Previous studies on the type-1 serine/threonine protein phosphatase (PP-1) activity in skeletal muscle from fasted subjects indicated increased amounts of activity in insulin-sensitive individuals, but increased protein amounts in insulin-resistant subjects. New isoforms of PP-1 have been cloned from muscle cDNA suggesting that PP-1 activity may be a composite of several proteins. Mutations in the coding regions of the skeletal muscle PP-1 isoforms could explain the activity and enzyme content differences. Currently, the genes for the skeletal muscle protein phosphatase isoforms are being characterized. The genomic clones for these genes are being analyzed and suitable PCR primer pairs chosen from the non-coding regions that will allow amplification of PP-1 coding regions. The coding regions of these genes are being examined in insulin- sensitive and -resistant persons for single stranded conformational polymorphisms (SSCP). SSCPs that relate to amino acid changes will be further tested for a relationship to insulin resistance and type II diabetes. At this time SSCP analysis has been completed on 40 subjects for 6 exons from PP-1 gamma-1. This covers 95% of the coding sequence. No sequence abnormalities were observed which were uniquely associated with insulin resistance.