The risk of developing type 2 diabetes mellitus (T2DM) is exceptionally high among both native and migrant South Asians. T2DM occurs more often and at a younger age and lower BMI, and the risk of coronary artery and cerebrovascular disease, and renal complications is higher for South Asians compared with people of White Caucasian descent. The high prevalence of T2DM and its related complications in South Asians, which comprise one-fifth of the total world's population, poses a major health and socioeconomic burden. The underlying cause of this excess risk, however, is still not completely understood. Therefore, gaining insight into the pathogenesis of T2DM in South Asians is of great importance. The predominant mechanism, in this ethnicity seems to be insulin resistance (IR) rather than an impaired β-cell function. In this systematic review, we describe several possible mechanisms that may underlie or contribute to the increased IR observed in South Asians.
South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians.Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458).Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P<0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signaling and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced.South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians.
Abstract A 5-day High-Fat High-Calorie diet (HFHC-diet) reduces insulin-stimulated glucose disposal (Rd) in South Asian, but not Caucasian healthy lean males. We aimed to investigate if differences in myocellular lipid handling are underlying this differential response. A two-step hyperinsulinemic-euglycemic clamp and muscle biopsies were performed in 12 healthy lean Caucasian and South Asian males (BMI < 25 kg/m 2 , 19–25 years) before and after a 5-day HFHC-diet (regular diet + 375 mL cream/day; 1275 kcal/day; 94% fat). Triglyceride extractions and Western Blots for lipid droplet and mitochondrial proteins were performed. Intramyocellular lipid content and HFHC-diet response were similar between ethnicities (group effect: P = 0.094; diet effect: +~30%, P = 0.044). PLIN5 protein content increased upon the HFHC-diet (P = 0.031) and tended to be higher in South Asians (0.87 ± 0.42 AU vs. 1.35 ± 0.58 AU, P = 0.07). 4-HNE tended to increase in South Asians upon the HFHC-diet (interaction effect: P = 0.057). In Caucasians ΔPLIN5 content correlated with ΔR d (Caucasians: r = 0.756, P = 0.011; South Asians: r = −0.085, P = 0.816), while in South Asians Δ4-HNE associated with ΔPLIN5 content (Caucasians: r = 0.312, P = 0.380; South Asians: r = 0.771, P = 0.003). These data indicate that in Caucasians, PLIN5 may be protective against HFHC-diet induced insulin resistance, which for reasons not yet understood is not observed in South Asians, who possess increased lipid peroxidation levels.
Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (β: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (β: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (β: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (β: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).
Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en-Y gastric bypass (RYGB) surgery.Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53·7 ± 8·9 years (mean ± SD)] scheduled to undergo RYGB surgery were included.Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance (MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery.Body mass index decreased from 41·3 ± 4·3 at baseline to 34·1 ± 2·8 kg/m(2) (P < 0·001) after 16 weeks. Glycemic control improved as well [HbA1c: 7·8 ± 1·1 to 6·8 ± 1·3% (62 ± 12 to 51 ± 14 mm) (P < 0·05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (-35·5 ± 9·6%) as compared to subcutaneous fat volume (-25·0 ± 6·3%) and in paracardial (-17·3 ±17·2%) as compared to epicardial fat volume (-6·4 ± 6·0%).This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change.
Background The glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes. Purpose To assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients. Study Type Prospective, double‐blind, randomized, placebo‐controlled trial. Population Forty‐seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26‐week treatment with liraglutide (1.8 mg/day) or placebo. Field Strength/Sequence 3T (balanced steady‐state free precession cine MRI, 2D and 4D velocity‐encoded MRI, 1 H‐MRS, T 1 mapping). Assessment Primary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]). Statistical Tests Data were analyzed according to intention‐to‐treat. Between‐group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA). Results Liraglutide ( n = 22) compared with placebo ( n = 25) did not change Edec (+0.2 mL/s 2 × 10 ‐3 (–0.3;0.6)), E/A (–0.09 (–0.23;0.05)), E/Ea (+0.1 (–1.2;1.3)) and ejection fraction (0% (–3;2)), but decreased stroke volume (–9 mL (–14;–5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (–0.6;1.6)), myocardial triglyceride content (+0.21% (–0.09;0.51)), and ECV (–0.2% (–1.4;1.0)) were unaltered. Data Conclusion Liraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease. Level of Evidence: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679–1688.
