Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes

OBJECTIVE - To investigate whether there are forms of early-onset autosomal -dominant type 2 diabetes that are distinct from typical maturity-onset dia betes of the young (MODY) and to characterize their phenotypic characterist ics. RESEARCH DESIGN AND METHODS - The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple gene rations and was not linked to known MODY genes (MODY gene-negative families ). All individuals underwent an oral glucose tolerance test and other clini cal measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carrie rs of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were simila rly examined. RESULTS - Subjects from MODY gene-negative pedigrees were diagnosed with di abetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MOD Y gene-negative patients who were insulin treated required more exogenous i nsulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 . U . kg(-1) . day(-1), P = 0.04), despite similar C-peptide levels. Among subjects not t reated with insulin, MODY gene-negative subjects had significantly higher s erum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 mu U/ml, P = 0 .027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). Th ey also had higher serum triglycerides (P = 0.02), higher cholesterol level s (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.0 01). Differences persisted when families were matched for age at diagnosis. CONCLUSIONS - Our findings indicate the existence of forms of early-onset a utosomal-dominant type 2 diabetes that are distinct from MODY and are frequ ently characterized by insulin resistance, similar to later-onset type 2 di abetes. Because of the Mendelian pattern of inheritance, the goal of identi fying the genes involved in these forms of diabetes appears to be particula rly feasible.