Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Laurie Wideman, Safrit-Ennis Distinguished Professor (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
Abstract: Diabetes resulting from heterozygosity for an inacti¬vating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of ß-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 • kg-1 • 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 ß-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of ß-cell dysfunction. Diabetes 49:1856–1864, 2000
Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).
PDF (Portable Document Format)
814 KB
Created on 1/1/2000
Views: 2228
Additional Information
- Publication
- Diabetes 49: 1856-1864.
- Language: English
- Date: 2000
- Keywords
- Diabetes