GENETIC-ANALYSIS OF HUMAN TYPE-1 PROTEIN PHOSPHATASE INHIBITOR-2 IN INSULIN-RESISTANT PIMA-INDIANS

The rate-limiting enzyme in insulin-mediated nonoxidative glucose disp osal, glycogen synthase, has reduced activity in insulin-resistant sub jects at risk for developing non-insulin-dependent diabetes mellitus ( NIDDM). The synthase-activating enzyme, type 1 protein phosphatase (PP 1), also has an abnormally low level of activity, Inhibitor 2 (I-2) re versibly inhibits and facilitates the proper conformation of free cata lytic subunits of PPI. This study investigates whether genetic alterat ion(s) in the I-2 coding locus (PPP1R2) could contribute to insulin re sistance in Pima Indians. We determined that the authentic PPP1R2 gene is located on chromosome 3q29 and consists of six exons. The previous ly reported homologue of PPP1R2 on chromosome 5 is identified as all i ntronless pseudogene, Comparative sequencing of PPP1R2 exons and splic e junctions revealed no mutations in insulin-resistant Pima Indians. T he information on the genomic structure of PPP1R2 is important for exp loring this gene as a potential candidate contributing to insulin resi stance and NIDDM in other populations. (C) 1997 Academic Press.