ORCID Profile
0000-0002-4583-8793
Current Organisation
University of Birmingham
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Publisher: Wiley
Date: 14-09-2017
DOI: 10.1111/DME.13439
Abstract: Residual β-cell function is present at the time of diagnosis with Type 1 diabetes. Preserving this β-cell function reduces complications. We hypothesized that exercise preserves β-cell function in Type 1 diabetes and undertook a pilot trial to address the key uncertainties in designing a definitive trial to test this hypothesis. A randomized controlled pilot trial in adults aged 16-60 years diagnosed with Type 1 diabetes within the previous 3 months was undertaken. Participants were assigned to control (usual care) or intervention (exercise consultation every month), in a 1 : 1 ratio for 12 months. The primary outcomes were recruitment rate, drop out, exercise adherence [weeks with ≥ 150 min of self-reported moderate to vigorous physical activity (MVPA)], and exercise uptake in the control group. The secondary outcomes were differences in insulin sensitivity and rate of loss of β-cell function between intervention and control at 6 and 12 months. Of 507 in iduals who were approached, 58 (28 control, 30 intervention) entered the study and 41 completed it. Participants were largely white European males, BMI 24.8 ± 3.8 kg/m We show that it is possible to recruit and randomize people with newly diagnosed Type 1 diabetes to a trial of an exercise intervention, and increase and maintain their exercise levels for 12 months. Future trials need to incorporate measures of greater adherence to exercise training targets, and include more appropriate measures of β-cell function. (Clinical Trials Registry No ISRCTN91388505).
Publisher: SAGE Publications
Date: 05-2012
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: Elsevier BV
Date: 08-2011
Publisher: American Diabetes Association
Date: 30-07-2018
DOI: 10.2337/DC18-0288
Abstract: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P & 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
Publisher: American Diabetes Association
Date: 12-07-2018
DOI: 10.2337/DC18-0087
Abstract: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk in iduals. We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6 P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS & .295, 95% CI 1.47–3.51 P = 0.0002). The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2006
Abstract: Genes for peripheral tissue-restricted self-antigens are expressed in thymic and hematopoietic cells. In thymic medullary epithelial cells, self-antigen expression imposes selection on developing autoreactive T cells and regulates susceptibility to autoimmune disease in mouse models. Less is known about the role of self-antigen expression by hematopoietic cells. Here we demonstrate that one of the endocrine self-antigens expressed by human blood myeloid cells, proinsulin, is encoded by an RNA splice variant. The surface expression of immunoreactive proinsulin was significantly decreased after transfection of monocytes with small interfering RNA to proinsulin. Furthermore, analogous to proinsulin transcripts in the thymus, the abundance of the proinsulin RNA splice variant in blood cells corresponded with the length of the variable number of tandem repeats 5′ of the proinsulin gene, known to be associated with type 1 diabetes susceptibility. Self-antigen expression by peripheral myeloid cells extends the umbrella of “immunological self” and, by analogy with the thymus, may be implicated in peripheral immune tolerance.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Parth Narendran.