These data indicate that serum resistin is highly heritable and has some common genetic background with traits related to insulin resistance, reinforcing the hypothesis that this adipokine may play a pathogenic role in insulin resistance-related abnormalities, including type 2 diabetes and cardiovascular disease.

Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n ‫؍‬ 638), type 2 diabetic patients without CAD (n ‫؍‬ 535), and type 2 diabetic patients with CAD (n ‫؍‬ 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in the three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value ‫؍‬ 0.027). Among diabetic patients (n ‫؍‬ 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26 -4.03; P ‫؍‬ 0.006) and having a myocardial infarction (MI) (n ‫؍‬ 156) by 50 years of age (3.17, 1.46 -6.88, P ‫؍‬ 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01-2.18; P ‫؍‬ 0.049) in diabetic patients who did not smoke (n ‫؍‬ 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI. Diabetes 54:3021-3025, 2005

OBJECTIVE -Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (ϩ45TϾG and ϩ276GϾT) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis Ͼ50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n ϭ 189) and/or (n ϭ 45) with coronary stenosis Յ50%.RESULTS -No association with CAD was observed for the ϩ45 SNP (P ϭ 0.48). By contrast, a significant association was observed for the ϩ276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037-0.46], P ϭ 0.002). A similarly protective effect of the ϩ276 T/T genotype was observed in 110 case and 45 control subjects for whom the CAD status had been determined by angiography (0.04 [0.006 -0.30], P ϭ 0.002).Serum adiponectin, although clearly related to several features of the proatherogenic/insulinresistant phenotype, was not different between control subjects and CAD patients (26 Ϯ 17 vs. 25 Ϯ 13 g/ml).CONCLUSIONS -In conclusion, the ϩ276 GϾT polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects. Diabetes Care 27:2015-2020, 2004T he prevalence of coronary artery disease (CAD) is two to four times more frequent in patients with type 2 diabetes than in nondiabetic individuals, representing the leading cause of death in this population (1-3). An important role in modulating the cardiovascular risk of diabetic patients is played by comorbidities such as dyslipidemia and hypertension or by environmental risk factors such as smoking. Factors intrinsic to the vascular wall, regulating its propensity to react to the diabetic milieu with endothelial dysfunction and activation of proinflammatory mechanisms, are also believed to be major players (4). These vascular pathways are under genetic control, but the genes that are involved are mostly unknown (5-7).Adiponectin is a circulating protein secreted by adipocytes that shares significant similarities with collagens VIII and X and complement protein C 1q (8,9). This adipokine has been recently shown to suppress the expression of class A scavenger receptors in macrophages, resulting in decreased uptake of oxidized LDL and reduced intracellular accumulation of cholesteryl esters (10). Adiponectin also has anti-inflammatory properties affecting the nuclear factor (NF)-B pathway and inhibiting monocyte adhesion to aortic endothelial cells (11,12). In addition to these effects on the vasculature, this molecule is a potent enhancer of insulin action on peri...

BackgroundHigh serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes.MethodsWe tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels.ResultsIn a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10–1.64) and 1.99 (1.55–2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10–1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06–1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343).ConclusionsThis is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry.