Glycogen-associated type 1 protein phosphatase (PP1) activity is determined by an isoform of the catalytic subunit complexed with the glycogen-targeting regulatory subunit encoded by the PPP1R3 gene that we mapped to chromosome 7q. Biochemical abnormalities of skeletal muscle PP1 correlate with insulin resistance in the Pima Indians, and we have recently found a common variant in the 3 untranslated region (3UTR) of PPP1R3 that causes decreased expression of this subunit in these subjects. The 3UTR polymorphism is associated with insulin resistance and type 2 diabetes, and correlated with variations in PPP1R3 expression. We have also determined that this region of PPP1R3 mRNA is involved in the binding of mRNA-destabilizing proteins, and that the polymorphism further modulates the relative binding of these factors. We hypothesize that this molecular mechanism may explain the contribution of PPP1R3 to insulin resistance and diabetes in the Pimas. This project has been terminated. - Pima Indians, insulin resistance, type 1 protein phosphatase, glycogen targeting subunit expression - Human Subjects
