Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20

• Published in: Diabetes (New York, N.Y.) Vol. 44; no. 6; pp. 699 - 704
• Main Authors: BYRNE, M. M, STURIS, J, FAJANS, S. S, ORTIZ, F. J, STOLZ, A, STOFFEL, M, SMITH, M. J, BELL, G. I, HALTER, J. B, POLONSKY, K. S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.1995
• Subjects: Adult; Biological and medical sciences; Blood Glucose - analysis; Chromosome abnormalities; Chromosomes, Human, Pair 20 - genetics; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Family; Female; Genes - genetics; Genetic aspects; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin Secretion; Male; Medical sciences; Mutation; Pancreatic beta cells; Physiological aspects; Type 2 diabetes; Endocrinopathy; Human; Maturity onset diabetes young; Pancreatic hormone; Chromosome 20; Glucose; Mutation; Insulin; Endocrine secretion
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.44.6.699

This study was undertaken to test the hypothesis that the diabetes susceptibility gene on chromosome 20q12 responsible for maturity-onset diabetes of the young (MODY) in a large kindred, the RW family, results in characteristic alterations in the dose-response relationships between plasma glucose concentration and insulin secretion rate (ISR) that differentiate this form of MODY from MODY in subjects with glucokinase mutations. Ten marker-positive subjects and six matched nondiabetic marker-negative subjects from the RW family received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the beta-cell to secrete more insulin in response to glucose. ISR was derived by deconvolution of peripheral C-peptide levels. Basal glucose and insulin levels were similar in marker-negative and marker-positive groups (5.3 +/- 0.2 vs. 5.0 +/- 0.2 mmol/l, P > 0.2, and 86.1 +/- 3.9 vs. 63.7 +/- 12.1 pmol/l, P > 0.1, respectively). However, the marker-positive subjects had defective insulin secretory responses to an increase in plasma glucose concentrations. Thus, as the glucose concentration was raised above 7 mmol/l, the slope of the curve relating glucose and ISR was significantly blunted in the marker-positive subjects (13 +/- 4 vs. 68 +/- 8 pmol.min-1.mmol-1 x 1, P < 0.0001).