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| ALTERED INSULIN SECRETORY RESPONSES TO GLUCOSE IN SUBJECTS WITH A MUTATION IN THE MODY1 GENE ON CHROMOSOME-20 |
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| Author(s): BYRNE MM, STURIS J, FAJANS SS, ORTIZ FJ, STOLTZ A, STOFFEL M, SMITH MJ, BELL GI, HALTER JB, POLONSKY KS |
| Source: DIABETES Volume: 44 Issue: 6 Pages: 699-704 Published: JUN 1995 |
| Times Cited: 96 References: 24 |
| 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 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 tvas significantly blunted in the marker-positive subjects (13 +/- 4 vs, 68 +/- 8 pmol . min(-1)mmol(-1). l, P < 0.0001), The reduced insulin secretory responses in the marker-positive subjects were most evident at higher plasma glucose concentrations > 7 mmol/l, and differences between the two groups were not significant at lower glucose levels between 5 and 7 mmol/l, After a 42-h glucose infusion, the amount of insulin secreted over the glucose concentration range 5-9 mmol/l increased by 54 +/- 16% in the marker-negative subjects, This priming effect of glucose on insulin secretion was not seen in 9 of the 10 marker-positive 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/l, 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 beta-cell dysfunction different from the defect in MODY subjects with glucokinase mutations. |
| Document Type: Article |
| Language: English |
| Reprint Address: BYRNE, MM (reprint author), UNIV CHICAGO, DEPT MED, 5841 S MARYLAND AVE, MC 1027, CHICAGO, IL 60637 USA |
Addresses:
1. UNIV CHICAGO, DEPT BIOCHEM & MOLEC BIOL, CHICAGO, IL 60637 USA
2. UNIV CHICAGO, HOWARD HUGHES MED INST, CHICAGO, IL 60637 USA
3. UNIV CHICAGO, PRITZKER SCH MED, CHICAGO, IL 60637 USA
4. UNIV MICHIGAN, MED CTR, DEPT INTERNAL MED, ANN ARBOR, MI 48109 USA
5. DEPT VET AFFAIRS MED CTR, ANN ARBOR, MI USA |
| Publisher: AMER DIABETES ASSOC, 1660 DUKE ST, ALEXANDRIA, VA 22314 |
| Subject Category: Endocrinology & Metabolism |
| IDS Number: RB888 |
| ISSN: 0012-1797 |
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