The regulatory G-subunit of the glycogen-associated form of protein phosphatase 1 (PP1) plays a crucial part in muscle tissue glycogen synthesis and breakdown. As impaired insulin stimulated glycogen synthesis in peripheral tissues is considered to be a pathogenic factor in subsets of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, the G-subunit of PP1 should be viewed as a candidate gene for inherited insulin resistance. When applying heteroduplex formation analysis and nucleotide sequencing of PP1G-subunit cDNA from 30 insulin resistant white NIDDM patients two cases were identified as heterozygous carriers of an Asp905 --> Tyr substitution. The carrier prevalence of the PP1G-subunit variant was 18% in 150 healthy subjects and 13% in 313 NIDDM subjects (chi 2 = 1.94, p = 0.16). Twenty-seven healthy subjects volunteered for a 4 h euglycaemic, hyperinsulinaemic clamp in combination with indirect calorimetry in order to elucidate the potential impact of the Tyr905 substitution on the whole body glucose metabolism. Interestingly, the Tyr905 variant was associated with altered routing of glucose: a decreased insulin stimulated non-oxidative glucose metabolism of peripheral tissues (glycogen synthesis) (p < 0.04) and an increased basal glucose oxidation rate (p < 0.04) when compared with wild type carriers. A population-based sample of 380 unrelated young healthy Caucasians was examined during a combined intravenous glucose and tolbutamide test to address whether the Asp905/Tyr905 polymorphism was associated with alterations in insulin secretion which might be secondary to the insulin resistance of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)