Familial hyperinsulinemia due to a structurally abnormal insulin: Definition of an emerging new clinical syndrome.

Abstract We have identified a patient with mild diabetes, marked fasting hyperinsulinemia (89 to 130 μU of insulin per milliliter), and a reduced fasting C-peptide: insulin molar ratio of 1.11 to 1.50 (normal, >4). The patient responded normally to exogenous insulin. However, her endogenous immunoreactive insulin showed reduced biologic activity during a glucose-clamp study with hyperglycemia and a reduced ability to bind to the insulin receptor and stimulate glucose transport in vitro. Family studies showed that five additional relatives in three generations had variable degrees of glucose intolerance, marked hyperinsulinemia, and a reduced peripheral C-peptide:insulin molar ratio. Restriction-endonuclease cleavage of DNA isolated from circulating leukocytes in the patient and in family members with hyperinsulinemia revealed loss of the Mboll recognition site in one allele of the insulin gene — consistent with a point mutation at position 24 or 25 in the insulin B chain. Other studies using high-pressure...