ALTERED INSULIN SECRETORY RESPONSES TO GLUCOSE IN SUBJECTS WITH A MUTATION IN THE MODY1 GENE ON CHROMOSOME-20

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.