Insulin resistance is predictive of the development of non-insulin- dependent diabetes mellitus in Pima Indians, and this abnormality is associated with decreased rates of glycogen synthesis in skeletal muscle and of its regulatory enzyme complex, the glycogen-bound type protein phosphatase (PP1). Glycogen-associated PP1 activity is determined by an isoform of the catalytic subunit complexed with the glycogen-targeting regulatory (G) subunit, and structural alterations of either component could result in the biochemical abnormalities observed in insulin resistant Pimas. Three genetically distinct PP1 catalytic subunit isoforms are known (PP1 alpha, PP1 beta, and PP1 gamma). We have previously determined the exon-intron structure of the genes coding for PP1 alpha catalytic subunit (PPP1CA; 7 exons), PP1 beta (PPP1CB, 8 exons), PP1 gamma (PPP1CC, 7 exons), and PP1 regulatory G-subunit (PPP1R3, 4 exons), and we also positioned PPP1R3 on chromosome 7q. We have isolated polymorphic repeat markers at all PPP1 genes, and so far we have analyzed markers at PPP1CA and PPP1CB. We found no evidence for linkage of PPP1CA or PPP1CB with fasting insulin or insulin action in vivo and similar linkage analyses of repeat markers at PPP1CC and PPP1R3 are in progress.
