FAMILIAL HYPERPROINSULINEMIA ASSOCIATED WITH NIDDM - A CASE-STUDY

OBJECTIVE - To report studies on an elderly patient with moderate NIDDM associated with marked fasting hyperinsulinemia. RESEARCH DESIGN AND METHODS - The propositus and several family members were studied by a combination of clinical, biochemical, and molecular genetic approaches to define the underlying genetic defect. RESULTS - Fasting levels of contrainsulin hormones were normal, and resistance to exogenous insulin was absent. Gel filtration and reverse-phase high-performance liquid chromatography revealed elevated amounts of a structurally abnormal proinsulin intermediate (AC proinsulin). A study of the family of the propositus showed the same abnormality in 4 of 5 members in 3 successive generations. Genetic analysis revealed a point mutation affecting residue 65 of human proinsulin (Arg-His) in one allele of the insulin gene in the propositus, a defect similar to that described previously in 3 other apparently unrelated lineages. CONCLUSIONS - This family exhibits a clear-cut relationship between increasing age and metabolic decompensation in all the hyperproinsulinemic members, suggesting that (inherited) metabolic stress and age both contribute to development of diabetes mellitus.