Adiponectin Receptor 1 Gene (ADIPOR1) as a Candidate for Type 2 Diabetes and Insulin Resistance

Adiponectin Receptor 1 Gene ( ADIPOR1 ) as a Candidate for Type 2 Diabetes and Insulin Resistance Hua Wang 1 , Hailing Zhang 1 , Yiwen Jia 1 , Zhengxian Zhang 1 , Rebekah Craig 1 , Xiaoqin Wang 1 and Steven C. Elbein 1 2 1 Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 2 Endocrinology Section, Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas Address correspondence and reprint requests to Steven C. Elbein, MD, Professor of Medicine, Central Arkansas Veterans Healthcare System, Endocrinology 111J/LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: elbeinstevenc{at}uams.edu Abstract Considerable data support adiponectin as an important adipose-derived insulin sensitizer that enhances fatty acid oxidation and alters hepatic gluconeogenesis. Adiponectin acts by way of two receptors, ADIPOR1 and ADIPOR2. ADIPOR1 is widely expressed in tissues, including muscle, liver, and pancreas, and binds the globular form of adiponectin with high affinity. To test the hypothesis that sequence variations in or near the ADIPOR1 gene contribute to the risk of developing type 2 diabetes and the metabolic syndrome, we screened the eight exons (including the untranslated exon 1) of the ADIPOR1 gene with flanking intronic sequences and the 5′ and 3′ flanking sequences. We identified 22 single nucleotide polymorphisms (SNPs) in Caucasian and African-American subjects, of which a single nonsynonymous SNP (N44K) in exon 2 was present only in African-American subjects. We typed 14 sequence variants that had minor allele frequencies >5%. No SNP was associated with type 2 diabetes in Caucasians or African Americans, and no SNP was a determinant of insulin sensitivity or insulin secretion among nondiabetic members of high-risk Caucasian families. However, the two alleles of a SNP in the 3′ untranslated region were expressed unequally, and ADIPOR1 mRNA levels were significantly lower among transformed lymphocytes from diabetic African-American individuals than among control cell lines. This altered gene expression might suggest a role for ADIPOR1 in the metabolic syndrome. LD, linkage disequilibrium SNP, single nucleotide polymorphism Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted April 23, 2004. Received March 4, 2004. DIABETES