Abnormal Insulin Secretion, Not Insulin Resistance, Is the Genetic or Primary Defect of MODY in the RW Pedigree WILLIAM H. HERMAN, STEFAN S. FAJANS, FRANCISCO J. ORTIZ, MARLA J. SMITH, JEPPE STURIS, GRAEME I. BELL, KENNETH S. POLONSKY, AND JEFFREY B. HALTER Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) associated with autosomal-dominant inheritance. In the RW pedigree, MODY is associated with polymorphic DNA markers on chromosome 20q. To determine the early abnormalities of insulin action and insulin secretion in MODY, we studied nondiabetic members of the RW pedigree with and without the gene marker. Six nondiabetic marker-negative and 5 nondiabetic marker-positive members of the RW pedigree were studied, as were 4 diabetic marker-positive family members. 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 further assessed during constant glucose infusion by deconvolution of plasma C-peptide and by pulse analysis. The nondiabetic marker-positive group had normal sensitivity to insulin and unimpaired acute insulin response to intravenous glucose (AIR_ lu ). However, the nondiabetic marker-positive group had decreased mean plasma C-peptide concentration and reduced absolute amplitude of insulin secretory oscillations during prolonged glucose infusion. These responses to From the Department of Internal Medicine, University of Michigan Medical Center (W.H.H., S.S.F., F.J.O., M.J.S., J.B.H.) and the Department of Veterans Affairs Medical Center (F.J.O., M.J.S., J.B.H.), Ann Arbor, Michigan; and the Department of Medicine (J.S., K.S.P.) and The Howard Hughes Medical Institute (G.I.B.), University of Chicago, Chicago, Illinois. Address correspondence and reprint requests to Dr. Stefan S. Fajans, Division of Endocrinology and Metabolism, 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, Ml 48109-0354. Received for publication 17 December 1992 and accepted in revised form 26 August 1993. MODY, maturity-onset diabetes of the young; NIDDM, non-insulin-depen- dent diabetes mellitus; ADA, adenosene deaminase; OGTT, oral glucose tolerance test; GM, Human Genetic Mutant Cell Repository; FSIVGTT, fre- quently sampled intravenous glucose tolerance test; BMI, body mass index; FPG, fasting plasma glucose; S,. insulin sensitivity index; SG, glucose effectiveness; Kg, rate of glucose disappearance; AIR, acute insulin re- sponse; AIRglu, acute insulin response to glucose; ISR, insulin secretion rate; CV, coefficient of variation; RIA, radioimmunoassay; ANOVA, analysis of variance. prolonged glucose infusion were similar to those observed in the diabetic group. No alterations of insulin secretion were observed in the nondiabetic marker-negative family members. Deranged and deficient insulin secretion, and not insulin resistance, appears to be the genetic or primary abnormality that characterizes nondiabetic individuals who are predisposed to MODY in the RW pedigree. Prolonged glucose infusion studies may reveal qualitative and quantitative defects in insulin secretion not identified by the AIR glu . Use of the AIR glu may not be able to exclude a primary p-cell defect in the pathogenesis of NIDDM. Diabetes 43:40-46, 1994 M aturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) that is characterized by onset in childhood, adolescence, or young adult life and is associated with autosomal-dominant inheritance (1). The RW pedigree, which includes >350 individuals from five generations and 69 subjects with diabetes, has been studied prospectively for 35 years (1,2). Because of the high prevalence of fasting hyper- glycemia, insulin requirements, and chronic complica- tions, the clinical characteristics of patients with MODY in this pedigree are similar to the more common forms of NIDDM (1,2). Studies of this pedigree have demon- strated linkage between MODY and polymorphic DNA markers on chromosome 20q. The tightest linkage of the gene responsible for MODY in the RW pedigree is with the adenosene deaminase (ADA) gene (3,4) and the D20S16 locus (5,6). The ADA gene and the D20S16 locus are closely linked on chromosome 20q. Thus, DNA typing for genetic markers now allows identification of nondiabetic members of the RW pedigree who are at risk for the development of diabetes. Controversy exists as to whether the genetic or primary abnormality in various types of NIDDM is insulin resis- 40 DIABETES, VOL. 43, JANUARY 1994 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/43/1/40/360340/43-1-40.pdf by guest on 01 January 2022