), continuous overlapping net glycaemic action-1 (CONGA-1 1.0 versus 1.2, P = 0.039), CONGA-2 (1.2 versus 1.4, P = 0.008) and J-index (25 versus 31, P = 0.003). Split prednisolone dosing reduces glycaemic variability and hyperglycaemia early post-kidney transplant.
Publisher: The Endocrine Society
Date: 06-1986
Abstract: We examined the effect of interferon-gamma (IFN gamma) on expression of the major histocompatibility proteins on cultured human islet cells isolated from adult and fetal pancreas and from an insulinoma. While the pancreatic beta-cells from different sources varied in their responses to IFN gamma, in all instances the expression of HLA-A,B,C protein was increased. Pancreatic beta-cells did not express HLA-DR protein, before or after culture of the islets in IFN gamma, although HLA-DR protein expression was induced on some non-beta-cells. These findings are at variance with those reported with thyroid follicular cells, in which IFN gamma induced expression of HLA-DR. We, therefore, conclude that the interaction between the immune and the endocrine systems may be endocrine cell specific. The up-regulation of HLA-A,B,C protein on beta-cells by IFN gamma provides a mechanism for enhanced targetting to the beta-cells of autoreactive cytotoxic T-lymphocytes and, hence, for lifying beta-cell destruction.
Publisher: Wiley
Date: 12-12-2014
DOI: 10.1111/DME.12644
Abstract: To study the frequency of islet antibodies in a large cohort of clinic- and community-based patients with Type 2 diabetes in northern India. We measured glutamic acid decarboxylase (GAD) antibodies in 618 adults with Type 2 diabetes (378 patients with diabetes attending a hospital clinic, 240 patients diagnosed in a community survey) and in 192 healthy subjects residing in north India. Islet antigen 2 (IA2) antibodies were also studied in a proportion of the patients with diabetes (n = 492) and in a control population (n = 191). GAD and IA2 antibodies were measured by immunoprecipitation of the respective (35) S-labelled recombinant antigen. We found that GAD antibodies were present in nine (1.5%) patients with diabetes (clinic population: 0.8%, community study: 2.5%), a prevalence similar to that among the subjects without diabetes (n = 2 1%). IA2 antibodies were detected in seven patients with Type 2 diabetes (1.4%) and in two healthy control subjects (1.0%). The frequency of either GAD or IA2 antibodies was similar in people with and without diabetes (3.2 vs 2.1%). No subject was found to have both antibodies. Insulin requirement was higher among antibody-positive than among antibody-negative patients (GAD antibody: 33 vs 6.3% P = 0.001 GAD or IA2 antibody: 23.1 vs 6.4% P = 0.02) however, other clinical features were similar in the two groups. In the present north-Indian population with Type 2 diabetes, the overall prevalence of GAD antibodies and the prevalence of either GAD or IA2 antibodies were considerably lower than those reported in white European populations.
Publisher: Wiley
Date: 07-1999
DOI: 10.1046/J.1464-5491.1999.00101.X
Abstract: To document aspirin usage and the prevalence of large and small vessel complications in patients with diabetes mellitus (DM) attending the outpatient diabetes clinics of a large public hospital. All patients attending diabetes outpatient clinics at The Royal Melbourne Hospital in Melbourne, Australia were surveyed over a 3-month period. Complete data were available on 629 of 632 (296 male) patients surveyed. Of the 29.3% of patients who were suffering from one or more macrovascular complication (ischaemic heart disease, cerebrovascular disease or peripheral vascular disease), 63% were currently on aspirin treatment. Of those not on aspirin, 65% had no contra-indication to aspirin treatment and a further 19% had only a relative contra-indication of either aspirin or warfarin treatment recorded. The published recommendations for the use of aspirin in patients with macrovascular disease were generally being followed in this clinic-based population. However, a significant proportion of patients without a contra-indication to treatment were still not receiving aspirin. The lack of clear evidence-based guidelines for aspirin use may be a factor in its under-prescription. This survey suggests clear evidence-based guidelines should be established and disseminated.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2013
Abstract: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. Australia New Zealand Clinical Trials Registry ACTRN12613000794707 .
Publisher: Springer Science and Business Media LLC
Date: 29-09-2005
DOI: 10.1007/S00125-005-1960-7
Abstract: 'Latent autoimmune diabetes in adults' (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes.
Publisher: SAGE Publications
Date: 1997
DOI: 10.1177/000456329703400115
Abstract: The Immulite parathyroid hormone (PTH) immunochemiluminometric assay (ICMA) was evaluated by measuring serum PTH concentrations in 134 volunteers and 251 patients with various diseases affecting bone and mineral metabolism and comparing with those measured by the Nichols Allegro immunoradiometric (IRMA) assay. Although the assays were highly correlated ( r=0·99, P ·0001), there were discrepancies at lower PTH concentrations which may be explained by the lower limit of detection of the ICMA assay. The anti-coagulants EDTA and heparin appeared to have significant effects on PTH measurement particularly at lower concentrations. Sera assayed by ICMA diluted out more uniformly than in the IRMA and there was no cross reactivity with parathyroid hormone-related peptide in either the IRMA or ICMA. Delays of up to 8 h in specimen handling did not appear to affect PTH measurements. The enhanced sensitivity of the Immulite ICMA intact PTH assay confers an advantage in the diagnosis of both hyper- and hypocalcaemia, while the shorter incubation times, automation and lack of radioactivity are important practical advantages.
Publisher: Springer Science and Business Media LLC
Date: 07-1994
DOI: 10.1007/BF03347753
Publisher: JMIR Publications Inc.
Date: 04-10-2021
Abstract: ecruitment and retention of research participants is challenging. Social media, particularly Facebook, has emerged as a tool for connecting with participants due to its high uptake in the community. The Environmental Determinants of Islet Autoimmunity (ENDIA) study is an Australia-wide prospective pregnancy-birth cohort following children who have a first-degree relative with type 1 diabetes (ACTRN1261300794707). A dedicated Facebook page was established for the ENDIA study in 2013 with the aim to enhance recruitment and support participant retention. he purpose of this investigation was to evaluate the long-term impact of Facebook as a recruitment and retention tool. The hypotheses were that (1) Facebook was an important source of referral to the ENDIA study, (2) the sociodemographic characteristics of participants recruited by Facebook would be different from those of participants recruited by other means (i.e., ‘conventional recruits’), and (3) recruitment by Facebook would be associated with long-term retention. We also evaluated the most effective types of Facebook content based on post engagement. ecruitment of 1511 ENDIA participants was completed in December 2019. Characteristics of participants recruited through Facebook were compared to conventional recruits using linear, logistic, and multinomial logistic regression models. A logistic regression model was used to determine the risk of study withdrawal. Data pertaining to 794 Facebook posts over 7.5 years from June 2013 until December 2020 were extracted using the Facebook ‘Insights’ function for thematic analysis. acebook was the third largest source of referral to the ENDIA study (300/1511 19.9%) behind in-person clinics (500/1511, 33.1%) and healthcare professional referrals (347/1511, 23.0%). The ENDIA Facebook page had 2337 followers at the close of recruitment. Approximately 20% of these could be identified as participating parents. Facebook recruits were more frequently Australian-born (P .001) enrolling postnatally (P=.01) and withdrew from the study at a significantly lower rate compared to conventional recruits (4.7% vs 12.3% P .001) after a median of follow-up of 3.3 years. acebook was a valuable recruitment tool for the ENDIA study and participants recruited through Facebook were three times less likely to withdraw during long-term follow-up. The sociodemographic characteristics of Facebook recruits were different to conventional recruits, but perhaps in unintended ways. Facebook content featuring stories and images of participants received the highest engagement despite the fact that most Facebook followers were not enrolled in the study. These findings should inform social media strategies for future cohort studies involving pregnant women and young families, and for type 1 diabetes risk studies. ustralia New Zealand Clinical Trials Registry: ACTRN1261300794707 R2-0.1186/1471-2431-13-124
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1111/J.1600-6143.2011.03855.X
Abstract: Despite substantial improvement in short-term results after kidney transplantation, increases in long-term graft survival have been modest. A significant impediment has been the morbidity and mortality attributable to cardiovascular disease (CVD). New-onset diabetes after transplantation (NODAT) is an independent predictor of cardiovascular events. This review examines recent literature surrounding diagnosis, outcomes and management of NODAT. Amongst otherwise heterogeneous studies, a common finding is the relative insensitivity of fasting blood glucose (FBG) as a screening test. Incorporating self-testing of afternoon capillary BG and glycohemoglobin (HbA(1c) ) detects many cases that would otherwise remain undetected without the oral glucose tolerance test (OGTT). Assessing the impact of NODAT on patient and graft survival is complicated by changes to diagnostic criteria, evolution of immunosuppressive regimens and increasing attention to cardiovascular risk management. Although recent studies reinforce a link between NODAT and death with a functioning graft (DWFG), there seems to be little effect on death-censored graft loss. The significance of glycemic control and diabetes resolution for patient outcomes remain notably absent from NODAT literature and treatment is also a neglected area. This review examines new and old therapeutic options, emphasizing the need to assess β-cell pathology in customizing therapy. Finally, areas warranting further research are considered.
Publisher: AMPCo
Date: 07-1998
DOI: 10.5694/J.1326-5377.1998.TB140188.X
Abstract: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus. 3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab) change in beta cell function over time and development of clinical diabetes. 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%) GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.
Publisher: Wiley
Date: 12-1992
DOI: 10.1111/J.1365-2265.1992.TB01479.X
Abstract: To evaluate the utility of 3H-adenine incorporation into intact rat thyroid epithelial cells (FRTL-5) as an alternative to radioimmunoassay for the measurement of cAMP following stimulation of these cells by serum thyroid-stimulating immunoglobulins from patients with Graves' disease. We determined the cAMP produced by FRTL-5 cells following incubation with serum from patients with a spectrum of autoimmune thyroid and other diseases using the 3H-adenine assay. We studied 27 patients with untreated Graves' disease, 10 with Graves' disease complicated by ophthalmopathy (all on antithyroid medication), 11 with Hashimoto's thyroiditis, five with multinodular goitre, one with thyroid carcinoma, 23 with type 1 diabetes mellitus, 19 with other autoimmune diseases and 10 controls. The 3H-cAMP produced in cells incubated with either bovine TSH (bTSH) or polyethylene glycol-precipitated serum immunoglobulins, was separated by sequential chromatography on Dowex and alumina columns, and counted. The thyroid-stimulating immunoglobulins index (3H-cAMP patient immunoglobulins/3H-cAMP control immunoglobulins) was calculated for each serum and considered positive if greater than 1.5 (+ve thyroid-stimulating immunoglobulins index, i.e. > 2 standard deviations above control). The thyroid-stimulating immunoglobulins index was correlated with measurement of thyrotrophin binding inhibitory immunoglobulins (TBII) by radioreceptor assay. The 3H-adenine assay has a sensitivity of 10(-11) M bTSH with maximal stimulation at 10(-9) M bTSH (30-fold). Twenty-five of 27 patients (92%) with untreated Graves' disease and four of 10 patients with Graves' disease complicated by ophthalmopathy had +ve thyroid-stimulating immunoglobulin indices. The thyroid-stimulating immunoglobulins index in patients with untreated Graves' disease correlated with their TBII assay result (r = 0.63, P < 0.001). In addition, the index was negative in patients with Hashimoto's thyroiditis, multinodular goitre, thyroid carcinoma, and type 1 diabetes mellitus. Of the patients with other autoimmune diseases only one (a patient with systemic lupus erythematosis) had a +ve thyroid-stimulating immunoglobulin index. Direct comparison of cAMP measurement by 3H-adenine incorporation and commercial radioimmunoassay showed an equal sensitivity to both bTSH and Graves' immunoglobulins. After cell preparation, results are obtained more quickly with the 3H-adenine assay than with a cAMP radioimmunoassay (5 hours compared to 2 days), and far more cheaply than by commercial radioimmunoassays. Measurement of thyroid-stimulating immunoglobulins using the incorporation of 3H-adenine into cAMP in FRTL-5 cells is sensitive, reproducible, rapid and specific. These features make this assay a viable alternative to RIA for the measurement of thyroid-stimulating immunoglobulins in patients with Graves's disease.
Publisher: Wiley
Date: 17-06-2020
DOI: 10.1111/DME.13987
Abstract: To measure pancreatic area and exocrine function in young children with recent-onset Type 1 diabetes to determine whether the exocrine pancreas is also affected in the pathophysiology of early childhood diabetes. Thirty-two children (14 boys) aged 5.5 (4.5, 7.3) median (IQR) years presenting with recent-onset Type 1 diabetes and 90 controls (44 boys) of similar age had ultrasound imaging of the pancreas. Children with Type 1 diabetes were receiving insulin and were without ketosis. Transverse and longitudinal areas of the pancreas were measured by digitalized outline. Pancreatic faecal elastase-1 was analysed using an enzyme-linked immunosorbent assay kit in recent-onset Type 1 diabetes and 38 first-degree relative control children. Pancreatic area and exocrine function were reduced in Type 1 diabetes. Mean transverse area (SD) in Type 1 diabetes was 6.82 cm Pancreatic area and accompanying subclinical exocrine function were reduced in very young children with recent-onset Type 1 diabetes. This supports changes in the exocrine pancreas in the pathophysiology of Type 1 diabetes presenting in early life.
Publisher: AMPCo
Date: 10-2000
Publisher: Oxford University Press (OUP)
Date: 07-2017
DOI: 10.1373/CLINCHEM.2016.270876
Abstract: It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A1c), the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period (P = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, P for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only (P = 0.01). Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.
Publisher: Springer Science and Business Media LLC
Date: 2004
Publisher: Wiley
Date: 10-04-2018
DOI: 10.1111/DME.13623
Abstract: To investigate the effect of a novel glucose alert system, comprising the Melbourne Glucose Alert Pathway and glucose-alert-capable networked blood glucose meters, on nursing and hospital medical officer responses to adverse glycaemia. A prospective, pre- and post-observational study was undertaken in non-critical care wards of a tertiary hospital over 4 months (n=148 or 660 patient-days). The intervention consisted of two components designed to promote a consistent staff response to blood glucose measurements: (1) a clinical escalation pathway, the Melbourne Glucose Alert Pathway, and (2) networked blood glucose meters, which provide a visual alert for out-of-range blood glucose measurement. All consecutive inpatients with diabetes were assessed for diabetes management and capillary blood glucose. The primary outcome was documented nursing and medical staff action in response to episodes of adverse glycaemia (blood glucose >15 mmol/l or <4 mmol/l). Secondary outcomes consisted of glycaemic measures. In response to episodes of adverse glycaemia, nursing action increased (proportion with nursing action: 45% to 73% P 15 mmol/l: 24% vs 16% P=0.012) and patient-days with mean blood glucose >15 mmol/l (7.4% vs 2.6% P=0.005) decreased. There was no difference in hypoglycaemia incidence. Use of a novel glucose alert system improved health professional responses to adverse glycaemia and decreased hyperglycaemia in the hospital setting.
Publisher: Mary Ann Liebert Inc
Date: 12-2016
Abstract: We compared glycemia, treatment satisfaction, sleep quality, and cognition using a nighttime Android-based hybrid closed-loop system (Android-HCLS) with sensor-augmented pump with low-glucose suspend function (SAP-LGS) in people with type 1 diabetes. An open-label, prospective, randomized crossover study of 16 adults (mean [SD] age 42.1 [9.6] years) and 12 adolescents (15.2 [1.6] years) was conducted. All participants completed four consecutive nights at home with Android-HCLS (proportional integral derivative with insulin feedback algorithm Medtronic) and SAP-LGS. percent continuous glucose monitoring (CGM) time (00:00-08:00 h) within target range (72-144 mg/dL). Secondary endpoints: percent CGM time above target (>144 mg/dL) below target (<72 mg/dL) glycemic variability (SD) symptomatic hypoglycemia adult treatment satisfaction sleep quality and cognitive function. The primary outcome for all participants was not statistically different between Android-HCLS and SAP-LGS (mean [SD] 59.4 [17.9]% vs. 53.1 [18]% p = 0.14). Adults had greater percent time within target range (57.7 [18.6]% vs. 44.5 [14.5]% p < 0.006) less time above target (42.0 [18.7]% vs. 52.6 [16.5]% p = 0.034) lower glycemic variability (35 [10.7] mg/dL vs. 46 [10.7] mg/dL p = 0.003) and less (median [IQR]) time below target (0.0 [0.0-0.4]% vs. 0.80 [0.0-3.9]% p = 0.025). In adolescents, time below target was lower with Android-HCLS vs. SAP-LGS (0.0 [0.0-0.0]% vs. 1.8 [0.1-7.9]% p = 0.011). Nocturnal symptomatic hypoglycemia was less (1 vs. 10 p = 0.007) in adolescents, but not adults (5 vs. 13 p = 0.059). In adults, treatment satisfaction increased by 10 points (p < 0.02). Sleep quality and cognition did not differ. Android-HCLS in both adults and adolescents reduced nocturnal hypoglycemia and, in adults, improved overnight time in target range and treatment satisfaction compared with SAP-LGS.
Publisher: Wiley
Date: 17-10-2017
DOI: 10.1111/DME.13508
Abstract: Sodium-glucose cotransporter 2 (SLGT2) inhibitors has been associated with an increased risk of genital infections secondary to increased glycosuria. We report a case of a 41-year-old man with type 2 diabetes treated with empagliflozin and metformin who presented with scrotal swelling. He described multiple preceding episodes of genital thrush for which he self-administered over-the-counter anti-fungal treatment. On examination, he was afebrile and hemodynamically stable. Perineal examination revealed grossly swollen and indurated scrotum with bilateral inguinal lymphadenopathy. Investigations showed elevated inflammatory markers and HbA1c of 99 mmol/mol (11.2%). Computed tomography revealed features consistent with Fournier's gangrene. He underwent emergency exploration and debridement under anaesthetic with a later return to theatre for further exploration, washout and application of a vacuum dressing. He then received a split skin graft to his perineum. He required a 2-week course of intravenous antibiotics and was discharged home on oral antibiotics. Empagliflozin was ceased on admission and he was commenced on a basal bolus insulin regimen for glycaemic optimisation. There is a wide clinical spectrum of genital infections associated with SGLT2 inhibitors with most being generally mild and easily treated. However, risk factors such as diabetes, obesity, immunosuppressed states, smoking, alcohol abuse and end-stage renal or liver failure may increase the risk of potentially more severe infections such as Fournier's gangrene. Timely cessation of SGLT2 inhibitors in in iduals with multiple risk factors may help prevent progression to more severe genital infections.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.DIABRES.2012.02.012
Abstract: Comprehensive data describing the effect of obesity on type 2 diabetes outcomes is lacking. We sought to address this by analyzing a tertiary hospital clinical database. We extracted clinical and biochemical data for patients who attended a tertiary hospital diabetes clinic between 1998 and 2011 and were aged less than 65 years. Body mass index (BMI) was correlated with the prevalence of vascular complications and with cardiovascular risk factors. The means of age and duration of diabetes for the 711 patients (392 men and 319 women) were 53 and 11 years respectively. BMI correlated with the prevalence of ischemic heart disease and, to a lesser degree, albuminuria, but not with the prevalence of cerebrovascular disease, neuropathy, retinopathy or renal function. BMI did not correlate with glycosylated hemoglobin, although obese patients used insulin both more frequently and at higher doses. In people with long-standing type 2 diabetes who attend a tertiary hospital outpatient clinic, ischemic heart disease, in contrast to other vascular complications, correlates robustly with BMI. These findings indicate that clinical trials of weight loss in type 2 diabetes should use cardiac endpoints as their primary outcomes.
Publisher: AMPCo
Date: 04-1999
Publisher: SAGE Publications
Date: 22-11-2022
DOI: 10.1177/19322968221140126
Abstract: While glucometric benchmarking has been used to compare glucose management between institutions, the value of longitudinal intra-institution benchmarking to assess quality improvement changes is not established. A prospective six-month observational study (October 2019–March 2020 inclusive) of inpatients with diabetes or newly detected hyperglycemia admitted to eight medical and surgical wards at the Royal Melbourne Hospital. Networked blood glucose (BG) meters were used to collect capillary BG levels. Outcomes were measures of glycemic control assessed by mean and threshold glucometric measures and comparison with published glucometric benchmarks. Intra-institution comparison was over the 2016-2020 period. In all, 620 admissions (588 unique in iduals) met the inclusion criteria, contributing 15 164 BG results over 4023 admission-days. Compared with the 2016 cohort from the same institution, there was increased BG testing (3.8 [SD = 2.2) vs 3.3 [SD = 1.7] BG measurements per patient-day, P .001), lower mean patient-day mean glucose (PDMG 8.9 mmol/L [SD = 3.2] vs 9.5 mmol/L [SD = 3.3], P .001), and reduced mean and threshold measures of hyperglycemia ( P .001 for all). Comparison with institutions across the United States revealed lower incidence of mean PDMG .9 or .7 mmol/L, and reduced hypoglycemia ( .9, .8, and .2 mmol/L), when compared with published benchmarks from an earlier period (2009-2014). Comprehensive digital-based glucometric benchmarking confirmed institutional quality improvement changes were followed by reduced hyperglycemia and hypoglycemia in a five-year comparison. Longitudinal glucometric benchmarking enables evaluation and validation of changes to institutional diabetes care management practices.
Publisher: Massachusetts Medical Society
Date: 12-10-2006
DOI: 10.1056/NEJMOA065061
Publisher: American Diabetes Association
Date: 2009
DOI: 10.2337/DC08-0821
Abstract: OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS—Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS—Follow-up of 548 subjects for 5.7 ± 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10–1.84], P = 0.007, and 1.29 [1.01–1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score & than in those with weight z score ≤0 over time (2.61 [1.26–5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS—Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.
Publisher: Wiley
Date: 07-2016
DOI: 10.1111/IMJ.13122
Abstract: Insulin-induced weight gain is a key concern for people with type 2 diabetes (T2D) and their treatment team. This study aimed to document the prevalence of insulin-induced weight gain and its impact on cardiovascular risk factors in patients attending the Royal Melbourne Hospital diabetes clinic. Clinical and biochemical data were extracted from a prospective clinic database and from the hospital record. These variables were correlated with the percentage weight change 1 year after starting insulin and compared between groups with or without clinically significant weight gain, defined as more than 7% of the baseline bodyweight. The population comprised 340 patients (184 male), representing 36% of people with T2D who commenced insulin at our clinic. Their mean ± SD age and duration of diabetes was 63 ± 11 and 13 ± 8 years respectively. The mean (95% CI) change in bodyweight at 1 year was 3.0 (2.5-3.5) kg, but this was not associated with deleterious changes in blood pressure or lipid profile. Weight gain was associated with higher insulin doses, the use of short-acting insulin and with lower baseline bodyweight. Clinically significant weight gain occurred in 87 patients and was associated with glucose-lowering regimens that included short-acting insulin or a thiazolidinedione, whereas regimens that incorporated other oral agents, particularly sulfonylureas, were associated with less weight gain. In this Australian tertiary hospital population with T2D, insulin-induced weight gain was common but was not associated with deleterious changes in blood pressure or lipids. Treatment regimens that avoid short-acting insulin but include oral agents other than thiazolidinediones might prevent insulin-induced weight gain in T2D.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.MARPOLBUL.2017.07.010
Abstract: An increasing number of studies highlight the risk of plastic pollution in the marine environment. However, systematic longitudinal data on the distribution and abundance of plastic debris remain sparse. Here we present the results of a two-year study of plastic pollution within the Tasman Sea, contrasted with a further year of data from the same region, in order to document how the density of debris varies across years in this area. Surface net tows were collected between Hobart, Tasmania and Sydney, Australia during the spring of 2013 and 2014 and compared with a subset of data from autumn 2012 from the same region. Substantial inter-annual variation in mean plastic abundance was observed over the three year period, ranging from to 248.04-3711.64pieceskm
Publisher: Springer Science and Business Media LLC
Date: 20-06-2011
Publisher: American Diabetes Association
Date: 08-2000
DOI: 10.2337/DIABETES.49.8.1319
Abstract: Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible in iduals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.
Publisher: Informa UK Limited
Date: 02-11-2019
Publisher: Springer Science and Business Media LLC
Date: 10-1990
DOI: 10.1007/BF00400213
Abstract: Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
Publisher: Elsevier BV
Date: 10-1984
DOI: 10.1016/0006-291X(84)91605-X
Abstract: The subunit structure of receptors for insulin and insulin-like growth factor-1 has been demonstrated on a rat insulinoma cell, RIN-m5F, grown in continuous culture. The specific binding of [125-I]-insulin-like growth factor-1 (2.9 +/- 0.42% mean +/- SEM) to the RIN-m5F cell was significantly greater than of [125I]-insulin (0.7 +/- 0.2%). Immunoprecipitation of receptors from [125I]-surface labeled cells and analysis by sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography revealed reduced subunits of Mr 130,000 and 90,000, identical to those for both insulin and insulin-like growth factor-1 receptors on classic target tissues. An apparent abundance of insulin-like growth factor-1 over insulin receptors could be due to downregulation of the latter by secreted insulin. These findings support a role for insulin and insulin-like growth factor-1 receptors in regulating metabolic or growth functions in the beta cell.
Publisher: American Diabetes Association
Date: 12-1987
Abstract: The sera of type I (insulin-dependent) diabetic subjects are reported to contain autoantibodies against a 64,000-Mr protein identified in [35S]methionine biosynthetically labeled pancreatic islet cells. We have attempted to localize this autoantigen to the surface of the β-cell and to define its properties. Sera from 10 newly diagnosed type I diabetic subjects, including five of the index sera originally used to identify the autoantigen, were shown to specifically precipitate a reduced protein of 67,000 Mr from Triton-solubilized, surface 125I-labeled cultured adult human islet and rat insulinoma (RINm5F) cells but not from fresh rat spleen cells. Further characterization revealed that this protein was bovine serum albumin (BSA) adsorbed to cells from fetal calf serum (FCS)-supplemented culture medium and precipitated by BSA antibodies present in many diabetic sera. No labeled proteins were specifically precipitated when surface 125I-labeled and solubilized human islet or RINm5F cells were precleared with anti-BSA immunoglobulins or when cells were first cultured in human serum. In contrast, a 64,000-Mr protein, clearly not BSA, was precipitated by diabetic globulins from human islets but not from RINm5F cells labeled with [35]Slmethionine. In addition, a protein of the same size as well as proteins of ∼35,000, 43,000, 140,000, and 200,000 Mr were specifically precipitated by diabetic globulins from freshly isolated human islets solubilized in Triton X- 100 and then labeled with 125I. These findings suggest that the 64,000-Mr antigen is not expressed on the surface of human islet cells, at least in culture, and therefore question its relevance as a target for islet cell surface antibodies in initiating β-cell damage. They also reveal the existence of other possible protein antigens in islet cells. Finally, our results indicate that assays for islet cell surface antibodies via immunofluorescence on cultured cells should be controlled for the presence of BSA antibodies.
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1365-2265.1991.TB03508.X
Abstract: To document the persistence of a sensitizing effect of human growth hormone on the ovarian responsiveness to human menopausal gonadotrophin in anovulatory patients resistant to standard gonadotrophin doses. We performed an open study of three patients given 4, 12 or 24 IU recombinant growth hormone on alternate days for 5-7 doses, concomitantly with gonadotrophin, and assessed gonadotrophin dose requirements before, during and after the cycle of growth hormone therapy. We studied two with isolated gonadotrophin deficiency and primary amenorrhoea and one with a pituitary tumour and hyperprolactinaemia which normalized with bromocriptine but in whom there was persisting secondary amenorrhoea. We measured body mass index, FSH, LH, prolactin, growth hormone, insulin-like growth factor I (IGF-I), oestradiol and inhibin at baseline and growth hormone, IGF-I, oestradiol and inhibin during treatment. In addition we noted the numbers of oules (75 IU) and the last pre-hCG dose of gonadotrophin used before, during and after growth hormone therapy. Baseline growth hormone levels were low but IGF-I levels were normal. IGF-I increased by 20% in the subject given 4 IU growth hormone, and by 50-100% in the other two. Pretreatment daily gonadotrophin dosage of 8-11 oules pre-hCG was reduced to 3-6 oules during growth hormone and 3-4 post growth hormone. This effect persisted for 4 cycles over 7 months in one subject. Growth hormone causes persisting ovarian sensitization to gonadotrophin and may produce a substantial lowering of gonadotrophin requirement for ovulation induction in patients with large dosage needs.
Publisher: The Endocrine Society
Date: 05-1992
DOI: 10.1210/JCEM.74.5.1569152
Abstract: Insulin autoantibodies (IAA) have been identified in newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients and in in iduals at high risk of developing the disease. However, the literature is not in agreement regarding the prevalence, significance, and predictive value of IAA. Previous workshops have shown that certain sera give markedly different results depending upon assay methodology and, therefore, have suggested that these discrepancies may be due to variations in the assay methodologies used: either the fluid phase RIA or the solid phase enzyme-linked immunosorbent assay (ELISA). Sera from controls (n = 61), newly diagnosed IDDM patients (n = 30), healthy subjects who later became diabetic (n = 8), and first degree relatives of diabetic probands (n = 22) were randomly numbered and sent without category identification to 19 RIA and 10 ELISA laboratories. Each laboratory's raw data from the control sera were used to determine the cut-off point for positive (3 SD above the mean of control sera) in the disease relevant categories. RIA and ELISA methods were comparable in obtaining a low frequency of IAA in control sera. However, the laboratories using RIA methods found a much higher percentage of sera to be IAA positive among both newly diagnosed patients and healthy in iduals who later developed diabetes than laboratories using ELISA methods (P less than 0.005). In contrast, there was considerable overlap in the percentage of sera from first degree relatives found positive by both assays. These data strongly suggest that IAA measured by RIA methodology are more disease related than those measured by ELISA methods. Consequently, RIA assays or assays proven to perform as well should be used to measure IAA associated with IDDM.
Publisher: American Society for Clinical Investigation
Date: 12-2006
DOI: 10.1172/JCI29602
Publisher: American Diabetes Association
Date: 08-1992
DOI: 10.2337/DIACARE.15.8.1053
Abstract: To compare the magnitude and reproducibility of the FPIR measured during two different IVGTT protocols in nondiabetic subjects. Nine control subjects each had two pairs of IVGTTs with either a 4-min infusion of 0.5 g/kg glucose or a 1-min infusion of 0.3 g/kg glucose. Blood glucose and serum insulin were measured before and 1, 2, 3, 5, and 10 min after completion of the glucose infusion. The FPIR was measured with either 1 + 3−, 2 + 3 + 5−, or 1 + 3 + 5-min serum insulins, areas under the insulin curve (0–5 or 0–10 min), or the ratio of serum insulin to blood glucose area. The FPIR was higher in eight of nine subjects with the short-infusion test, but the within-subject variation of the two methods was identical. Reproducibility was not significantly improved with an integrated insulin area or insulin-to-glucose ratio measurement. Reproducibility of the FPIR measured during IVGTT is not significantly affected by the duration of the glucose infusion. However, the magnitude of the difference in FPIR observed between the two protocols highlights the need for standardization of the methodology if the IVGTT is to be used in studies of the preclinical stage of IDDM.
Publisher: Wiley
Date: 19-07-2012
DOI: 10.1111/J.1463-1326.2012.01637.X
Abstract: Evaluate anti-interleukin-1β (IL-1β) antibody, canakinumab, in patients with type 2 diabetes and impaired glucose tolerance (IGT) in whom hyperglycaemia may trigger IL-1β-associated inflammation leading to suppressed insulin secretion and β-cell dysfunction. This 4-week, parallel-group study randomized 190 patients with type 2 diabetes 2 : 1, canakinumab versus placebo, into the following treatment arms: metformin monotherapy, metformin + sulfonylurea, metformin + sulfonylurea + thiazolidinedione or insulin ± metformin. IGT population (n = 54) was randomized 1 : 1, canakinumab versus placebo. Primary efficacy assessment was change from baseline in insulin secretion rate (ISR) relative to glucose 0-2 h. Mean changes from baseline to week 4 in ISR relative to glucose at 0-2 h or other time points were not statistically significant for canakinumab versus placebo across groups. ISR (relative to glucose) at 0-0.5 h (first-phase insulin secretion) numerically favoured canakinumab versus placebo in insulin-treated patients {difference in mean change from baseline [point estimate (PE)] 3.81 pmol/min/m(2)/mmol/l p = 0.0525} and in the IGT group (PE 3.92 pmol/min/m(2)/mmol/l p = 0.1729). Mean change from baseline in fasting plasma glucose favoured canakinumab in the type 2 diabetes/metformin group and the IGT group however, differences were not statistically significant. Mean change from baseline in peak insulin level and insulin AUC 0-4 h were statistically significantly higher in the canakinumab group in IGT patients. Canakinumab was well tolerated and consistent with known safety experience. The trend towards improving ISR relative to glucose 0-0.5 h in patients treated with insulin supports the hypothesis that insulin secretion can be improved by blocking IL-1β.
Publisher: Wiley
Date: 12-2009
Publisher: The Endocrine Society
Date: 21-04-2021
Abstract: Islet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk in iduals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number it has been robustly shown that nearly all multiple-autoantibody-positive in iduals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression among multiple-autoantibody-positive in iduals is highly heterogenous. Accurate prediction of the most rapidly progressing in iduals is crucial for efficient and informative clinical trials and for identification of candidates most likely to benefit from disease modification. This is increasingly relevant with the recent success in delaying clinical disease in presymptomatic subjects using immunotherapy, and as the field moves toward population-based screening. There have been many studies investigating islet autoantibody characteristics for their predictive potential, beyond a simple categorical count. Predictive features that have emerged include molecular specifics, such as epitope targets and affinity longitudinal patterns, such as changes in titer and autoantibody reversion and sequence-dependent risk profiles specific to the autoantibody and the subject’s age. These insights are the outworking of decades of prospective cohort studies and international assay standardization efforts and will contribute to the granularity needed for more sensitive and specific preclinical staging. The aim of this review is to identify the dynamic and nuanced manifestations of autoantibodies in type 1 diabetes, and to highlight how these autoantibody features have the potential to improve study design of trials aiming to predict and prevent disease.
Publisher: American Diabetes Association
Date: 11-1999
DOI: 10.2337/DIABETES.48.11.2145
Abstract: The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range & .5%), anti-GAD antibodies (& .0 U), and anti-IA2 antibodies (& .0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.
Publisher: Springer Science and Business Media LLC
Date: 07-1991
DOI: 10.1007/BF00403293
Abstract: The pulmonary response to instilled particulates involves initial efflux of polymorphonuclear leukocytes (PMNs) and increased production of alveolar macrophages (AMs). The relationships of the cell migration and ision components of the AM production to the initial PMN response after intrapulmonary carbon or latex administration are examined. Supernatants of lung lavages taken during early PMN migration to the alveoli promote sequential migration of PMNs, migration of monocytes, and ision of pulmonary interstitial cells in normal mice. Supernatants taken during the phase of increased cell ision in the lung produce no such effects, implying tht factors responsible for chemotaxis and mitosis are generated rapidly and are short-lived. A possible source is the interaction of AMs with particles, since supernatants of such incubations induce an inflammatory response in vivo. Similarly, when a synthetic chemoattractant is used, efflux of PMNs is followed by macrophages arising from migration of monocytes and from ision of interstitial cells. The results suggest that particulate instillation in the lung stimulates a standard inflammatory response in which rapid generation of a factor(s) chemotactic for PMNs also attracts mononuclear cells to the alveoli. The initial efflux of cells may be explained by migration from the blood, but continued demand or replacement requires mitotic activity of precursors. For the alveolar macrophages, this includes ision of cells in the pulmonary interstitium.
Publisher: American Diabetes Association
Date: 05-2008
DOI: 10.2337/DC07-1868
Abstract: OBJECTIVE—Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and in idual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS—A total of 5,269 people aged ≥30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS—Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646] hazard ratio [HR] 0.98 [95% CI 0.84–1.13] P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634] 0.87 [0.75–1.01] P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08% HR 7.04 [95% CI 1.60–31.0] P = 0.01) but reduced the risk of the renal component (0.80 [0.68–0.93] P = 0.005) prevention of diabetes was independently associated with prevention of the renal component (P & 0.001). CONCLUSIONS—Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.
Publisher: Springer Science and Business Media LLC
Date: 07-1995
DOI: 10.1007/BF03401595
Publisher: Springer Science and Business Media LLC
Date: 02-2001
DOI: 10.1038/84872
Abstract: Type 1 diabetes (T1D or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.
Publisher: Wiley
Date: 03-03-2020
DOI: 10.1111/DOM.14009
Publisher: Mary Ann Liebert Inc
Date: 02-1998
Abstract: In most trials, at least 50% of patients with Graves' disease treated with antithyroid drugs (ATD) relapse after achieving euthyroidism. At present, there are no definitive prognostic parameters available early in treatment to indicate those likely to achieve long-term remission. Because thyrotropin receptor antibodies (TRAb) are specific for Graves' disease, the possibility that their rate of change early in treatment (0 to 6 months) might be such an indicator was explored. TRAb were measured both as thyrotropin binding inhibitory immunoglobulins (TBII) and as thyroid-stimulating antibodies (TSAb) in 85 patients with untreated Graves' disease at 6-month intervals throughout their ATD treatment. The patients in the study were treated for a minimum period of 12 months and were categorized retrospectively into two groups depending on whether or not they remained in remission after ATD treatment. Remission was deemed as reached in patients who remained euthyroid for a minimum period of 15 months after cessation of ATD. The mean initial TBII and TSAb values in the nonremission group were significantly higher than in the remission group (p < 0.001 for both parameters). The rates of fall in mean TBII levels were similar for each group in the first 6 months of treatment, but while they continued to fall in the remission group over the next 6 to 12 months, mean values for the nonremission group plateaued and failed to fall to control levels within that period. These results indicate that changes in TRAb levels, measured either as TBII or TSAb, occur more rapidly in the second 6 months of treatment in patients who ultimately achieve remission than those who do not. If TBII fall to control levels by 12 months, the patient has at least a 70% chance of ultimately achieving remission with ATD treatment alone.
Publisher: American Diabetes Association
Date: 10-2004
DOI: 10.2337/DIACARE.27.10.2348
Abstract: OBJECTIVE—Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate β-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS—A total of 38 in iduals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was β-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly the secondary outcome was immunity to islet antigens, measured monthly for 12 months. RESULTS—No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible β-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as β-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS—Results from this pilot study suggest that intranasal insulin does not accelerate loss of β-cell function in in iduals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2005
Abstract: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of %, but nearly all had a 5-year stroke risk of %. Despite this, half of the cohort were obese (BMI 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/IMJ.15322
Publisher: Elsevier BV
Date: 07-2019
Publisher: American Diabetes Association
Date: 06-1993
Abstract: OBJECTIVE— To help standardize methodology for intravenous glucose tolerance testing in preclinical IDDM by comparing a 30-s bolus and a 3-min infusion of glucose. RESEARCH DESIGN AND METHODS— We tested 20 healthy nondiabetic adults at four centers (in Seattle, Boston, Melbourne, and London). Each subject had four intravenous glucose tolerance tests (two bolus and two infusion). The acute insulin response to glucose was calculated as the mean of the 1′ + 3′, the mean of 1′ to 10′, or as the integrated area from 0 to 10′. Glucose and insulin profiles and intrasubject coefficient of variation were compared. RESULTS— With the infusion protocol, the 1′ insulin was significantly higher, resulting in a higher acute insulin response to glucose when calculated as 1′ + 3′ (525 ± 66 vs. 376 ± 35 pM, P & 0.004). When calculated over 10 min, however, the acute insulin response to glucose was not different between protocols. In addition, the intrasubject coefficient of variation was significantly better when calculated over 10 min in both protocols, but no significant differences were noted between the bolus and infusion (infusion: AIRg [area from 0 to 10′] 10.4 ± 2.1% vs. AIRg [1′ + 3′] 14.9 ± 2.8%, P & 0.007 bolus: AIRg [area from 0 to 10′] 14.6 ± 2.8% vs. AIRg [1′ + 3′] 19.8 ± 3.5%, P & 0.007). Comparison of the insulin assays between the four centers showed close correlation and gave indistinguishable results in terms of within-subject coefficient of variation. Glucose profiles were similar in both protocols. Although the glucose values were lower with the bolus protocol from 4′ to 40′, the rate of fall from 10 to 30′ (and thus the rate of glucose disposal) was indistinguishable between the two. CONCLUSIONS— These data suggest that neither protocol gives significant advantage over the other. However, to allow comparison of the acute insulin response to glucose between different protocols used in centers around the world, the ICARUS 3-min infusion protocol is recommended, with acute insulin response to glucose calculated over 10 min after the end of glucose administration this reduces the within-subject coefficient of variation and provides similar acute insulin response to glucose with both protocols.
Publisher: Wiley
Date: 20-12-2004
DOI: 10.1111/J.1464-5491.2004.01363.X
Abstract: To design a multidisciplinary, evidenced-based, clinical guideline for the assessment, investigation and management of inpatients with acute diabetes related foot complications. A systematic search of both published (identified by searching all major electronic databases and hand searching key journals) and unpublished literature (derived from national and internationally recognized experts) identified 266 articles specific to diabetes related foot complications. Of these, 126 (47%) were assessed to be methodologically sound and clinically relevant. A narrative summary with the articles tabulated according to their level of evidence was prepared. A multidisciplinary expert group of health professionals, with a known interest and recognized expertise in diabetes related foot complications, was established to assess the evidence. The multidisciplinary expert group used the identified literature and clinical experience to create a comprehensive, evidence-based, clinical guideline for the assessment, investigation and management of acute diabetes related foot complications. Included within the guideline is a novel, diabetes specific classification system, which codes for the presence/absence and severity of the four principle causative factors (Neuropathy, Vascular compromise, Ulceration and Infection) in the development of acute diabetes related foot complications. Through the creation and implementation of this evidence-based clinical guideline, specific for acute diabetes related foot complications, it is hoped that health professionals will be better equipped to make informed decisions for this patient population. This may benefit the in idual and health system through reductions in utation rate, length of hospital stay and health expenditure.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2010
DOI: 10.1007/S00125-010-1854-1
Abstract: We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5 years. Lower estimated GFR (eGFR) vs eGFR ≥90 ml min⁻¹ 1.73 m⁻² was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01-1.29] for eGFR 60-89 ml min⁻¹ 1.73 m⁻² 1.59 [1.28-1.98] for eGFR 30-59 ml min⁻¹ 1.73 m⁻² p < 0.001 adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01-1.54] and 1.19 [0.76-1.85], respectively p = 0.001 for trend) when eGFR ≥90 ml min⁻¹ 1.73 m⁻². CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models.
Publisher: Wiley
Date: 2015
DOI: 10.1111/IMJ.12619
Abstract: Healthcare professional (HCP) time supporting insulin pump therapy (IPT) has not been documented, yet it is important in planning and allocating resources for effective care. This study aims to determine HCP time spent in IPT patient care to inform resource planning for optimal IPT delivery. Twenty-four Australian adult IPT-experienced institutions (14 government funded, seven private, three both) collected data between April 2012 and January 2013 prospectively, including: patient demographics, HCP classification, purpose of HCP-patient interaction, interaction mode and HCP time with the patient. A subset of patients was tracked from pre-pump education until stable on IPT. Data on 2577 HCP-adult patient interactions (62% face-to-face, 29% remote, 9% administrative) were collected over 12.2 ± 6.4 weeks for 895 patients age 35.4 ± 14.2 years 67% female 99% type 1 diabetes, representing 25% of all IPT patients of the institutions. Time (hours) spent on IPT interactions per centre per week were: nurses 5.4 ± 2.8, dietitians 0.4 ± 0.2 and doctors 1.0 ± 0.5. IPT starts accounted for 48% of IPT interaction time. The percentage of available diabetes clinic time spent on outpatient IPT interactions was 20.4%, 4.6% and 2.7% for nurses, dietitians and doctors respectively. Fifteen patients tracked from pre-pump to stabilisation over 11.8 ± 4.5 weeks, required a median (range) of 9.2 (3.0-20.9), 2.4 (0.5-6.0) and 1.8 (0.5-5.4) hours per patient from nurses, dietitians and doctors respectively. IPT patient care represents a substantial investment in HCP time, particularly for nurses. Funding models for IPT care need urgent review to ensure this now mainstream therapy integrates well into healthcare resources.
Publisher: Wiley
Date: 02-2003
DOI: 10.1034/J.1399-0039.2003.00013.X
Abstract: Insulin dependent diabetes mellitus (type I DM) is caused by an autoimmune process which culminates in destruction of pancreatic beta cells with resultant loss of insulin production. Preceding the clinical diagnosis of type I DM is a preclinical stage characterized by autoantibodies to insulin, glutamic acid decarboxylase (GAD) and a tyrosine phosphatase-like molecule (IA-2). We have studied both HLA class I and class 2 allele distributions in diabetic probands and autoantibody positive in iduals in members of 452 families recruited for the Australian type I diabetes DNA repository. The results demonstrate that progression to autoimmunity as measured by the appearance of autoantibodies is strongly associated with the class 2 alleles DRB1*03 and DRB*04 and with DRB1*03/04 heterozygosity. In contrast, the progression to clinical disease appears associated with class I alleles A24, A30 and B18 while A1, A28, B14 and B56 appear negatively associated. The class 2 alleles appear to have a minimal role in the progression from autoantibody positivity to clinical disease. These results are consistent with the view that CD4+ T cells responding to peptides in the context of class 2 molecules are responsible for initiating autoantibody production, while the destruction of islet cells leading to clinical expression of the disease is the function of CD8+ T cells recognizing relevant peptides in the context of class I molecules.
Publisher: American Diabetes Association
Date: 09-2003
Publisher: Springer Science and Business Media LLC
Date: 26-01-2020
Publisher: Elsevier BV
Date: 12-1996
DOI: 10.1016/S0140-6736(96)98014-9
Abstract: Transanal endoscopic microsurgery (TEM) is considered the technique of choice for adenoma and low-risk T1 rectal cancer. The adequacy of such treatment for high-risk T1 tumours, however, is still controversial. The aim of the study is to evaluate our results with local excision of high-risk T1 cancers. Demographic, clinical data pertaining to patients undergoing TEM for T1 rectal cancer between 1999 and 2015 was retrospectively collected. Long-term outcomes were assessed for the entire cohort. Patients were classified into two groups: favourable and high-risk cancer features. Three hundred and fifty-five TEM procedures were recorded in the study period. Forty-three patients were included in the present study. There were 20 females and 23 males, the median age was 69 ± 9. The median tumour distance from the anal verge was 6 cm (range 1-13 cm). Post-operative histopathology showed well/moderately differentiated T1 adenocarcinoma in 30 patients and poorly differentiated in 13. The overall survival for patients with favourable and high-risk features groups were 93.5% and 77%, respectively, while the local recurrence (LR) was 3.5% and 23.1%, respectively. Nine patients with high-risk features received adjuvant radiotherapy one (11.1%) of them experienced LR. Local excision by TEM augmented by adjuvant radiotherapy may be a feasible alternative for selected patients with high-risk T1 rectal cancer. The addition of radiotherapy seems to decrease the rates of LR.
Publisher: American Diabetes Association
Date: 08-2010
DOI: 10.2337/DC10-ER08C
Publisher: Elsevier BV
Date: 12-1994
Abstract: To determine whether the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) is increased by measurement of glutamic acid decarboxylase antibodies (GADAb) in first-degree relatives of patients with insulin-dependent diabetes mellitus (IDDM), we measured GADAb in those developing IDDM and in relatives found to be ICA- or IAA-positive in our family screening study. First-degree relatives (n = 2904) were followed for 2.4 (median, range 0.04-5.8) years. Of the subjects developing IDDM, 11/14 (78%) had ICA > or = 20JDF units, 1/14 (7%) had IAA > or = 100 nU/ml and 6/14 (43%) had GADAb (> or = 460 nU/ml, measured by precipitation of enzymatic activity). Of the four subjects with ICA < 20 and IAA or = 20 or IAA > or = 100 were followed for 3.1 (median range 0.1-5.4) years. Survival analysis showed that diabetes-free survival in this group was not influenced significantly by GADAb positivity. In conclusion, GADAb in the absence of ICA and IAA are uncommon in first-degree relatives who progress to IDDM and the presence of GADAb does not increase the risk for IDDM in ICA- or IAA-positive relatives.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.CCT.2019.105892
Abstract: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.
Publisher: Wiley
Date: 04-2000
DOI: 10.1046/J.1464-5491.2000.00267.X
Abstract: To determine the role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indian patients by measuring islet autoantibodies. In a cross-sectional study, 145 young patients with diabetes (onset < 30 years) were sub ided into the following categories: Type 1 diabetes (n = 83), malnutrition-modulated diabetes mellitus (MMDM, n = 31) and fibro-calculous pancreatic diabetes (FCPD, n = 31). MMDM subjects presented with emaciation and severe insulin-requiring but ketosis-resistant diabetes, while FCPD was associated with idiopathic chronic calcific pancreatitis. Antibodies to glutamic acid decarboxylase (GADA) and IA-2 (IA-2 A) were detected by immunoprecipitation of 35S-labelled recombinant antigens and cytoplasmic islet cell antibody (ICA) by indirect immunofluorescence. GADA were present in a significant proportion (23%) of patients with MMDM. In contrast, IA-2 A was increased only among patients with Type 1 diabetes (22%), but not MMDM (3%, P < 0.05). Among patients with a duration of diabetes < 2 years, GADA and/or IA-2 A were found in 61% of Type 1 diabetic and 37% of MMDM patients (P < 0.01). MMDM patients who were positive for GADA had a shorter duration of diabetes, but did not differ in their age at onset of diabetes, body mass index, fasting plasma C-peptide, or frequency of thyroid microsomal and parietal cell antibodies. FCPD subjects had the lowest prevalence of autoantibodies: IA-2 and ICA were absent, while GADA were present in 7% (P < 0.05 vs. Type 1 diabetes). GADA, though not IA-2 A, were present in a substantial proportion of patients with the MMDM variant of diabetes, suggesting that islet autoimmunity may play a role in its pathogenesis. In contrast, none of the islet antibodies was increased in subjects with FCPD, making it likely that it is a secondary type of diabetes.
Publisher: AMPCo
Date: 05-2017
DOI: 10.5694/MJA16.00712
Abstract: To determine the relationship between glycaemic control trajectory and the long term risk of severe complications in people with type 1 diabetes mellitus, as well as the effects of paediatric and adult HbA1c levels. Data linkage study of data for adults with childhood-onset type 1 diabetes (diagnosed during 1975-2010) who had transitioned from paediatric diabetes care at the Royal Children's Hospital (Melbourne) to adult diabetes care at the Royal Melbourne Hospital during 1992-2013. Severe complications were categorised as severe diabetic retinopathy (SDR), chronic kidney disease, ulceration or utation, and death. Mean HbA1c levels were calculated for the paediatric and adult periods. Four glycaemic control trajectories were defined according to mean paediatric and adult HbA1c levels: stable low (paediatric and adult HbA1c ≤ 66 mmol/mol) improving (paediatric HbA1c > 66 mmol/mol, adult HbA1c ≤ 66 mmol/mol) worsening (paediatric HbA1c ≤ 66 mmol/mol, adult HbA1c > 66 mmol/mol) and stable high (paediatric and adult HbA1c > 66 mmol/mol). 503 eligible participants (253 men) were identified, 26 (5.2%) of whom had at least one severe complication, including 16 with SDR (3.2%). No-one in the stable low group, but 4% of the improving, 1% of the worsening, and 7% of the stable high groups developed SDR. Higher mean paediatric (per 10.9 mmol/mol increase: odds ratio [OR], 2.9 95% CI, 1.9-4.3 P < 0.01) or adult HbA1c levels (OR, 2.1 95% CI, 1.4-3.1 P < 0.01) were associated with increased risk of SDR, as was longer duration of type 1 diabetes (per additional year: OR, 1.3 95% CI, 1.2-1.5 P < 0.01). SDR was associated with higher paediatric HbA1c levels, independent of glycaemic control during adulthood it was not documented in patients with a stable low glycaemic control trajectory.
Publisher: Wiley
Date: 2008
DOI: 10.1002/PDI.1202
Publisher: Mary Ann Liebert Inc
Date: 2019
Abstract: Hybrid closed loop (HCL) insulin delivery with the Medtronic Minimed 670G system is effective and safe in people with type 1 diabetes (T1D). This study compared glucose control, closed loop (CL) exits, and alarm frequency with the standard HCL (s-HCL) versus enhanced HCL (e-HCL) Medtronic system. Pump-experienced T1D adults (n = 11 9 female mean [SD] age: 51 years [15 years] HbA1c 7.5% [1.0%] or 58 mmol/mol [7.7 mmol/mol]) were assigned, in random order, s-HCL or e-HCL for 1 week each in a supervised live-in setting. e-HCL incorporated enhanced bolus reminders and iterative changes, broadening glucose and insulin delivery parameters permitting persistence in CL. For both s-HCL and e-HCL, insulin delivery was by a Medtronic pump with identical interventions (missed bolus, exercise, high-glycemic index, and high-fat meals), insulin action times, and insulin-carbohydrate ratios implemented. The primary outcome was continuous glucose monitoring time in target range. Analysis was by paired t-test for normally distributed data and Wilcoxon-signed rank test otherwise. e-HCL resulted in significantly fewer CL alerts and exits. Time in target and mean glucose favored e-HCL but did not reach statistical significance. No episodes of severe hypoglycemia or ketoacidosis occurred. Relative to s-HCL, e-HCL use significantly decreases CL exits and alerts, and tended to improve glycemia without compromising safety, despite multiple food and exercise challenges during the study. Longer term studies at home are merited.
Publisher: Elsevier BV
Date: 11-1992
DOI: 10.1016/0168-8227(92)90006-D
Abstract: Insulin antibodies (IAA) can be detected in the serum of the majority of newly diagnosed IDDM patients prior to insulin therapy. In first degree relatives of IDDM patients, IAA are associated with an increased risk of development of IDDM. However, the disease specificity of IAA, detected by radiobinding assays, has not been addressed. We thus tested sera from patients with autoimmune disease for IAA. One of 29 (3%) patients with Graves' disease and five of 27 (19%) patients with SLE had IAA levels exceeding the range for normal controls. IAA were not detected in sera from 29 patients with Addison's disease, 15 patients with pernicious anaemia or 10 patients with increased gamma globulins. Non-specific binding of 125I-labelled insulin was increased in serum from 14 (21%) s les from patients with Graves' disease, 10 (37%) patients with SLE, one (3.2%) of 29 patients with Addison's disease and two (13%) of 15 patients with pernicious anaemia. The increased non-specific binding most likely relates to immunoglobulin binding as it was also found in eight of 10 patients with oligoclonal or polyclonal increase in gamma globulins. Our findings suggest that moderate elevations of IAA are not uncommon in patients with SLE, in whom increased non-specific binding of insulin is also common. This observation is of importance in preclinical diabetes screening studies.
Publisher: American Society for Clinical Investigation
Date: 04-1992
DOI: 10.1172/JCI115698
Publisher: Wiley
Date: 08-1987
DOI: 10.1111/J.1445-5994.1987.TB00071.X
Abstract: A possible immunogenetic basis for diabetes in chronic pancreatitis was explored by studying 19 patients with both disorders, most of whom required treatment with insulin. In contrast to patients with insulin-dependent (Type 1) diabetes, patients with diabetes and chronic pancreatitis had residual beta cell function but blunted C-peptide responses to intravenous glucagon, absence of circulating islet cell antibodies, and HLA-DR types similar to control subjects and patients with chronic pancreatitis without diabetes. Diabetes complicating chronic pancreatitis is therefore not associated with the biochemical or immunogenetic markers characteristic of Type 1 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
DOI: 10.1038/S41598-018-22491-7
Abstract: To optimise fecal s ling for reproducible analysis of the gut microbiome, we compared different methods of s le collection and sequencing of 16S rRNA genes at two centers. S les collected from six in iduals on three consecutive days were placed in commercial collection tubes (OMNIgeneGut OMR-200) or in sterile screw-top tubes in a home fridge or home freezer for 6–24 h, before transfer and storage at −80 °C. Replicate s les were shipped to centers in Australia and the USA for DNA extraction and sequencing by their respective PCR protocols, and analysed with the same bioinformatic pipeline. Variation in gut microbiome was dominated by differences between in iduals. Minor differences in the abundance of taxa were found between collection-processing methods and day of collection, and between the two centers. We conclude that collection with storage and transport at 4 °C within 24 h is adequate for 16S rRNA analysis of the gut microbiome. Other factors including differences in PCR and sequencing methods account for relatively minor variation compared to differences between in iduals.
Publisher: Oxford University Press (OUP)
Date: 10-1985
Abstract: The clinicopathologic features of an adult with insulinoma and pancreatic islet cell hyperplasia, who presented with hyperinsulinemic hypoglycemia are reported, together with in vitro studies on the patient's pancreatic islets. Islet cell hyperplasia with ductal proliferation and budding and beta cell degranulation was demonstrated by immunochemical means. The in vitro studies of cultured hyperplastic islet cells support the clinicopathologic features. Thus, in comparison with control islets maintained in culture for up to 14 days, hyperplastic islets could be cultured for up to 60 days, during which time cell overgrowth required subculture on three occasions. Furthermore, in contrast to control islets the release of both insulin and somatostatin from cultured hyperplastic islets was refractory to glucose, glucagon, and tolbutamide theophylline was the only secretagogue to stimulate insulin and somatostatin release from hyperplastic islets in vitro. Indirect immunofluorescence revealed the presence of islet cell surface autoantibodies in the plasma of this patient reactive with both normal human islets and a rat insulinoma line (RIN-m5F). These studies demonstrate the proliferative capacity and relatively undifferentiated functional state of hyperplastic islets in vitro. They provide further evidence that islet cell ision is capable of being stimulated in adult life. The pathogenic significance of islet cell surface autoantibodies in hyperplastic islet cell disease and insulinoma warrants further investigation.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.JAUT.2008.04.026
Abstract: Type 1 diabetes (T1D) satisfies many of the criteria for an autoimmune disease. The impact of the environment to promote the development of T1D and the ability to identify in iduals at risk for T1D years before clinical presentation afford lessons for other autoimmune diseases, in regard to gene-environment interactions and the potential for rational approaches to pre-clinical diagnosis and prevention. Public health measures aimed at the modern pro-inflammatory environment are required to stem the rising tide not only of T1D but other autoimmune and chronic inflammatory disorders. In the non-obese diabetic (NOD) model of spontaneous autoimmune diabetes, compelling evidence indicates that adaptive autoimmunity to the pancreatic beta cell is initially targeted against proinsulin. Proof-of-principle studies in the NOD mouse, which established that insulin and proinsulin peptides could be applied as tools to induce immune tolerance and protect against diabetes development, await successful translation to at-risk humans. Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases.
Publisher: Royal College of Psychiatrists
Date: 11-1994
Abstract: To investigate an association between HPA axis dysfunction, depression and cognitive impairment, we assessed subjects with mild Alzheimer's disease (AD). Sixteen non-depressed subjects with AD according to NINCDS/ADRDA criteria and 18 normal controls underwent the insulin hypoglycaemia (IH) test and the dexamethasone suppression test (DST). The AD subjects showed a blunted response of adrenocorticotrophic hormone (ACTH) to IH compared with controls ( P = 0.019). ACTH response (area under curve) correlated with a score for cognitive ability (CAMCOG) ( r = 0.64, P 0.01). AD subjects had a shorter time to peak cortisol level than controls ( P = 0.004), although total cortisol response was normal. The AD subjects show evidence of adrenal hyper-responsiveness and normal immediate (rate-sensitive) glucocorticoid feedback. An association between HPA axis dysfunction and organic brain pathology in AD subjects may be mediated by cell loss in the hippoc us.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Cambridge University Press (CUP)
Date: 1996
DOI: 10.1017/S0033291700033675
Abstract: Adrenal sensitivity was assessed in 16 non-depressed patients with NINCDS/ADRDA Alzheimer's disease (AD) and 18 control subjects by measuring cortisol response to low dose (0·05 μg/kg i.v.) exogenous adrenocorticotrophic hormone (ACTH). Controlling for sex and medication, both peak cortisol level (peak–baseline) and area under cortisol response curve (AUC above baseline) were significantly greater in AD subjects. This shows that HPA axis hyperactivity, as demonstrated by enhanced adrenal sensitivity to ACTH, occurs in AD. Similar findings have been reported to occur in depression. Among AD subjects, AUC cortisol response correlated with current age ( r = 0·70, P = 0·001) and age at onset of dementia ( r = 0·73, P = 0·001) and an inverse correlation was seen between cortisol AUC and cognitive test (CAMCOG) score ( r = −0·51, P = 0·044). Our findings suggest that HPA axis hyperactivity in AD is associated with advancing age and cognitive dysfunction. Such changes may be cause, or consequence, of neuronal loss.
Publisher: American Diabetes Association
Date: 28-03-2019
DOI: 10.2337/DC18-2342
Abstract: To investigate if early electronic identification and bedside management of inpatients with diabetes improves glycemic control in noncritical care. We investigated a proactive or early intervention model of care (whereby an inpatient diabetes team electronically identified in iduals with diabetes and aimed to provide bedside management within 24 h of admission) compared with usual care (a referral-based consultation service). We conducted a cluster randomized trial on eight wards, consisting of a 10-week baseline period (all clusters received usual care) followed by a 12-week active period (clusters randomized to early intervention or usual care). Outcomes were adverse glycemic days (AGDs) (patient-days with glucose & or & mmol/L [& or & mg/dL]) and adverse patient outcomes. We included 1,002 consecutive adult inpatients with diabetes or new hyperglycemia. More patients received specialist diabetes management (92% vs. 15%, P & 0.001) and new insulin treatment (57% vs. 34%, P = 0.001) with early intervention. At the cluster level, incidence of AGDs decreased by 24% from 243 to 186 per 1,000 patient-days in the intervention arm (P & 0.001), with no change in the control arm. At the in idual level, adjusted number of AGDs per person decreased from a mean 1.4 (SD 1.6) to 1.0 (0.9) days (−28% change [95% CI −45 to −11], P = 0.001) in the intervention arm but did not change in the control arm (1.8 [2.0] to 1.5 [1.8], −9% change [−25 to 6], P = 0.23). Early intervention reduced overt hyperglycemia (55% decrease in patient-days with mean glucose & mmol/L, P & 0.001) and hospital-acquired infections (odds ratio 0.20 [95% CI 0.07–0.58], P = 0.003). Early identification and management of inpatients with diabetes decreased hyperglycemia and hospital-acquired infections.
Publisher: Elsevier BV
Date: 10-1996
DOI: 10.1016/S0168-8227(96)01336-8
Abstract: The etiology of malnutrition-related diabetes mellitus (MRDM)--protein-deficient pancreatic diabetes (PDPD) and fibro-calculous pancreatic diabetes (FCPD)-is unclear. We studied the role of autoimmunity against pancreatic islet cells in the etiology of these two subtypes of MRDM by measuring islet-cell antibodies (ICA) in 23 patients with PDPD, 25 with FCPD and 62 with Type 1 diabetes. Three patients (13%) with PDPD had detectable ICA. Including a patient with a high titre of ICA (> 80 JDF units). The frequency of ICA in patients with PDPD was significantly lower than subjects with Type 1 diabetes (22/62, 35% P < 0.05). Among patients studied at onset. ICA prevalence was lower in the PDPD patients (1/7, 14%) compared to subjects with Type 1 diabetes (8/20, 40%). No patient of FCPD had detectable ICA (P < 0.001 vs. Type 1 diabetes subjects). We conclude that autoimmunity may play a role in the etiology of some patients with the PDPD subtype of MRDM. However, FCPD is unlikely to have an autoimmune etiology.
Publisher: The Endocrine Society
Date: 10-1985
Abstract: In order to obtain an appropriate tissue model to study human diabetes we isolated islet cells from pancreata obtained from brain-dead, heart-beating kidney donor subjects by collagenase dispersion and tissue culture. The presence of viable islet cells was confirmed by both immunofluorescence staining and hormone release experiments. Insulin and somatostatin release were determined on culture day 3 or 4 when amylase measurements indicated an absence of functional exocrine cells. Glucose, alpha-ketoisocaproic acid, theophylline, glucagon, and tolbutamide each stimulated insulin release 2- to 3-fold and somatostatin release 1.5- to 2-fold. Epinephrine and somatostatin both inhibited glucose-stimulated insulin release. Successful subculture of islet cells was achieved after dispersion of primary cultures with dispase. Subcultured islet cells released insulin into the medium during a subsequent 8-day period and when challenged with glucose responded with a 1.6-fold increase in insulin output. Cells cultured on glass coverslips were used to detect, by indirect immunofluorescence, islet cell surface antibodies (ICSA) in the sera of patients with insulin-dependent diabetes mellitus. Of 15 sera from patients with newly diagnosed insulin-dependent diabetes mellitus 9 were ICSA positive, whereas all of 10 control sera were negative in contrast, using rat insulinoma cells only 4 diabetic sera were positive, as well as 2 control sera. These findings demonstrate the functional viability of adult human islet cells in primary and secondary culture. Cultured human islet cells are a novel, sensitive, and specific system for detecting ICSA and for studying autoimmune effects, and provide a potential source of islet cells for transplantation.
Publisher: Elsevier BV
Date: 09-2006
Publisher: Brill | Wageningen Academic
Date: 2007
Publisher: The Endocrine Society
Date: 30-10-2020
Abstract: Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized. The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk. Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019. 15 tertiary care diabetes centers in the Australasian Diabetes Data Network. Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure. Standardized systolic and diastolic blood pressure scores and non–high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18 P & 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03 P & 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine. BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.
Publisher: Walter de Gruyter GmbH
Date: 2007
Publisher: American Society for Clinical Investigation
Date: 20-09-2018
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: The American Association of Immunologists
Date: 04-2008
DOI: 10.4049/JIMMUNOL.180.7.4458
Abstract: T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) induce diabetes in nonobese diabetic (NOD) mice. TCR transgenic mice with CD8+ T cells specific for IGRP206–214 (NOD8.3 mice) develop accelerated diabetes that requires CD4+ T cell help. We previously showed that immune responses against proinsulin are necessary for IGRP206–214-specific CD8+ T cells to expand. In this study, we show that diabetes development is dramatically reduced in NOD8.3 mice crossed to NOD mice tolerant to proinsulin (NOD-PI mice). This indicates that immunity to proinsulin is even required in the great majority of NOD8.3 mice that have a pre-existing repertoire of IGRP206–214-specific cells. However, protection from diabetes could be overcome by inducing islet inflammation either by a single dose of streptozotocin or anti-CD40 agonist Ab treatment. This suggests that islet inflammation can substitute for proinsulin-specific CD4+ T cell help to activate IGRP206–214-specific T cells.
Publisher: AMPCo
Date: 07-1997
DOI: 10.5694/J.1326-5377.1997.TB138790.X
Abstract: There are currently four principal glycohaemoglobin assay techniques (ion-exchange chromatography, electrophoresis, affinity chromatography and immunoassay) and about 20 different methods that measure different glycated products and report different units. Standardisation will lead to all assays reporting results in a standard unit, the HbA1c percentage of total serum haemoglobin, and should be in place within the next one to three years. In the interim, clinicians using glycohaemoglobin assays should be aware that the ranges indicating good and poor glycaemic control can vary markedly between different assays. The reproducibility of some assays may be insufficient to provide definitive evidence of changes in glycaemic control. Some assays may be so imprecise that they are unable to separate patients with good and poor control. INTERIM RECOMMENDATIONS 1 The terminology to be used for the assay is glycohaemoglobin (GHb) assay (recommendation from the combined meetings of the International Federation of Clinical Chemistry [IFCC] Working Group on HbA1c standardisation and the American Association of Clinical Chemistry [AACC] Subcommittee on Glycohemoglobin). 2 The unit of measurement for GHb assays should be reported as %HbA1c (Diabetes Control and Complications Trial equivalent). 3 Other units, such as % total GHb or %HbA1, should not be used. Assays producing these units should be converted to %HbA1c reporting units. 4 Assays with high precision are highly desirable. The IFCC/AACC are currently recommending between-run coefficients of variation of less than 5% for manufacturers of kits and instruments. However, between-run coefficients of variation of less than 3% are far more clinically useful and therefore desirable.
Publisher: American Diabetes Association
Date: 08-2006
DOI: 10.2337/DC06-0204
Abstract: OBJECTIVE—Poststroke hyperglycemia (PSH) is common and has adverse effects on outcome. In this observational study, we aimed to describe the frequency and temporal profile of PSH using a continuous glucose monitoring system (CGMS) in patients with and without diabetes. RESEARCH DESIGN AND METHODS—Fifty-nine patients with acute hemispheric ischemic stroke were prospectively studied with the CGMS, regardless of medication, admission plasma glucose value, and diabetes status. The CGMS records interstitial glucose every 5 min for 72 h. RESULTS—On admission, 36% of patients had preexisting diabetes. At the earliest analyzed time point of 8 h from stroke onset, 50% of nondiabetic subjects and 100% of diabetic patients were hyperglycemic (≥7 mmol/l). This early-phase hyperglycemia was followed by a decrease in glucose 14–16 h poststroke when only 11% of nondiabetic and 27% of diabetic patients were hyperglycemic. A late hyperglycemic phase 48–88 h poststroke was observed in 27% of nondiabetic and 78% of diabetic patients. Thirty-four percent of nondiabetic and 86% of diabetic patients were hyperglycemic for at least a quarter of the monitoring period. Multivariate regression analysis demonstrated that diabetes, insular cortical ischemia, and increasing age independently predicted higher glucose values. CONCLUSIONS—Poststroke hyperglycemia is common and prolonged despite treatment based on current guidelines. There are early and late hyperglycemic phases in nondiabetic as well as diabetic patients. Treatment protocols with frequent glucose measurement and intensive glucose-lowering therapy for a minimum of 72 h poststroke need to be evaluated.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-10-2013
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.DIABRES.2011.07.028
Abstract: We aimed to determine the associations between metformin or sulphonylurea monotherapy at study entry into the FIELD diabetes trial and (1) metabolic risk factors, (2) risk of a first major cardiovascular (CVD) outcome, and (3) the effect of each therapy on the risk-modifying effect of fenofibrate. Patients receiving metformin or sulphonylureas without insulin therapy were compared for the relative risk of CVD outcomes, adjusted for differences in baseline characteristics likely to affect risk. Metformin-treated patients were likely to be younger, female, or obese. Metformin was associated with higher levels of lipids (other than LDL-C) and homocysteine (P<0.001). Sulphonylurea-treated patients had a longer history of diabetes and more CVD and microvascular disease. Sulphonylurea treatment was associated with higher plasma creatinine and lower plasma HDL-C (P<0.001). The risks of all CVD outcomes were higher for those on sulphonylureas than diet alone, but were nonsignificant after adjustment for the duration and intensity of diabetes and severity of risk factors. Metformin and sulphonylureas did not significantly influence the benefits of fenofibrate on CVD outcomes. Apparent differences in the risk of CVD outcomes associated with oral hypoglycemics therapy were largely abolished by adjustment for diabetes and CVD risk factors.
Publisher: Mary Ann Liebert Inc
Date: 12-2022
Publisher: Hindawi Limited
Date: 02-2021
DOI: 10.1111/PEDI.13178
Abstract: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls. Eighty participants (25 diagnosed with T1D, 17 with confirmed IA, 38 sibling or unrelated controls) from the Australian T1D Gut Study cohort were studied (median [IQR] age 11.7 [8.9, 14.0] years, 43% female). A Food Frequency Questionnaire characterized daily macronutrient intake over the preceding 6 months. Plasma and fecal SCFA were measured by gas chromatography gut microbiome composition and ersity by 16S rRNA gene sequencing. A 10 g increase in daily carbohydrate intake associated with higher plasma acetate in IA/T1D (adjusted estimate +5.2 (95% CI 1.1, 9.2) μmol/L p = 0.01) and controls (adjusted estimate +4.1 [95% CI 1.7, 8.5] μmol/L p = 0.04). A 5 g increase in total fat intake associated with lower plasma acetate in IA/T1D and controls. A 5% increase in noncore (junk) food intake associated with reduced richness (adjusted estimate -4.09 [95%CI -7.83, -0.35] p = .03) and evenness (-1.25 [95% CI -2.00, -0.49] p < 0.01) of the gut microbiome in IA/T1D. Fiber intake associated with community structure of the microbiome in IA/T1D. Modest increments in carbohydrate and fat intake associated with plasma acetate in all youth. Increased junk food intake associated with reduced ersity of the gut microbiome in IA/T1D alone. These associations with the gut microbiome in IA/T1D support future efforts to promote SCFA by using dietary interventions.
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/IMJ.14805
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1992
Publisher: American Diabetes Association
Date: 08-1994
Abstract: Glutamic acid decarboxylase antibodies (GADAbs) are being increasingly used in clinical and research programs for the prediction and classification of insulin-dependent diabetes mellitus (IDDM). A number of different assay formats for the measurement of GADAbs have been reported, but the degree of concordance between assays is unknown. In this study, GADAbs were measured on 16 coded sera in 34 assays to examine concordance between GADAb assays and establish the feasibility of an international GADAb standard of measurement unit. The 16 lyophilized coded s les consisted of sera from healthy control subjects (n = 2), IDDM patients (n = 3), a patient with polyendocrine autoimmunity (n = 1), and duplicate dilutions of plasmapheresis serum from a patient with stiff-man syndrome (SMS). A high level of concordance was found in the ranking of GADAb levels (P = 0.99, Friedman's test) in the s les. Thirteen (38%) assays could reproducibly distinguish dilutions of SMS serum and detect GADAbs in all IDDM and polyendocrine autoimmunity sera tested. Although assessed on only four s les, disease specificity was 100% in 29 assays. The majority of assays that immunoprecipitated radiolabeled GAD gave high results for sensitivity and specificity. Enzyme-linked immunosorbent assays and assays using immunofluorescence were generally less sensitive. Several assays, in particular those measuring GAD enzymatic activity immunoprecipitated in fluid phase from rat brain homogenate, showed a prozone-like phenomenon in the SMS dilution curve. Interpolation of results from a standard curve into workshop units resulted in relatively low scatter in s les with lower levels of GADAbs. Hence, the use of an international reference serum to enable comparison of results between laboratories appears feasible. A second serum exchange is currently in progress to explore differences in sensitivity and specificity using larger numbers of disease and control sera.
Publisher: Hindawi Limited
Date: 09-06-2020
DOI: 10.1111/PEDI.13056
Publisher: American Diabetes Association
Date: 11-1986
Abstract: To examine whether products of the immune system interact with the pancreatic β-cell, rat insulinoma cells (RIN-m5F line) were cultured in the presence of conditioned medium from concanavalin A–activated mouse spleen cells (CAS medium). Indirect immunofluorescence and flow cytometry revealed that after culture in CAS medium, RIN-m5F cells had an 8- to 10-fold increase in class I major histocompatibility complex (MHC) proteins, whereas class II MHC proteins remained undetectable, and the level of insulin and/or insulin-like growth factor 1 receptors was unchanged. The stimulation of class I MHC expression on RIN-m5F cells by CAS medium could be mimicked by recombinant interferon-γ. Analysis of 125I–surface-labeled cells by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and autoradiography revealed that in the presence of CAS medium, there was a major increase in the expression of proteins of 48,000, 32,000, and 12,000 Mr and a minor increase in proteins of 17,000 and 9000 Mr. Precipitation with monoclonal antibody identified the 48,000- and 12,000-Mr proteins as the class I MHC protein and β2-microglobulin, respectively. The ability of lymphokine-conditioned medium to increase the expression of RIN-m5F cell surface proteins, including the class I MHC proteins, provides a potential mechanism for enhancing the immunemediated destruction Of the β-cell.
Publisher: Wiley
Date: 07-2001
DOI: 10.1046/J.1468-1293.2001.00073.X
Abstract: This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the in idual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.
Publisher: Hindawi Limited
Date: 15-08-2016
DOI: 10.1111/PEDI.12425
Abstract: The incidence of type 1 diabetes globally has increased dramatically over the last 50 years. Proposed environmental reasons for this increase mirror the modern lifestyle. Type 1 diabetes can be viewed as part of the non- communicable disease epidemic in our modern society. Meanwhile rapidly evolving new technologies are advancing our understanding of how human microbial communities interface with the immune system and metabolism, and how the modern pro-inflammatory environment is changing these communities and contributing to the rapid rise of non-communicable disease. The majority of children who present with clinical type 1 diabetes are of school age however 80% of children who develop type 1 diabetes by 18 years of age will have detectable islet autoantibodies by 3 years of age. The evolving concept that type 1 diabetes in many children has developmental origins has directed research questions in search of prevention back to pregnancy and early life. To this end the world's first pregnancy to early childhood cohort study in at-risk children has commenced.
Publisher: Elsevier BV
Date: 07-1993
DOI: 10.1016/0002-9343(93)90235-H
Abstract: To identify the number of cases of hyperthyroidism that followed the performance of contrast radiography in elderly patients at a geriatric hospital in a non-iodine-deficient area and to determine the clinical course of the condition. All patients over a 20-month period with biochemical hyperthyroidism (plasma free thyroxine level greater than 25.0 pmol/L and thyroid-stimulating hormone level less than 0.10 IU/L) were identified. Clinical features of hyperthyroidism and exposure to nonionic contrast media radiographs within the previous 12 months were sought. Follow-up extended from 6 to 22 months. A total of 28 patients with hyperthyroidism (aged 70 to 96 years) were identified. Seven patients (25%) had documented biochemical development of hyperthyroidism (five) or subsequent hyperthyroidism (two) 3 to 8 weeks after nonionic contrast media radiography. The four patients who underwent scanning had a multinodular thyroid, and thyroid antibodies were not detected in five of five patients. Although the condition appeared self-limited and six of six patients were euthyroid after 18 months, the condition was not benign progress and recovery were adversely affected by hyperthyroidism. Four patients had a good response to treatment with an antithyroid drug (carbimazole). Iodine-induced thyrotoxicosis following contrast radiography was found in 7 of 28 cases of hyperthyroidism seen at a geriatric hospital. Although the condition appears ultimately self-limited, pharmacologic control of severe clinical features may be required. The frequency of this condition in a non-iodine-deficient area appears related to the more common occurrence of autonomous thyroid nodules in the elderly. Because performance of contrast radiography is more common in this age group, the recognition and treatment of iodine-induced thyrotoxicosis are of increasing clinical importance.
Publisher: BMJ
Date: 08-2018
DOI: 10.1136/BMJOPEN-2017-020275
Abstract: Automated insulin delivery (also known as closed loop, or artificial pancreas) has shown potential to improve glycaemic control and quality of life in people with type 1 diabetes (T1D). Automated insulin delivery devices incorporate an insulin pump with continuous glucose monitoring(CGM) and an algorithm, and adjust insulin in real time. This study aims to establish the safety and efficacy of a hybrid closed-loop (HCL) system in a long-term outpatient trial in people with T1D aged 12 – years of age, and compare outcomes with standard therapy for T1D as used in the contemporary community. This is an open-label, multicentre, 6-month, randomised controlled home trial to test the MiniMed Medtronic 670G system (HCL) in people with T1D aged 12 – years, and compare it to standard care (multiple daily injections or continuous subcutaneous insulin infusion (CSII), with or without CGM). Following a run-in period including diabetes and carbohydrate counting education, dosage optimisation and baseline glucose control data collection, participants are randomised to either HCL or to continue on their current treatment regimen. The primary aim of the study is to compare the proportion of time spent in target sensor glucose range (3.9–10.0 mmol/L) on HCL versus standard therapy. Secondary aims include a range of glucose control parameters, psychosocial measures, health economic measures, biomarker status, user/technology interactions and healthcare professional expectations. Analysis will be intention to treat. A study in adults with an aligned design is being conducted in parallel to this trial. Ethics committee permissions were gained from respective institutional review boards. The findings of the study will provide high-quality evidence on the role of HCL in clinical practice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: American Diabetes Association
Date: 09-1991
Abstract: A simple, direct assay for T-lymphocyte reactivity to islet antigen(s) in human insulin-dependent diabetes mellitus (IDDM) should facilitate preclinical diagnosis and the evaluation of intervention therapy to avert autoimmune-mediated β-cell destruction. In subjects with preclinical or clinical IDDM, we measured the reactivity of peripheral blood mononuclear cells (PBMCs) incubated over 6 days with either adult human islets or fetal pig proislets, or other fetal pig tissues, and with human insulin. With islets, the stimulation index (SI) of [3H]thymidine uptake by PBMCs exceeded the mean + 2SD of control subjects in 6 of 6 preclinical subjects (SI 8.7 ± 3.7), 7 of 11 clinical subjects (SI 5.2 ± 3.4), and 1 of 12 control subjects (SI 2.7 ± 1.7) with insulin, the responses were less in frequency and magnitude, being 4 of 6 (2.7 ± 1.6), 3 of 11 (2.2 ± 1.1), and 0 of 12 (1.20 ± 0.55), respectively. The mean responses to islets of PBMCs from preclinical and clinical subjects differed significantly from control subjects (P & 0.02 by 2-tailed Kruskal-Wallis test). Secretion of granulocyte macrophage colony–stimulating factor by PBMCs over 6 days was assayed in the preclinical group and generally paralleled the uptake of [3H]thymidine. PBMC reactivity to islets appeared to be at least as sensitive a marker of preclinical IDDM as autoantibodies to a 64,000-Mr protein, presumably the enzyme glutamic acid decarboxylase, in fetal pig proislets. In conclusion, islet-reactive T lymphocytes in subjects with preclinical and clinical IDDM can be identified in bulk culture of PBMCs. Detection of these autoreactive T lymphocytes should be of value in the diagnosis of preclinical IDDM and in monitoring the effects of immunotherapy.
Publisher: AMPCo
Date: 10-2015
DOI: 10.5694/MJA14.01691
Abstract: Type 1 diabetes (T1D) is caused by an autoimmune attack on pancreatic beta cells that leads to insulin deficiency. The incidence of T1D in Australia has doubled over the past 20 years. T1D treatment focuses on physiological insulin replacement, aiming for near-normal blood glucose levels. Hypoglycaemia is a significant cause of morbidity and mortality in T1D. Optimal T1D management is complex, and is enhanced by empowering in iduals in all aspects of managing diabetes. New technologies, including insulin pumps, continuous glucose monitors and sensor-augmented pumps, can assist people achieve better glycaemic control and reduce the risk of severe hypoglycaemia. Women with T1D can achieve significantly better outcomes during pregnancy and for their infants by planning for their pregnancy and by intensive glycaemic control. Several trials are underway that seek to identify the determinants of autoimmunity and to develop therapies that prevent T1D in at-risk in iduals. Pancreatic and islet cell transplants are proven therapies, but are only offered to in iduals with diabetes and renal failure (pancreas) or severe hypoglycaemia unawareness (islet cell transplants). Although T1D is still associated with considerable premature mortality, recent findings show that a significant improvement in life expectancy has occurred.
Publisher: Wiley
Date: 20-07-2016
DOI: 10.1002/AJH.24469
Publisher: MDPI AG
Date: 29-03-2023
Abstract: Background: We sought research experiences of caregivers and their children were enrolled in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Methods: ENDIA is a pregnancy–birth cohort investigating early-life causes of type 1 diabetes (T1D). Surveys were sent to 1090 families between June 2021 and March 2022 with a median participation of years. Caregivers completed a 12-item survey. Children ≥ 3 years completed a four-item survey. Results: The surveys were completed by 550/1090 families (50.5%) and 324/847 children (38.3%). The research experience was rated as either “excellent” or “good” by 95% of caregivers, and 81% of children were either “ok”, “happy” or “very happy”. The caregivers were motivated by contributing to research and monitoring their children for T1D. Relationships with the research staff influenced the experience. The children most liked virtual reality headsets, toys, and “helping”. Blood tests were least liked by the children and were the foremost reason that 23.4% of the caregivers considered withdrawing. The children valued gifts more than their caregivers. Only 5.9% of responses indicated dissatisfaction with some aspects of the protocol. The self-collection of s les in regional areas, or during the COVID-19 pandemic restrictions, were accepted. Conclusions: This evaluation identified modifiable protocol elements and was conducted to further improve satisfaction. What was important to the children was distinct from their caregivers.
Publisher: SAGE Publications
Date: 08-2010
Abstract: Background and Purpose Three network laboratories measured antibodies to islet autoantigens. Antibodies to glutamic acid decarboxylase (GAD65 [GADA]) and the intracellular portion of protein tyrosine phosphatase (IA-2ic [IA-2A]) were measured by similar, but not identical, methods in s les from participants in the Type 1 Diabetes Genetics Consortium (T1DGC). Methods All laboratories used radiobinding assays to detect antibodies to in vitro transcribed and translated antigen, but with different local standards, calibrated against the World Health Organization (WHO) reference reagent. Using a common method to calculate WHO units/mL, we compared results reported on s les included in the Diabetes Autoantibody Standardization Program (DASP), and developed standard methods for reporting in WHO units/mL. We evaluated intra-assay and inter-assay coefficient of variation (CV) in blind duplicate s les and assay comparability in four DASP workshops. Results Values were linearly related in the three laboratories for both GADA and IA-2A, and intra-assay technical errors for values within the standard curve were below 13% for GADA and below 8.5% for IA-2A. Correlations in s les tested 1—2 years apart were %. Over the course of the study, internal CVs were 10—20% with one exception, and the laboratories concordantly called s les GADA or IA-2A positive or negative in 96.7% and 99.6% of duplicates within the standard curve. Despite acceptable CVs and general concordance in ranking s les, the laboratories differed markedly in absolute values for GADA and IA-2A reported in WHO units/mL in DASP over a large range of values. Limitations With three laboratories using different assay methods (including calibrators), consistent values among them could not be attained. Conclusions Modifications in the assays are needed to improve comparability of results expressed as WHO units/mL across laboratories. It will be essential to retain high intra- and inter-assay precision, sensitivity and specificity and to confirm the accuracy of harmonized methods. Clinical Trials 2010 7: S56—S64. ctj.sagepub.com
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/IMJ.13507
Abstract: We describe three cases of severe hyponatraemia in the setting of primary polydipsia that were managed in our centre in 2016. Despite receiving different solute loads, large volume diuresis and rapid correction of serum sodium occurred in all cases. Given the potentially catastrophic consequence of osmotic demyelination, we highlight the judicious use of desmopressin and hypotonic fluid infusion to mitigate sodium overcorrection in this setting.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
Publisher: AMPCo
Date: 08-2012
DOI: 10.5694/MJA12.10988
Abstract: For many years, the diagnosis of diabetes has been made through the laboratory-based measurement of fasting or random blood glucose levels, or using the oral glucose tolerance test. A glycated haemoglobin (HbA(1c)) level ≥ 6.5% (48 mmol/mol) is now also acceptable for diagnosing diabetes. Caution is needed in interpreting HbA(1c) test results in the presence of conditions affecting red blood cells or their survival time, such as haemoglobinopathies or anaemia.
Publisher: Wiley
Date: 04-1985
DOI: 10.1111/J.1445-5994.1985.TB04008.X
Abstract: 'Secondary failure' of oral hypoglycemics, in non-insulin dependent diabetics, has been attributed to dietary non-compliance, inadequate drug dosage, metabolic stress, or true drug failure. Progressive loss of beta cell function is a suggested mechanism for true drug failure but on the basis of little documented evidence. In view of this, we have measured basal and glucagon-stimulated C-peptide levels, human leukocyte antigen (HLA) types, and islet cell antibodies in 20 non-insulin dependent diabetics with 'secondary failure' of oral agents. There were 16 females and four males with a mean ideal body weight of 1.30 units and mean duration of diabetes of 9.5 years. Fasting insulin (mean +/- SD: 15.1 +/- 10.6 mU/l) and fasting C-peptide (2.3 +/- 1.2 micrograms/l) were normal or slightly elevated in all but one patient. Mean C-peptide increased from 2.3 +/- 1.2 micrograms/l to 3.5 +/- 2.2 micrograms/l (152% over basal) 6 minutes after 1 mg i.v. glucagon. In 15 patients the C-peptide response was greater than 130% of basal. Islet cell cytoplasmic antibodies were detected in only two patients. The distribution of HLA types was not significantly different from a control population, with no increase in DR3 or DR4. Thus, absolute insulin deficiency is uncommon in non-insulin dependent diabetics with 'secondary failure' of oral hypoglycemic agents and such patients do not exhibit the immuno-genetic markers of insulin-dependent diabetes.
Publisher: Springer Science and Business Media LLC
Date: 10-2004
DOI: 10.1007/S00125-004-1507-3
Abstract: Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to type 1 diabetes. Islet-antibody-positive first-degree relatives of type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR. Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase. Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin-glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes.
Publisher: American Diabetes Association
Date: 11-1989
Abstract: Recent biochemical studies have shown that the cytoplasmic islet cell–antibody autoantigen has properties of a monosialoganglioside (GM). To characterize islet glycolipids and ascertain whether islets express unique gangliosides, we determined the pattern of ganglioside expression in whole human pancreas and isolated human islets using high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC). The major gangliosides detected in glycolipid extracts of whole human pancreas were GM3, GD3 (disialoganglioside), and in a lesser amount, a GD1a-comigrating ganglioside. In contrast to whole human pancreas, isolated human islets were found to predominantly express GM3, an acidic glycolipid comigrating with GM2, and a ganglioside with mobility between GM2 and GM1 by both HPLC and HPTLC. Quantitation of the major ganglioside UV peaks seen on HPLC gave the following results. In whole pancreas, GM3 represented 66.7% of total gangliosides detected an asialoglycolipid comigrating with GM2, 2.0% a ganglioside migrating between GM2 and GM1, 2.6% GD3, 22.6% and a GD1a-comigrating ganglioside, 6.1%. In isolated islets, these components were found at the following levels: GM3, 14.9% GM2-comigrating glycolipid, 74.2% a ganglioside migrating between GM2 and GM1, 9.8% GD3, 1.1% and the GD1a-comigrating ganglioside, not detectable.
Publisher: AMPCo
Date: 07-1999
Publisher: American Diabetes Association
Date: 22-03-2011
DOI: 10.2337/DB10-1360
Abstract: Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment. We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin. β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk in iduals.
Publisher: American Diabetes Association
Date: 09-08-2016
DOI: 10.2337/DC16-0691
Abstract: To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes. A 52-week, double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin. HbA1c level was reduced 0.34–0.54% (3.7–5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences [ETDs]: 1.8 mg liraglutide −0.20% [95% CI −0.32 −0.07] 1.2 mg liraglutide −0.15% [95% CI −0.27 −0.03] 0.6 mg liraglutide −0.09% [95% CI −0.21 0.03]). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 [95% CI 0.88 0.96] 1.2 mg liraglutide 0.95 [95% CI 0.91 0.99] 0.6 mg liraglutide 1.00 [95% CI 0.96 1.04]). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide −4.9 kg [95% CI −5.7 −4.2] 1.2 mg liraglutide −3.6 kg [95% CI −4.3 −2.8] 0.6 mg liraglutide −2.2 kg [95% CI −2.9 −1.5]). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 [95% CI 1.07 1.59] 1.2 mg liraglutide 1.27 [95% CI 1.03 1.55] 0.6 mg liraglutide 1.17 [95% CI 0.97 1.43]), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 [95% CI 1.13 4.34]). Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.DIABRES.2014.03.009
Abstract: We hypothesised that higher body weight, a proposed risk factor for type 1 diabetes mellitus, would be associated with increased penetrance of lower risk genes. In adults at diagnosis of the slowly progressive form of type 1 diabetes mellitus we found that higher body mass index was associated with the absence of the highest risk HLA genes.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.DIABRES.2013.12.005
Abstract: To investigate severe hypoglycaemia (SH) in adults with type 1 diabetes and its associations with impaired awareness of hypoglycaemia (IAH), clinical, psychological and socio-demographic factors. Attendees of three specialist diabetes clinics in Melbourne, Australia completed questions about frequency of SH in the past six months impaired awareness of hypoglycaemia (Gold score) and measures of general emotional well-being (WHO-5), diabetes-specific positive well-being (subscale of W-BQ28), diabetes-related distress (PAID) and fear of hypoglycaemia (HFS). Of 422 participants (mean ± SD age 37.5 ± 15.0 years 54% women), 78 (18.5%) reported at least one SH event and 86 (20.5%) had IAH. SH and IAH frequencies were similar at all clinics. In total, 194 SH events were reported, with 10 people experiencing 40% of events. Compared with those without SH, participants with SH had longer diabetes duration, were younger at diabetes onset and more likely to have IAH (p<0.01). Those with SH had greater fear of hypoglycaemia and diabetes-related distress, poorer general emotional well-being, and lower diabetes-specific positive well-being, (p<0.01). There were no associations with age, gender, insulin regimen or HbA1c. This study has identified that SH and IAH in Australian adults with type 1 diabetes exist at similar levels to those reported in US and European research. SH was significantly associated with IAH and fear of hypoglycaemia. Assessment of hypoglycaemia, IAH and psychological well-being as part of a routine diabetes clinic visit was well accepted by attendees and enabled identification of those who may benefit from medical, educational or therapeutic interventions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
Publisher: Springer Science and Business Media LLC
Date: 21-08-2004
DOI: 10.1007/S00125-004-1485-5
Abstract: Diabetes is a rapidly rising independent risk factor for atherosclerosis and serious illness. This risk can be reduced by lifestyle changes and/or various drugs. Novel therapies to prevent diabetes, as well as new risk factors for diabetes, atherosclerosis and obesity require testing and identification. People with impaired fasting glucose or impaired glucose tolerance were randomised to ramipril (15 mg/day) or placebo and rosiglitazone (8 mg/day) or placebo with a 2x2 factorial design. They are assessed semi-annually for the primary outcome (diabetes or death). Diabetes is diagnosed if two consecutive plasma glucose levels exceed diagnostic thresholds (i.e. fasting >/=7.0 mmol/l or 2-h >/=11.1 mmol/l) within a 3-month period. Assuming an annual primary outcome incidence of 5%, there is more than 90% power to detect a 22% reduction. Approximately 20% of participants are having annual carotid ultrasounds to assess the effects on atherosclerosis. Patients screened but not randomised are being followed prospectively to identify determinants of obesity, diabetes and related disorders. A total of 24,872 in iduals in 21 countries were screened over 2 years and are eligible for follow-up. Of these, 5269 were randomised: 1835 (35%) had isolated impaired glucose tolerance, 739 (14%) had isolated impaired fasting glucose, and 2692 (51%) had both disorders. Annual carotid ultrasounds are currently being performed in 1406 randomised in iduals. The DREAM trial and related studies will determine if ramipril or rosiglitazone reduces the number of cases of diabetes and atherosclerosis, and will identify novel risk factors for diabetes.
No related grants have been discovered for Peter Colman.