ORCID Profile
0000-0001-9422-7852
Current Organisation
Garvan Institute of Medical Research
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Publisher: American College of Physicians
Date: 04-2014
DOI: 10.7326/L14-5007-2
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.JINORGBIO.2005.06.006
Abstract: Urate and ascorbate are the major water-soluble low molecular weight antioxidants in serum. Much attention has been devoted to the effect of these antioxidants on lipoprotein peroxidation in vivo and on their effect on copper-induced peroxidation ex vivo. These studies revealed that urate inhibits ascorbate oxidation in vitro, whereas the effect of ascorbate on urate oxidation has not been systematically studied thus far. The present study addresses mechanistic aspects of the kinetics of copper-induced oxidation of both these antioxidants and their mutual effects in aqueous solutions. We found that: (i) ascorbate becomes oxidized much faster than urate. (ii) Urate inhibits the oxidation of ascorbate but, even in the presence of excess urate, ascorbate becomes oxidized much faster than urate. (iii) Ascorbate, as well as the products of its oxidation (and/or hydrolysis) inhibit the copper-induced oxidation of urate. All these results are consistent with the hypothesis that the rate of ascorbate oxidation is determined by the rate of reoxidation of reduced copper (Cu(I)) to Cu(II) by molecular oxygen, whereas the rate of urate oxidation is governed by the rate of oxidation of urate within a 2:1 urate/copper complex. We think that the mutual effects of urate and ascorbate on each other's oxidation are likely to enhance their inhibitory effect on lipid peroxidation in biologically relevant systems including membranes and lipoproteins.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-09-2020
DOI: 10.1126/SCITRANSLMED.AAZ8048
Abstract: SMOC1 is a liver-secreted glucose-responsive protein that improves glycemic control through CREB-mediated suppression of hepatic glucose output.
Publisher: Wiley
Date: 29-07-2021
DOI: 10.1111/APT.16549
Abstract: Poor dietary intake is associated with the development of malnutrition, micronutrient deficiencies, anaemia and osteoporosis in in iduals with inflammatory bowel disease. While trials are underway to manipulate the diet of people with IBD, there has been no comprehensive systematic review of the dietary intake of adults with IBD. To conduct a systematic evaluation and meta‐analysis of the dietary intake of adults with IBD, including macronutrients, micronutrients and food group data. CINAHL, Embase, Medline and Scopus were searched from 1 January 2000 to 25 September 2020 for cohort, case–control or cross‐sectional studies that reported usual dietary intake in adults. Data were pooled and reported as weighted mean intake for: all adults with IBD Crohn's disease ulcerative colitis active disease remission males females. A random‐effects meta‐analysis model compared intake with healthy in iduals. Forty studies were identified and 19 were included in the meta‐analysis. All subgroups of adults with IBD consumed inadequate energy (mean intake in adults with IBD 1980 ± 130 kcal), fibre (14 ± 4 g), folate (246 ± 33 mg) and calcium (529 ± 114 mg) per day. Intake of breads and cereals, legumes, fruit, vegetables and dairy were inadequate. Compared to healthy in iduals, adults with IBD consume significantly less dietary fibre (SMD −0.59 95% CI: −0.73, −0.46). This review provides improved clarity about the dietary intake of adults with IBD. Future attention is required to improve diet quality and increase understanding of factors influencing dietary intake in IBD.
Publisher: MDPI AG
Date: 04-01-2019
DOI: 10.3390/JCM8010045
Abstract: Background: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. Aims: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults (ii) initial high and low dose SGLT2 inhibitor combination therapy. Methods: PubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24–26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed. Results: In 4 RCTs (n = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI) −0.55% (−0.67, −0.43)) and weight (−2.00 kg (−2.34, −1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (−0.59% (−0.72, −0.46)) and weight (−0.57 kg (−0.89, −0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction −0.47 kg (−0.88, −0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy. Conclusions: Initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.TEM.2011.12.005
Abstract: In most humans, obesity and insulin resistance coexist. However, a unique group of obese in iduals, who exhibit better insulin sensitivity than expected for their adiposity, has been the focus of recent research interest. We critically examine cross-sectional and lifestyle intervention studies in obese humans classified as 'insulin-sensitive' versus 'insulin-resistant' and review the few longitudinal studies comparing rates of cardiovascular disease, type 2 diabetes and all-cause mortality in these groups of in iduals. We suggest that reduced deposition of fat, particularly of bioactive lipid intermediates, in muscle and liver is potentially protective. We propose that dynamic interventional studies in insulin-sensitive obese humans may increase understanding of the metabolic factors that play a role in obesity-associated insulin resistance in humans.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 2012
Publisher: MDPI AG
Date: 07-06-2018
DOI: 10.3390/NU10060739
Publisher: The Endocrine Society
Date: 08-2013
DOI: 10.1210/ER.2012-1041
Abstract: Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount. Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties. Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance. There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear. Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.
Publisher: American Physiological Society
Date: 09-2020
DOI: 10.1152/AJPENDO.00207.2020
Abstract: Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.
Publisher: Elsevier BV
Date: 2003
Publisher: Elsevier BV
Date: 07-2011
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.TEM.2009.09.008
Abstract: Reactive oxygen species (ROS) are postulated to be a common trigger of insulin resistance. For ex le, treatment of adipocytes with either tumor-necrosis factor-alpha or dexamethasone increases ROS before impairing glucose uptake. Similarly, treatment with mitochondria-specific antioxidants preserves insulin sensitivity in animal models of insulin resistance. However, it remains unclear whether ROS contribute to insulin resistance in humans. First-degree relatives (FDRs) of type 2 diabetes subjects are at increased risk of developing insulin resistance and type 2 diabetes. Here we review the documented metabolic impairments in FDRs that could contribute to insulin resistance via increased oxidative stress. We propose that lipotoxic intermediates and lipid peroxides in skeletal muscle interfere with insulin signaling and might cause insulin resistance in these 'at risk' in iduals.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41467-021-23240-7
Abstract: Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese ( db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2010
DOI: 10.1007/S00125-010-1768-Y
Abstract: The purpose of the study was to test prospectively whether healthy in iduals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary in iduals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic cl ). Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ in iduals having gained significantly more weight than FH- in iduals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001). Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy in iduals. However, in iduals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy in iduals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding. ClinicalTrials.gov NCT00562393 The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.IJCARD.2003.12.013
Abstract: To find the relative contribution of various inflammation-sensitive proteins including fibrinogen, immunoglobulins (IgG, IgM and IgA), ceruloplasmin and high sensitivity C-reactive protein (hs-CRP) to the induction and/or maintenance of enhanced erythrocyte adhesiveness/aggregation in the peripheral blood of in iduals with atherothrombotic risk factors. The degree of erythrocyte adhesiveness/aggregation was determined by a simple slide test and image analysis. In addition, we measured various inflammation-sensitive protein levels including fibrinogen, ceruloplasmin, immunoglobulins and hs-CRP in a group of 234 in iduals with atherothrombotic risk factors and healthy ones. Pearson partial correlations and multiple linear regression analysis were performed. Fibrinogen was found to be the major protein contributing to the enhanced erythrocyte adhesiveness/aggregation, explaining 30% of the model. Fibrinogen and IgG together explained 32.4% of the model. Other inflammation-sensitive proteins did not reach statistical significance and were excluded from the model. Among inflammation-sensitive proteins measured in our cohort, fibrinogen is the dominant contributor to erythrocyte adhesiveness/aggregation in the peripheral blood of in iduals with atherothrombotic risk factors and healthy ones. These findings may pave the way for the development of therapeutic strategies directed at the attenuation of erythrocyte aggregability in in iduals with atherothrombosis.
Publisher: American Diabetes Association
Date: 11-12-2013
DOI: 10.2337/DC13-1728
Publisher: MDPI AG
Date: 27-08-2023
DOI: 10.3390/PATHOGENS12091087
Abstract: Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
Publisher: Springer New York
Date: 25-11-2014
Publisher: Elsevier BV
Date: 12-2014
Publisher: The Endocrine Society
Date: 21-12-2021
Abstract: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown. This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance. This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI] ≤ 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] & 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI & 25 kg/m2, HOMA-IR & 1.5, n = 11) or insulin resistant (Obresistant, BMI & 25 kg/m2, HOMA-IR & 3.0, n = 20), and type 2 diabetes (T2D, n = 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic cl , body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA. In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive in iduals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ± 0.333 mmol/L, P = .03) and T2D (3.36 ± 0.582 mmol/L, P & .001) vs Obsensitive (1.16 ± 0.143 mmol/L), but were similar between Obsensitive and lean (2.31 ± 0.329 mmol/L) in iduals. Total BAs were positively associated with waist circumference (R = 0.245, P = .041), visceral fat (R = 0.360, P = .002), and fibroblast growth factor 21 (R = 0.341, P = .004) and negatively associated with insulin sensitivity (R = –0.395, P = .001), abdominal subcutaneous fat (R = –0.352, P = .003), adiponectin (R = –0.375, P = .001), and liver fat (Hounsfield units, an inverse marker of liver fat, R = –0.245, P = .04). Conjugated BAs were additionally elevated in T2D in iduals (P & .001). BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified.
Publisher: Wiley
Date: 29-07-2013
DOI: 10.1002/OBY.20508
Abstract: While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. Healthy in iduals (n = 40) were overfed by 1,250 kcal day(-1) for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic cl ), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed. Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P ≤ 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 ± 5% and 38 ± 8% respectively, P ≤ 0.01). Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright © 2013 The Obesity Society.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.BIOCHI.2015.09.012
Abstract: Type 2 diabetes is increasingly being recognised as a global health crisis (World Health Organisation). Insulin resistance is closely associated with obesity and precedes the development of type 2 diabetes. However, there is now increasing evidence to suggest that diet itself may independently be associated with type 2 diabetes risk. A diet with a high acid load (or high potential renal net acid load, PRAL) can result in a decrease in pH towards the lower end of the normal physiological range, which may in turn lead to the development of insulin resistance. Conversely, reducing dietary acid load (the so called 'alkaline diet') may be protective and prevent the onset of type 2 diabetes. Here, we explore the influence of dietary acid load on the development of mild metabolic acidosis and induction of insulin resistance. Whilst large prospective cohort studies link high dietary acid load or low serum bicarbonate with the development of type 2 diabetes, the effect of a diet with a low acid (or high alkaline) load remains unclear. Further interventional studies are required to investigate the influence of dietary composition on the body's acid/base balance, insulin resistance and incidence of type 2 diabetes.
Publisher: Elsevier BV
Date: 2003
Publisher: BMJ
Date: 02-2021
DOI: 10.1136/BMJOPEN-2020-042493
Abstract: Crohn’s disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia’s first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal s les are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be s led whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. S les will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. ACTRN12619000911190.
Publisher: Wiley
Date: 07-2012
DOI: 10.1002/DMRR.2302
Abstract: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation' however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. Immune cell phenotypes and activation status were analysed by flow cytometry cross-sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 ± 5.4 kg/m2), overweight (n = 13, BMI 27.4 ± 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 ± 1.9 kg/m2) subjects. Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T-cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity.
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 12-2007
Publisher: Public Library of Science (PLoS)
Date: 07-08-2013
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.DIABET.2014.03.006
Abstract: Low-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH-) a family history of type 2 diabetes. Following a 3-day lead in energy balanced diet, FH+ (n = 9) and FH- men (n = 11) were overfed by 5200 kJ/day (45% fat) for 28 days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic-euglycaemic cl ) and body fat (DXA) were assessed in all in iduals at baseline and day 28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n = 11). Body weight, fat mass and fasting insulin levels were increased by overfeeding (P < 0.01) and insulin was increased significantly more in FH+ men (P<0.01). Serum sex hormone binding globulin (SHBG) and 5α-dihydrotestosterone (DHT) were reduced with overfeeding (P < 0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P < 0.05). Overfeeding reduced mRNA expression of 3β-hydroxysteroid dehydrogenase (HSD) and 17βHSD (P ≤ 0.007), independently of group. 5α-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P = 0.04). Overfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes.
Publisher: Elsevier BV
Date: 2003
Publisher: Elsevier BV
Date: 06-2007
Publisher: American Diabetes Association
Date: 11-07-2013
DOI: 10.2337/DC12-1663
Abstract: Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying. Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline. ID glutamine stimulated glucagon-like peptide 1 (GLP-1 healthy: P & 0.05 T2DM: P & 0.05), glucose-dependent insulinotropic polypeptide (GIP P = 0.098 P & 0.05), glucagon (P & 0.01 P & 0.001), insulin (P = 0.05 P & 0.01), and phasic pyloric pressures (P & 0.05 P & 0.05), but did not lower blood glucose (P = 0.077 P = 0.5). Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.
Publisher: Oxford University Press (OUP)
Date: 02-1998
Abstract: The process of sperm chromatin decondensation occurs when a spermatozoon enters an ovum. Protamine disulphide bonds are reduced to SH and the polycationic protamines combine with the polyanionic egg protein, nucleoplasmin, thus being stripped from DNA which then combines with histones. Defective chromatin decondensation will thus prevent further development of the male pronucleus. In this study human sperm s les were incubated in vitro at 28 degrees C (using a medium in which the polyanion, heparin, substitutes for nucleoplasmin and beta-mercaptoethanol for egg glutathione) for 10, 20 and 30 min before stopping the reaction with formalin (to 3.6%). The DNA of the fixed cells was stained with Acridine Orange by a one-step method and subjected to flow cytometry and data analysis, in which a zone characteristic of condensed chromatin is outlined on red-green fluorescence contour plots. After 20 min of incubation 97% of the control spermatozoa that were in the mature window (WIN M) had decondensed and moved out of this region. Defects in sperm decondensation were seen in four semen s les of the 20 that were tested. In cases where spermatozoa fail to produce a fertilized egg the cause may lie with defective chromatin quality, including failure of the sperm chromatin to decondense. The method described here is a simple procedure for detecting sperm s les containing such defective cells.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/238056
Abstract: The postprandial state is hypothesised to be proinflammatory and prooxidative, but the relative contributions of fat versus carbohydrate are unclear. Therefore, we examined inflammation and oxidative stress responses in serum and skeletal muscle before and after 1000 kcal meals, which were high in either fat or carbohydrate in 15 healthy in iduals. Serum and muscle expression of IL6 was elevated 3 hours after each meal, independently of macronutrient composition ( P 0.01 ). Serum IL18 was decreased after high-fat meal only ( P 0.01 ). Plasma total antioxidative status and muscle Cu/Zn-superoxide dismutase were decreased after high-carbohydrate meal only ( P 0.05 ). We conclude that a high-carbohydrate meal may evoke a greater postprandial oxidative stress response, whereas both fat and carbohydrate increased IL6. We speculate that the observed increases in postprandial IL6, without increases in any other markers of inflammation, may indicate a normal IL6 response to enhance glucose uptake, similar to its role postexercise.
Publisher: MDPI AG
Date: 11-08-2017
DOI: 10.3390/NU9080861
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/10715760400016113
Abstract: Oxidative modifications of LDL are involved in atherogenesis. Previously we have developed a simple assay to evaluate the susceptibility of lipids to copper-induced peroxidation in the relatively natural milieu of unfractionated serum in the presence of excess citrate. Based on our previous results we have proposed that the inducer of peroxidation in our optimized assay is a copper-citrate complex. Recent investigations indicate that under certain conditions a copper-albumin complex may induce peroxidation of ascorbate. Two different complexes may be formed in albumin-containing systems (e.g. serum) namely 1:1 and 2:1 copper-albumin complexes. The aim of the present work was to evaluate the possibility that at least one of these complexes may be responsible for the induction of peroxidation of lipids in lipidic systems containing copper and albumin, including our optimized assay. Towards this end, we have investigated the dependence of copper-induced peroxidation on the concentration of added albumin in lipidic systems in the absence and presence of citrate. In all the systems investigated in this study (PLPC liposomes, LDL, HDL and mixtures of HDL and LDL) we found that at low concentrations of free copper (e.g. in the presence of excess citrate) the 2:1 copper-albumin complex is redox-active and that this complex is the major contributor to the initiation of lipid peroxidation in these systems and in our optimized assay. The possible relevance of the induction of peroxidation in vivo by the latter complex has yet to be studied.
Publisher: Public Library of Science (PLoS)
Date: 20-11-2014
Publisher: MDPI AG
Date: 31-12-2020
DOI: 10.3390/NU13010135
Abstract: Inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease, are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract that are increasing in prevalence and incidence globally. They are associated with significant morbidity, reduced quality of life to in idual sufferers and are an increasing burden on society through direct and indirect costs. Current treatment strategies rely on immunosuppression, which, while effective, is associated with adverse events. Epidemiological evidence suggests that diet impacts the risk of developing IBD and modulates disease activity. Using diet as a therapeutic option is attractive to patients and clinicians alike due to its availability, low cost and few side effects. Diet may influence IBD risk and disease behaviour through several mechanisms. Firstly, some components of the diet influence microbiota structure and function with downstream effects on immune activity. Secondly, dietary components act to alter the structure and permeability of the mucosal barrier, and lastly dietary elements may have direct interactions with components of the immune response. This review will summarise the mechanisms of diet–microbial–immune system interaction, outline key studies examining associations between diet and IBD and evidence demonstrating the impact of diet on disease control. Finally, this review will outline current prescribed dietary therapies for active CD.
Publisher: American Diabetes Association
Date: 14-06-2010
DOI: 10.2337/DB10-0162
Abstract: Chronic low-grade inflammation is a feature of obesity and is postulated to be causal in the development of insulin resistance and type 2 diabetes. The aim of this study was to assess whether overfeeding induces peripheral insulin resistance in lean and overweight humans, and, if so, whether it is associated with increased systemic and adipose tissue inflammation. Thirty-six healthy in iduals undertook 28 days of overfeeding by +1,250 kcal/day (45% fat). Weight, body composition, insulin sensitivity (hyperinsulinemic-euglycemic cl ), serum and gene expression of inflammation markers, immune cell activation, fat cell size, macrophage and T-cell numbers in abdominal subcutaneous adipose tissue (flow cytometry and immunohistochemistry) were assessed at baseline and after 28 days. Subjects gained 2.7 ± 1.6 kg (P & 0.001) and increased fat mass by 1.1 ± 1.6% (P & 0.001). Insulin sensitivity decreased by 11% from 54.6 ± 18.7 to 48.9 ± 15.7 μmol/(kg of FFM)/min (P = 0.01). There was a significant increase in circulating C-reactive protein (P = 0.002) and monocyte chemoattractant protein-1 (P = 0.01), but no change in interleukin-6 and intercellular adhesion molecule-1. There were no changes in fat cell size, the number of adipose tissue macrophages or T-cells, or inflammatory gene expression and no change in circulating immune cell number or expression of their surface activation markers after overfeeding. Weight gain-induced insulin resistance was observed in the absence of a significant inflammatory state, suggesting that inflammation in subcutaneous adipose tissue occurs subsequent to peripheral insulin resistance in humans.
Publisher: Public Library of Science (PLoS)
Date: 07-05-2012
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.CLNU.2015.08.002
Abstract: Western diets rich in animal protein and poor in fruit and vegetables increase the body acid load, a predictor of type 2 diabetes risk. The relationships between dietary acid load, mild metabolic acidosis and insulin resistance remain unclear. The objective of this study was to assess the association between dietary acid load, body acid/base markers and peripheral insulin resistance at baseline and following a short-term overfeeding intervention in healthy in iduals. In a cross-sectional study of 104 men and women, insulin sensitivity was measured by hyperinsulinemic-euglycemic cl . Plasma lactate, a marker of metabolic acidosis, was assessed and acid load scores (potential renal acid load, PRAL and net endogenous acid production, NEAP) derived from diet diaries. The cohort was grouped into lean and overweight/obese and the latter further classified as insulin-sensitive (Obsen) and insulin-resistant (Obres) based on hyperinsulinemic-euglycemic cl glucose infusion rate (GIR, top tertile vs. bottom 2 tertiles). A subset of 40 in iduals participated in an overfeeding intervention (+1250 kcal/day) for 28 days and studies repeated. Obsen and Obres were matched for adiposity (BMI and fat mass, both P = 1). Fasting plasma lactate was higher in Obres (0.78 [0.63-1.14] mmol/L) compared with both lean (0.71 [0.44-0.90] mmol/L, P = 0.02) and Obsen (0.67 [0.56-0.79] mmol/L, P = 0.04) and not different between lean and Obsen (P = 0.9). Overfeeding was characterized by an increase in dietary acid load scores PRAL (P = 0.003) and NEAP (P = 0.05), a reduction in GIR necessary to maintain euglycemia (P = 0.03) and an increase in fasting plasma lactate (P = 0.02). The change in lactate was inversely associated with the change in GIR (r = -0.36, P = 0.03). Mild metabolic acidosis, measured by plasma lactate, aligns with insulin resistance independent of obesity and is induced by short-term increases in energy and dietary acid load in healthy humans. Further studies are required to determine whether buffering mild metabolic acidosis improves insulin resistance and reduces diabetes risk.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2013
DOI: 10.1007/S00125-012-2811-Y
Abstract: Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic in iduals before and during a hyperinsulinaemic-euglycaemic cl . Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160 also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant in iduals. These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome.
Publisher: MDPI AG
Date: 15-12-2022
Abstract: The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described erse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic cl with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman’s rank correlation analyses that passed the Benjamini–Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p 7.2 × 10−4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify erse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2004
Abstract: Enhanced red blood cell (RBC) aggregation has an adverse effect on microcirculatory blood flow and tissue oxygenation. It has been previously shown that obesity is associated with increased RBC aggregation. The objectives of the present study were to further characterize obesity-related RBC aggregation and to examine whether the enhanced aggregation is a plasma- or cellular-dependent process. Obese (body mass index (BMI)=40+/-6.3 kg/m2, n=22) and nonobese (BMI=24+/-3.4 kg/m2, n=18) in iduals were evaluated for inflammation markers and aggregation parameters. Aggregation parameters were derived from the distribution of RBC population into aggregate sizes, and from the variation of the distribution as a function of flow-derived shear stress, using a cell flow properties analyzer. To differentiate plasmatic from cellular factors, we determined the aggregation in the presence of autologous plasma or dextran-500 kDa and calculated the plasma factor (PF) in the obese group. PF ranges from 0 to 1. When the PF=1, the aggregation is all due to plasmatic factors, when PF=0, the altered aggregation depends entirely on cellular factors, whereas 0<PF<1 reflects the joint contribution of cellular and plasmatic factors. Obese subjects had relatively larger aggregates that were more resistant to dispersion by flow. The calculated PF in the obese group was 0.9, indicating a pronounced contribution of plasma to RBC aggregation in obesity. Our results suggest that obese in iduals present pathological plasma-dependent RBC aggregation, which is probably triggered by plasma macromolecules associated with the inflammatory response. These findings impact the future attempts to develop strategies aimed at attenuation of the enhanced RBC aggregation in obese in iduals.
Publisher: Public Library of Science (PLoS)
Date: 18-10-2013
Publisher: Elsevier BV
Date: 11-2021
Publisher: MDPI AG
Date: 08-05-2019
DOI: 10.3390/JCM8050623
Abstract: Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese in iduals. Methods: In iduals studied using the hyperinsulinaemic-euglycaemic cl at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) 25 kg/m2) or overweight/obese (BMI ≥ 25 kg/m2), with the latter further ided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median cl M-value (M/I, separate cut-offs for men and women). Fifty-seven in iduals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic cl , dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver. Results: In the whole cohort, M/I did not change over time (p = 0.40) it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime ≤ 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman’s r = 0.76, p = 1.1 × 10−7). Conclusions: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese in iduals predisposed to further metabolic deterioration over time.
Publisher: Wiley
Date: 25-07-2014
DOI: 10.1111/OBR.12199
Publisher: Wiley
Date: 16-04-2021
DOI: 10.1111/DME.14564
Abstract: Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an in idual's response to metformin in Type 1 diabetes. ACTRN12619001440112.
Publisher: BMJ
Date: 10-2020
DOI: 10.1136/BMJOPEN-2020-037859
Abstract: Metformin and diets aimed at promoting healthy body weight are the first line in treating type 2 diabetes mellitus (T2DM). Clinical practice, backed by clinical trials, suggests that many in iduals do not reach glycaemic targets using this approach alone. The primary aim of the Personalised Medicine in Pre-diabetes—Towards Preventing Diabetes in In iduals at Risk (PREDICT) Study is to test the efficacy of personalised diet as adjuvant to metformin in improving glycaemic control in in iduals with dysglycaemia. PREDICT is a two-arm, parallel group, single-masked randomised controlled trial in adults with pre-diabetes or early-stage T2DM (with glycated haemoglobin (HbA1c) up to 8.0% (64 mmol/mol)), not treated with glucose-lowering medication. PREDICT is conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney). Enrolment of participants commenced in December 2018 and expected to complete in December 2021. Participants are commenced on metformin (Extended Release, titrated to a target dose of 1500 mg/day) and randomised with equal allocation to either (1) the Personalised Nutrition Project algorithm-based diet or (2) low-fat high-dietary fibre diet, designed to provide caloric restriction (75%) in in iduals with body mass index kg/m 2 . Treatment duration is 6 months and participants visit the Clinical Research Facility five times over approximately 7 months. The primary outcome measure is HbA1c. The secondary outcomes are (1) time of interstitial glucose .8 mmol/L and (2) glycaemic variability (continuous glucose monitoring), (3) body weight, (4) fat mass and (5) abdominal visceral fat volume (dual-energy X-ray absorptiometry), serum (6) low-density lipoprotein cholesterol (7) high-density lipoprotein cholesterol and (8) triglycerides concentrations, (9) blood pressure, and (10) liver fat (Fibroscan). The study has been approved by the St Vincent’s Hospital Human Research Ethics Committee (File 17/080, Sydney, Australia) and the Weizmann Institutional Review Board (File 528-3, Rehovot, Israel). The findings will be published in peer-reviewed open access medical journals. NCT03558867 .
Publisher: Elsevier BV
Date: 07-2014
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 2004
No related grants have been discovered for Dorit Samocha-Bonet.