As insulin resistance and NIDDM may both have a genetic basis, we are searching systematically for the involvement gene(s) using sib-pair linkage analyses of evenly spaced microsatellite markers in the Pima Indians of the Gila River Indian Community, a population with the highest known prevalence of this disease. Previously, we found evidence for linkage and association of insulin resistance and NIDDM with a cluster of microsatellite markers within a 2-3 cM genomic segment at the 7q21.3 - q22.1 chromosomal band. Based on these findings we concluded that there could be a gene in the region 7q21.3 - q22.1 contributing to diabetes susceptibility. Subsequent analysis of candidate genes within this interval, including a novel isoform of pyruvate dehydrogenase kinase (PDK4) did not reveal any genetic abnormalities in affected Pima Indians. However, recent analysis of all genotyped markers on chr.7 using a statistically more powerful multi-point sib-pair method, as well as a parametric (LOD score) analysis revealed the most consistent linkage of insulin action and NIDDM within markers within the 7q31 region. Recently, we have mapped to this segment the PPP1R3 gene encoding the glycogen-targeting subunit of type-1 protein phosphatase that regulates glycogen synthesis in skeletal muscle. Furthermore, we found a polymorphism in this gene that seems to contribute to insulin resistance and NIDDM in the Pima Indians (see project #Z01DK 69058).
