The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n ‫؍‬ 89) and women (n ‫؍‬ 129) with a broad range of age (

OBJECTIVEHuman blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response.RESEARCH DESIGN AND METHODSWe identified studies that measured the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians. We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). We calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance.RESULTSWe found that Caucasian subpopulations were located around the middle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable.CONCLUSIONSOur findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset.

THE AMERICAN DIABETES ASSOCIATIONGENNID STUDY GROUP* OBJECTIVE -We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with firstdegree relatives with type 2 diabetes.RESEARCH DESIGN AND METHODS -Women with (n ϭ 332) and without (n ϭ 663) a history of GDM were compared regarding 1) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2) the prevalence of type 2 diabetes, and 3) self-reported CVD.RESULTS -Women with prior GDM were younger (48.6 Ϯ 0.7 vs. 52.4 Ϯ 0.6 years [means Ϯ SE]; P Ͻ 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P Ͻ 0.005). Although both groups were obese (BMI 34.4 Ϯ 1.2 vs. 33.7 Ϯ 0.6 kg/m 2 ), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P Ͻ 0.001) and type 2 diabetes (93.4 vs. 63.3%; P Ͻ 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21-2.82]; P ϭ 0.005) that occurred at a younger age (45.5 Ϯ 2.2 vs. 52.5 Ϯ 1.9 years; P ϭ 0.02) and was independent of metabolic syndrome (1.74 [1.10 -2.76]; P ϭ 0.02) and type 2 diabetes (1.56 [1.002-2.43]; P Ͻ 0.05).CONCLUSIONS -Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes.

Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.bioinformatics | meta-analysis | integration | obesity | hyperglycemia