FOXC2 and CAPN10 as candidate genes for obesity, insulin resistance and type 2 diabetes

Abstract: The worldwide prevalence of obesity and type 2 diabetes is increasing rapidly. Both disorders depend on genetic and environmental factors. The studies included in this thesis investigated the possible association of the FOXC2 and CAPN10 genes with obesity, insulin resistance, type 2 diabetes, and related phenotypes. FOXC2 encodes a forkhead transcription factor, which was identified as a key regulator of adipocyte metabolism in mice overexpressing FOXC2 in adipose tissue. The exact function of FOXC2 in humans remains unknown. FOXC2 mRNA levels in both visceral fat and skeletal muscle correlated with measures of insulin sensitivity and FOXC2 mRNA expression was significantly higher in visceral compared to subcutaneous fat in humans. FOXC2 mRNA levels were upregulated in response to insulin in cultured human adipocytes. A common variant in the 5' untranslated region of the gene (C-512T) was identified. The C-allele was associated with higher triglyceride levels and higher HOMA-IR indeces in female sibling pairs as well as with obesity, and the Metabolic Syndrome in males. However, no association was found between this polymorphism and type 2 diabetes. CAPN10, encoding the cysteine protease calpain-10, was the first type 2 diabetes susceptibility gene discovered by a genome-wide scan and positional cloning. We found that CAPN10 mRNA expression is a heritable trait. Furthermore, a polymorphism in the gene (SNP-43) was associated with reduced CAPN10 mRNA levels in both subcutaneous fat and skeletal muscle. Subjects with normal glucose tolerance, but not subjects with impaired glucose tolerance, upregulated CAPN10 mRNA levels in response to fat during a hyperinsulinemic euglycemic clamp. These results suggest that the C-allele at FOXC2 C-512T and low FOXC2 mRNA expression predispose individuals to obesity and insulin resistance but not to type 2 diabetes. CAPN10 mRNA expression is a heritable trait and influenced by variation at SNP-43. Although CAPN10 SNP-43 is not associated with obesity, low CAPN10 mRNA expression, or inability to upregulate CAPN10 mRNA levels in response to elevated FFA and insulin, may predispose towards insulin resistance and type 2 diabetes.