Genetic Analysis of Human Type 1 Protein Phosphatase Inhibitor 2 in Insulin-Resistant Pima Indians

The rate-limiting enzyme in insulin-mediated nonoxidative glucose disposal, glycogen synthase, has reduced activity in insulin-resistant subjects at risk for developing non-insulin-dependent diabetes mellitus (NIDDM). The synthase-activating enzyme, type 1 protein phosphatase (PP1), also has an abnormally low level of activity. Inhibitor 2 (I-2) reversibly inhibits and facilitates the proper conformation of free catalytic subunits of PP1. This study investigates whether genetic alteration(s) in the I-2 coding locus (PPP1R2) could contribute to insulin resistance in Pima Indians. We determined that the authenticPPP1R2gene is located on chromosome 3q29 and consists of six exons. The previously reported homologue ofPPP1R2on chromosome 5 is identified as an intronless pseudogene. Comparative sequencing ofPPP1R2exons and splice junctions revealed no mutations in insulin-resistant Pima Indians. The information on the genomic structure ofPPP1R2is important for exploring this gene as a potential candidate contributing to insulin resistance and NIDDM in other populations.