title: 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.affiliation: Geriatric Research Laboratory, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Clocquet
authors.forename: J M
authors.initials: JM
authors.lastname: Egan
authors.forename: D A
authors.initials: DA
authors.lastname: Stoffers
authors.forename: D C
authors.initials: DC
authors.lastname: Muller
authors.forename: L
authors.initials: L
authors.lastname: Wideman
authors.forename: G A
authors.initials: GA
authors.lastname: Chin
authors.forename: W L
authors.initials: WL
authors.lastname: Clarke
authors.forename: J B
authors.initials: JB
authors.lastname: Hanks
authors.forename: J F
authors.initials: JF
authors.lastname: Habener
authors.forename: D
authors.initials: D
authors.lastname: Elahi
mesh_terms: D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D006579:Heterozygote; D018398:Homeodomain Proteins; D007328:Insulin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology; D007700:Kinetics; D008657:Metabolic Clearance Rate; D009154:Mutation; D010179:Pancreas / Q000254:growth & development; D010375:Pedigree; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon