Altered Insulin Secretory Responses to Glucose in Diabetic and Nondiabetic Subjects With Mutations in the Diabetes Susceptibility Gene MODY3 on Chromosome 12

Abstract

One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject 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. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels <8 mmol/l. As glucose rose above this level, however, the increase in insulin secretion in these subjects was significantly reduced. Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5–9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects. In conclusion, in nondiabetic MODY3 subjects insulin secretion demonstrates a diminished ability to respond when blood glucose exceeds 8 mmol/l. The priming effect of glucose on insulin secretion is preserved. Thus, β-cell dysfunction is present before the onset of overt hyperglycemia in this form of MODY. The defect in insulin secretion in the nondiabetic MODY3 subjects differs from that reported previously in nondiabetic MODY1 or mildly diabetic MODY2 subjects.