OBJECTIVE-Serum retinol binding protein 4 (RBP4) is a new liver-and adipocyte-derived signal that may contribute to insulin resistance. Therefore, the RBP4 gene represents a plausible candidate gene involved in susceptibility to type 2 diabetes.RESEARCH DESIGN AND METHODS-In this study, the RBP4 gene was sequenced in DNA samples from 48 nonrelated Caucasian subjects. Five novel and three known single nucleotide polymorphisms (SNPs) were identified. Furthermore, five recently reported SNPs were genotyped in 90 subjects. Six SNPs, representative of their linkage disequilibrium groups, were then genotyped in 934 diabetic and 716 nondiabetic subjects. RESULTS-A haplotype of six common SNPs (A-G-G-T-G-C)was significantly increased in 934 case subjects with type 2 diabetes compared with 537 healthy control subjects with normal glucose tolerance (P ϭ 0.02; odds ratio 1.37 [95% CI 1.05-1.79]). Furthermore, in the cohort of 716 nondiabetic Caucasian subjects, carriers of the A-G-G-T-G-C haplotype had significantly higher mean fasting plasma insulin and 2-h plasma glucose than subjects without the haplotype. Two single SNPs (rs10882283 and rs10882273) were also associated with BMI, waist-to-hip ratio, and fasting plasma insulin, and several SNPs were associated with circulating free fatty acids (all adjusted P Ͻ 0.05). In addition, subjects carrying a previously reported diabetes-associated haplotype had significantly higher mRNA levels in visceral adipose tissue (adjusted P Ͻ 0.05) in a subgroup of nondiabetic subjects (n ϭ 170) with measurements of RBP4 mRNA expression in visceral and subcutaneous fat depots. CONCLUSIONS-Our data indicate a role of RBP4 genetic variation in susceptibility to type 2 diabetes and insulin resistance, possibly through an effect on RBP4 expression. Diabetes 56:3095-3100, 2007 S erum retinol binding protein 4 (RBP4) is a new adipocyte-derived signal linking adipose tissue dysfunction to systemic insulin resistance and thereby likely contributing to the pathogenesis of type 2 diabetes. Serum RBP4 is elevated in insulin-resistant mice, as well as in humans, with obesity and type 2 diabetes and can be normalized by insulin-sensitizing drugs (1). Moreover, RBP4 serum levels highly correlate with the degree of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes, as well as in nonobese subjects with family history of type 2 diabetes (2). Recently, we found increased RBP4 mRNA expression in visceral compared with subcutaneous adipose tissue and serum RBP4 concentrations correlated with RBP4 mRNA expression, intra-abdominal fat mass, total body fat mass, A1C, and insulin resistance (3).RBP4 is encoded by the RBP4 gene, which maps to chromosome 10q23-q24, a region that has been linked to increased risk for type 2 diabetes in different populations (4,5). Despite known physiology as well as chromosomal location, to date, very few studies on the effects of genetic variation in the RBP4 gene on increased metabolic risk in humans have been reported (6,7). We therefor...

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