A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance

Previous linkage studies in Mexican-Americans localized a major susceptibil ity locus for type 2 diabetes, NIDDM1, to chromosome 2q. This evidence for linkage to type 2 diabetes was recently found to be associated with a commo n G->A polymorphism (UCSNP-43) within the CAPN10 gene. The at-risk genotype was homozygous for the UCSNP-43 G allele. In the present study among Pima Indians, the UCSNP-43 GIG genotype was nor associated with an increased pre valence of type 2 diabetes. However, Pima Indians with normal glucose toler ance, who have a G/G genotype at UCSNP-43, were found to have decreased rat es of postabsorptive and insulin-stimulated glucose turnover that appear to result from decreased rates of glucose oxidation. In addition, G/G homozyg otes were found to have reduced C4PN10 mRNA expression in their skeletal mu scle. A decreased rate of insulin-mediated glucose turnover, or insulin res istance, is one mechanism by which the polymorphism in CAPN10 may increase susceptibility to type 2 diabetes mellitus in older persons.