The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21st century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.

OBJECTIVE -To report prevalence rates of acanthosis nigricans (AN) and hyperinsulinemia and the association of AN with hyperinsulinemia compared with other known or suspected risk factors for type 2 diabetes in young American Indians. RESEARCH DESIGN AND METHODS-A random sample of Cherokee Nation members aged 5-40 years was invited to participate in the Cherokee Diabetes Study, a cross-sectional study of type 2 diabetes and its risk factors in a young American Indian population. Data were collected by personal interview, medical history, physical examination (including anthropometric and blood pressure measurements and examination of the neck for AN), and laboratory analyses of blood specimens. Levels of insulin, lipids, and glucose were measured on fasting blood specimens. Diabetes status was determined according to the American Diabetes Association criteria.RESULTS -A total of 2,205 participants were examined. Overall prevalence rates for AN and hyperinsulinemia were 34.2 and 47.2%, respectively. In general, the rates for both increased with age and degree of Indian heritage and were higher in female subjects, overweight/obese individuals, those with type 2 diabetes, and those with a parental history of type 2 diabetes. In addition, both had significantly higher age-and sex-adjusted means for selected known or suspected risk factors for type 2 diabetes. AN remained significantly associated with hyperinsulinemia (P ϭ 0.0001) in multivariate analysis.CONCLUSIONS -AN is independently associated with hyperinsulinemia and therefore may be useful as an early indicator of high risk for diabetes.

Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.

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Background: Vitamin D deficiency is an unrecognized epidemic found in India and also worldwide. Despite the high prevalence of diabetes among Indians, there is a paucity of data showing the relationship between vitamin D status and cardiometabolic disparities. In this study, we have examined the relationship between vitamin D and cardiometabolic traits in a population from India. Methods: Circulating 25(OH)D levels were measured in 3,879 participants from the Asian Indian Diabetic Heart Study using ELISA kits. Results: Vitamin D levels were significantly reduced (p < 0.0001) in both men and women with obesity. However, compared to women, serum vitamin D was consistently lower in men (p < 0.02), irrespective of the presence of obesity and type 2 diabetes. Multivariate regression revealed strong interaction of vitamin D with body mass index that resulted in increased fasting glucose (p = 0.001) and reduced homeostasis model assessment of β-cell function (HOMA-B; p = 0.01) in normoglycemic individuals. However, in gender-stratified analysis, this association was restricted to men for both fasting glucose (p = 2.4 × 10^-4) and HOMA-B (p = 0.001). Conclusions: Our findings suggest that vitamin D deficiency may significantly enhance the risk of cardiometabolic disease among Asian Indians. Future randomized trials and genetic studies are expected to clarify the underlying mechanisms for gender differences in vitamin D deficiency, and whether vitamin D-driven improvement in testosterone may contribute to beneficial cardiometabolic outcomes in men.