ABNORMAL INSULIN-SECRETION, NOT INSULIN-RESISTANCE, IS THE GENETIC ORPRIMARY DEFECT OF MODY IN THE RW PEDIGREE

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-d ependent diabetes mellitus (NIDDM) associated with autosomal-dominant inheritance. In the RW pedigree, MODY is associated with polymorphic D NA markers on chromosome 20q. To determine the early abnormalities of insulin action and insulin secretion in MODY, we studied nondiabetic m embers of the RW pedigree with and without the gene marker. Six nondia betic marker-negative and 5 nondiabetic marker-positive members of the RW pedigree were studied, as were 4 diabetic marker-positive family m embers. Unrelated, young, healthy subjects served as comparison groups . insulin action and insulin secretion were assessed with a frequently sampled intravenous glucose tolerance test. Insulin secretion was fur ther assessed during constant glucose infusion by deconvolution of pla sma C-peptide and by pulse analysis. The nondiabetic marker-positive g roup had normal sensitivity to insulin and unimpaired acute insulin re sponse to intravenous glucose (AIR(glu)). However, the nondiabetic mar ker-positive group had decreased mean plasma C-peptide concentration a nd reduced absolute amplitude of insulin secretory oscillations during prolonged glucose infusion. These responses to prolonged glucose infu sion were similar to those observed in the diabetic group. No alterati ons of insulin secretion were observed in the nondiabetic marker-negat ive family members. Deranged and deficient insulin secretion, and not insulin resistance, appears to be the genetic or primary abnormality t hat characterizes nondiabetic individuals who are predisposed to MODY in the RW pedigree. Prolonged glucose infusion studies may reveal qual itative and quantitative defects in insulin secretion not identified b y the AIR(glu). Use of the AIR(glu) may not be able to exclude a prima ry beta-cell defect in the pathogenesis of NIDDM.