Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease

Abstract

Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as possible links between increased adipose mass and metabolic abnormalities. Among these molecules, adiponectin has drawn much attention because of its insulin-sensitizing and antiatherogenic actions, suggesting that genetic deficits in its production or action may contribute to insulin resistance and coronary artery disease (CAD). A meta-analysis of the data published to date supports this hypothesis. Two independent effects, corresponding to the two linkage disequilibrium blocks that can be identified at the adiponectin locus, appear to be present. In the 5' block, the g.-11391G-->A variant has a modest but significant effect on adiponectinemia, with a mean difference between genotypes of 1.64 ng/ml (95% CI 0.88-2.41). In the 3' block, the g.+276G-->T variant is a strong determinant of insulin resistance and CAD, with minor allele homozygotes having a lower homeostasis model assessment of insulin resistance (HOMA(IR)) index (-0.36 units, 95% CI 0.24-0.47) and a lower cardiovascular risk (odds ratio 0.55, 95% CI 0.38-0.80) than carriers of other genotypes. No consistent effect on BMI or risk of type 2 diabetes is evident. Polymorphisms in the genes coding for the adiponectin receptors may also influence the risk of insulin resistance and CAD, but data on these genes are still too sparse to draw firm conclusions. In summary, the studies published to date indicate that polymorphisms at the adiponectin locus are indeed predictors of circulating adiponectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis.