Adiponectin is a protein secreted by adipocytes that modulates insulin action. To assess whether variants of this gene contribute to the prevalence of insulin resistance in Caucasians, we genotyped 413 nondiabetic individuals for two single nucleotide polymorphisms (SNPs) at this locus. The two SNPs (45T3 G and 276G3 T) were chosen because of their association with type 2 diabetes in Japanese. Whereas each polymorphism was significantly associated with some correlate of insulin resistance, the haplotype defined by the two together was strongly associated with many components of the insulin resistance syndrome. Homozygotes for the risk haplotype had higher body weight (P ‫؍‬ 0.03), waist circumference (P ‫؍‬ 0.004), systolic (P ‫؍‬ 0.01) and diastolic (P ‫؍‬ 0.003) blood pressure, fasting glucose (P ‫؍‬ 0.02) and insulin (P ‫؍‬ 0.005) levels, homeostasis model assessment (HOMA) for insulin resistance (P ‫؍‬ 0.003), and total to HDL cholesterol ratio (P ‫؍‬ 0.01). Homozygotes also had significantly lower plasma levels of adiponectin (P ‫؍‬ 0.03), independent of sex, age, and body weight. In an independent study group of 614 Caucasians, including 310 with type 2 diabetes, the risk haplotype was confirmed to be associated with increased body weight (P ‫؍‬ 0.03) but not with type 2 diabetes per se. We conclude that variability at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome, but given the nature of the two SNPs, the risk haplotype is most probably a marker in linkage disequilibrium with an as yet unidentified polymorphism that affects plasma adiponectin levels and insulin sensitivity. Diabetes 51: 2306 -2312, 2002

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.؊11391G3 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. O ur view of adipose tissue has undergone dramatic changes over the past 15 years. Previously believed to be a mere energy depot, adipose tissue is now considered a major endocrine organ regulating whole-body metabolism as well as inflammatory and immune responses (1,2). These actions are mediated by a number of molecules-collectively known as adipokines-that are secreted by adipocytes and act in an autocrine, paracrine, or endocrine fashion, adapting metabolic fluxes to the amount of stored energy (1,2). The discovery of such endocrine function of the adipose tissue has prompted the hypothesis that a genetic dysregulation of the adipokine network may contribute to the pathogenesis of insulin resistance and related disorders such as type 2 diabetes and cardiovascular disease. Of all the molecules that have been shown to be produced by the adipose tissue, adiponectin has drawn special attention, largely due to its effects on both insulin sensitivity and inflammation, and the fact that its expression and serum levels can be modulated by peroxisome proliferatoractivated receptor (PPAR)-␥ agonists drugs (Fig. 1). In this article, we will review the evidence that has been thus far gathered on the role of genetic variants in the adiponectin and adiponectin receptors genes as modulators of adiponectin-circulating levels and susceptibility to insulin resistance traits. We will also discuss the directions in which research on this topic is heading. ADIPONECTIN: A SALUTARY ADIPOKINEAdiponectin, also known as adipocyte complement-related protein 30 (Acrp30), gelatin-binding protein 28 (Gbp28), adipose most abundant transcript 1(apM1), or AdipoQ, is exclusively produced by adipocytes (3-6). It is abundantly present in serum, where it circulates in two higher-order forms: a low-molecular weight dimer of trimers and a larger high-molecular weight complex of 12-18 subunits (7). Serum levels are 15% higher in women than in men (8). Data from both animal and human studies indicate that adiponectin has insulin-enhancing as well as anti-inflammatory actions (rev. in 9). Adiponectin levels are markedly reduced in obese/diabetic mice, and injection of the adiponectin globular domain to these animals ameliorates ...

The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) [n = 49], P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28-7.0], P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.