Insulin Resistance and Body Fat Distribution in South Asian Men Compared to Caucasian Men

South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians.Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27+/-3 and 27+/-3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size.Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22+/-6 and 15+/-4% of body weight; p-value<0.0001), higher SA fat (3.5+/-1.9 and 2.2+/-1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0+/-0.5 and 1.0+/-0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491+/-1393 and 1648+/-864 microm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = -0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = -0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians.Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat

Role of ENPP1 on Adipocyte Maturation

BACKGROUND: It is recognized that the ability of adipose tissue to expand in response to energy excess, i.e. adipocyte maturation, is important in determining systemic abnormalities in glucose and lipid metabolism. Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1, also known as PC-1) has been recently reported to be involved in the pathogenesis of insulin resistance and related diseases. However, its role on adipose tissue physiology as a mechanism of systemic insulin resistance is not understood. This study was performed to evaluate whether ENPP1 is regulated during adipogenesis and whether over-expression in adipocytes can affect adipocyte maturation, a potential novel mechanism of ENPP1-related insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: ENPP1 expression was found down-regulated during 3T3-L1 maturation, and over-expression of human ENPP1 in 3T3-L1 (pQCXIP-ENPP1 vector) resulted in adipocyte insulin resistance and in defective adipocyte maturation. Adipocyte maturation was more efficient in mesenchymal embryonal cells from ENPP1 knockout mice than from wild-type. CONCLUSIONS: We identify ENPP1 as a novel mechanism of defective adipocyte maturation. This mechanism could contribute to the pathogenesis of insulin resistance in absence of obesity

Fat Oxidation, Fitness and Skeletal Muscle Expression of Oxidative/Lipid Metabolism Genes in South Asians: Implications for Insulin Resistance?

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methodology/Principal Findings:&lt;/b&gt; Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4&#177;5.7 ml.kg−1.min−1, p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77&#177;2.02 vs 6.55&#177;2.60 mg.kg−1.min−1 at 55% VO2max, p = 0.013), and absolute (3.46&#177;2.20 vs 6.00&#177;1.93 mg.kg−1.min−1 at 25 ml O2.kg−1.min−1, p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions/Significance:&lt;/b&gt; These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.&lt;/p&gt

Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (<it>PPARG2</it>; rs 1801282); insulin-like growth factor two binding protein 2 (<it>IGF2BP2</it>; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (<it>CDK5</it>; rs7754840); a zinc transporter and member of solute carrier family 30 (<it>SLC30A8</it>; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (<it>CDKN2A</it>; rs10811661); hematopoietically expressed homeobox (<it>HHEX</it>; rs 1111875); transcription factor-7-like 2 (<it>TCF7L2</it>; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(<it>KCNJ11</it>; rs 5219); and fat mass obesity-associated gene (<it>FTO</it>; rs 9939609)].</p> <p>Methods</p> <p>We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.</p> <p>Results</p> <p>Four of the nine SNPs revealed a significant association with T2D; <it>PPARG2 </it>(Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03–0.52); p = 0.005], <it>IGF2BP2 </it>[OR 1.37; 95% CI (1.04–1.82); p = 0.027], <it>TCF7L2 </it>[OR 1.64; 95% CI (1.20–2.24); p = 0.001] and <it>FTO </it>[OR 1.46; 95% CI (1.11–1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of <it>CDK5 </it>(rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of <it>TCF7L2 </it>(rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.</p> <p>Conclusion</p> <p>To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.</p

Transforming Growth Factor β Signaling Pathway Associated Gene Polymorphisms May Explain Lower Breast Cancer Risk in Western Indian Women

Transforming growth factor β1 (TGFB1) T29C and TGF β receptor type 1 (TGFBR1) 6A/9A polymorphisms have been implicated in the modulation of risk for breast cancer in Caucasian women. We analyzed these polymorphisms and combinations of their genotypes, in pre menopausal breast cancer patients (N = 182) and healthy women (N = 236) from western India as well as in breast cancer patients and healthy women from the Parsi community (N = 48 & 171, respectively). Western Indian women were characterized by a higher frequency of TGFB1*C allele of the TGF β T29C polymorphism (0.48 vs 0.44) and a significantly lower frequency of TGFBR1*6A allele of the TGFBR1 6A/9A polymorphism (0.02 vs 0.068, p<0.01) as compared to healthy Parsi women. A strong protective effect of TGFB1*29C allele was seen in younger western Indian women (<40 yrs; OR = 0.45, 95% CI 0.25–0.81). Compared to healthy women, the strikingly higher frequencies of low or intermediate TGF β signalers in patients suggested a strong influence of the combination of these genotypes on the risk for breast cancer in Parsi women (for intermediate signalers, OR = 4.47 95%CI 1.01–19.69). The frequency of low signalers in Parsi healthy women, while comparable to that reported in Europeans and Americans, was three times higher than that in healthy women from western India (10.6% vs 3.3%, p<0.01). These observations, in conjunction with the low incidence rate of breast cancer in Indian women compared to White women, raise a possibility that the higher frequency of TGFB1*29C allele and lower frequency of TGFBR1*6A allele may represent important genetic determinants that together contribute to a lower risk of breast cancer in western Indian women

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

A randomized, controlled trial of 3.0 mg of liraglutide in weight management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagonlike peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P&lt;0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P&lt;0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P&lt;0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.)