Obesity and
insulin resistance have been recognized as leading causes of major health issues. We have endeavored to depict the molecular mechanism of
insulin resistance, focusing on the function of adipocyte. We have investigated a role of
PPARgamma on the pathogenesis of Type II diabetes. Heterozygous
PPARgamma-deficient mice were protected from the development of
insulin resistance due to adipocyte
hypertrophy under a high-fat diet. Moreover, a Pro12Ala polymorphism in the human
PPARgamma2 gene was associated with decreased risk of Type II diabetes in Japanese. Taken together with these results,
PPARgamma is proved to be a thrifty gene mediating Type II diabetes. Pharmacological inhibitors of
PPARgamma/RXR ameliorate high-fat diet-induced
insulin resistance in animal models of Type II diabetes. We have performed a genome-wide scan of Japanese Type 2 diabetic families using affected sib pair analysis. Our genome scan reveals at least 9 chromosomal regions potentially harbor susceptibility genes of Type II diabetes in Japanese. Among these regions, 3q26-q28 appeared to be very attractive one, because of the gene encoding
adiponectin, the expression of which we had found enhanced in
insulin-sensitive
PPARgamma-deficient mice. Indeed, the subjects with the G/G genotype of SNP276 in the
adiponectin gene were at increased risk for Type II diabetes compared with those having the T/T genotype. The plasma
adiponectin levels were lower in the subjects with the G allele, suggesting that genetically inherited decrease in
adiponectin levels predispose subjects to
insulin resistance and Type II diabetes. Our work also confirmed that replenishment of
adiponectin represents a novel treatment strategy for
insulin resistance and Type II diabetes using animal models. Further investigation will be needed to clarify how
adiponectin exerts its effect and to discover the molecular target of
therapies.