The -8503 G/A polymorphism of the adiponectin receptor 1 gene is associated with insulin sensitivity dependent on adiposity.

Adiponectin has beneficial effects on insulin sensitivity. Unexpectedly, adiponectin knockout mice exhibit no or only mild insulin resistance. Nevertheless, under a high-fat/high-carbohydrate diet, severe insulin resistance was induced in those animals (1). Consistent with this, recent evidence (2) suggests that the relationship of adiponectin with insulin sensitivity is stronger with increasing adiposity. In addition, a haplotype in the adiponectin gene was associated with type 2 diabetes only in obese and morbidly obese subjects but not in lean subjects (3). Single nucleotide polymorphisms (SNPs) of the genes encoding adiponectin receptor (ADIPOR) 1 and 2 were associated with type 2 diabetes (4) or prediabetes phenotypes (5) in some but not in all (6) studies. We found that the 8503 G/A SNP of the ADIPOR1 gene was associated with insulin sensitivity (7). In a very recent study (6) in rather lean subjects with a mean BMI of 21 kg/m, no associations with insulin sensitivity were found. In our study (7), subjects were more obese (BMI 26 kg/m). This new information lead us to investigate whether the association of the 8503 G/A SNP of ADIPOR1 with insulin sensitivity is modulated by adiposity. If this was the case, then this may partly explain the inconsistent results regarding SNPs of ADIPOR1 and 2. Recently reported data (7) from 502 nondiabetic Caucasians were analyzed. Insulin sensitivity was estimated from an oral glucose tolerance test and determined during a euglycemic-hyperinsulinemic clamp (n 299). Subjects were divided into two groups by the median percentage of body fat (PFAT). In the more obese group (n 250, PFAT 27– 55%), carriers of the 8503 A allele had lower insulin sensitivity estimated from the oral glucose tolerance test using the formula proposed by Matsuda and DeFronzo (8) (G/G, G/A, and A/A: 14.4 0.8, 11.9 0.9, and 9.2 1.7 arbitrary units, respectively, P 0.003, ANOVA) and determined during the clamp (0.07 0.005, 0.06 0.005, and 0.04 0.01 mol kg 1 min 1 pmol/l , respectively, P 0.007) compared with homozygous carriers of the G allele, independent of age, sex, and PFAT. In contrast, in the lean group (n 252, PFAT 7–26%), no significant relationships were found (oral glucose tolerance test: 24.6 1.0, 27.2 1.1, and 23.0 2.4, respectively, P 0.60; clamp: 0.13 0.006, 0.13 0.007, and 0.12 0.016, respectively, P 0.84). In summary, we show that the A allele of the 8503 G/A SNP of the ADIPOR1 gene is associated with less insulin sensitivity only in more obese but not in lean individuals. This finding may be important for further studies on the relationships of genetic variants of ADIPOR1 and possibly of ADIPOR2 with metabolism.