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

Abstract

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes 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 mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp 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 x kg(-1) x min(-1)). Fasting plasma glucose 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 both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented 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 during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.

• Authors: A R Clocquet, J M Egan, D A Stoffers, D C Muller, L Wideman, G A Chin, W L Clarke, J B Hanks, J F Habener, D Elahi
• Journal: Diabetes (Diabetes) Vol. 49 Issue 11 Pg. 1856-64 (Nov 2000) ISSN: 0012-1797 [Print] United States
• PMID: 11078452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Blood Glucose
• C-Peptide
• Fatty Acids, Nonesterified
• Homeodomain Proteins
• Insulin
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein
• Glucagon

Topics

• Blood Glucose (analysis, metabolism)
• C-Peptide (blood)
• Diabetes Mellitus, Type 2 (genetics, physiopathology)
• Fasting
• Fatty Acids, Nonesterified (blood)
• Glucagon (blood)
• Glucose Clamp Technique
• Heterozygote
• Homeodomain Proteins
• Insulin (genetics, metabolism, pharmacology)
• Insulin Secretion
• Islets of Langerhans (drug effects, physiopathology)
• Kinetics
• Metabolic Clearance Rate
• Mutation
• Pancreas (growth & development)
• Pedigree
• Trans-Activators (genetics, physiology)