Affiliation:
1. Departments of Medicine, The University of Chicago and Pritzker School of Medicine Chicago, Illinois
2. Department of Internal Medicine, University of Michigan Medical Center Ann Arbor, Michigan
3. Department of Veterans Affairs Medical Center Ann Arbor, Michigan
4. Biochemistry, and Molecular Biology and the Howard Hughes Medical Institute, The University of Chicago and Pritzker School of Medicine Chicago, Illinois
Abstract
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 β-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 · 1, P < 0.0001). The reduced insulin secretory responses in the marker-positive subjects were most evident at higher plasma glucose concentrations >7 mmol/1, and differences between the two groups were not significant at lower glucose levels between 5 and 7 mmol/1. After a 42-h glucose infusion, the amount of insulin secreted over the glucose concentration range 5–9 mmol/1 increased by 54 ± 16% in the markernegative subjects. This priming effect of glucose on insulin secretion was not seen in 9 of the 10 markerpositive subjects. In contrast, previous results in MODY subjects with glucokinase mutations showed persistence of the glucose-priming effect on ISR and continued increases, although subnormal, of ISR as plasma glucose concentration rises from 7–12 mmol/1. In conclusion, subjects from the RW family who have inherited the at-risk allele of the MODY1 gene appear to have a characteristic pattern of altered insulin secretory responses to glucose. These alterations are present before the onset of hyperglycemia, suggesting a unique mechanism of (β-cell dysfunction different from the defect in MODY subjects with glucokinase mutations.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
60 articles.
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