Mutations in the insulin receptor gene are known to be a cause of some rare forms of extreme insulin resistance. The relevance of mutations in the insulin receptor gene as well as other candidate genes in the pathogenesis of the more common aging-related type II diabetes mellitus are currently unknown. Leading on from our report last year we studied two amino acid substitutions in IRS-1 in Pima indians, a minority population at risk for NIDDM. These substitutions had been associated with NIDDM in a Danish population. Neither, substitution was observed in 242 diabetic or 190 nondiabetic Pima indians. We then looked for other mutations in IRS-1.