Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree

• Published in: Diabetes (New York, N.Y.) Vol. 43; no. 1; pp. 40 - 46
• Main Authors: HERMAN, W. H, FAJANS, S. S, ORTIZ, F. J, SMITH, M. J, STURIS, J, BELL, G. I, POLONSKY, K. S, HALTER, J. B
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 1994
• Subjects: Adolescent; Adult; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Child; Chromosomes, Human, Pair 20; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Genetic Markers; Glucose Tolerance Test; Humans; Insulin - metabolism; Insulin Resistance - physiology; Insulin Secretion; Male; Medical sciences; Pancreas; Pancreatic secretions; Pedigree; Polymorphism, Genetic; Secretions; Sex Factors; Tolbutamide; Type 2 diabetes; Endocrinopathy; Genetic mapping; Human; Maturity onset diabetes young; Pancreatic hormone; Family study; Insulin; Biological activity; Protein hormone; F20-Chromosome; Predisposition; Diagnosis; Hormonal investigation
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.43.1.40

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 (AIRglu). 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 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.