Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (Insulin promoter factor 1 gene)

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due t o a genetic defect of beta -cell function referred to as maturity-onset dia betes of the young 4, IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mut ation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clam p on seven heterozygous members (NM) and eight normal genotype members (NN) , During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol . kg(-1) . min(-1)). Fasting plasma glu cose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in bot h groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insul in and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with th e NN group, At a glucose level of 16.8 mmol/l above fasting level, GLP-1 au gmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell duri ng each glycemic plateau, and a further reduction occurred during the GLP-1 infusion, Sigmoidal dose-response curves of glucose clearance versus insul in levels during the hyperglycemic clamp in the two small groups showed bot h a left shift and a lower maximal response in the NM group compared with t he NN group, which is consistent with an increased insulin sensitivity in t he NM subjects, A sharp decline occurred in the dose-response curve for sup pression of nonesterified fatty acids versus insulin levels in the NM group . We conclude that the Pro63fsdelC IPF-1 mutation is associated with a seve re impairment of <beta>-cell sensitivity to glucose and an apparent increas e in peripheral tissue sensitivity to insulin and is a genetically determin ed cause of beta -cell dysfunction.