Diabetes Complications in NIDDM Kindreds Linked to the MODY3 Locus on Chromosome 12q

Abstract

OBJECTIVE To assess the prevalence of diabetes complications and the severity of diabetes in kindreds with NIDDM linked to the MODY3 locus (chromosome 12q) and to compare these parameters with data obtained in glucokinase (GCK)-deficient and other-MODY (unlinked to any of the three known loci) families, as well as with data from families with a late age of onset of NIDDM. RESEARCH DESIGN AND METHODS Clinical and biological data were obtained from 667 affected members of 7 MODY3, 25 GCK-deficient, 6 other-MODY, and 81 NIDDM families. Severity of diabetes (glucose tolerance status and insulin secretion) was assessed by an oral glucose tolerance test. Neurological examination and eye fundus examination were performed in 349 and 251 subjects, respectively, and proteinuria was tested with strips in 282 family members. RESULTS A higher prevalence of proliferative retinopathy was observed in MODY3 (21%) and NIDDM subjects (23%) than in GCK-deficient (3%) and other-MODY subjects (8%; P = 0.004). Proteinuria was detected in 19, 7, 5, and 0% (P = 0.07) of subjects, respectively. Prevalence of neuropathy was higher in NIDDM (17%; P = 0.005) than in MODY3 (4%), GCK-deficient (5%) and other-MODY (0%) subjects. MODY3 and NIDDM subjects had significantly higher fasting glucose levels than subjects in the other groups. Glucose levels after 2 h were significantly higher, and the ratios of insulin to glucose levels were significantly lower in MODY3 subjects than in the other three groups. CONCLUSIONS The MODY3 subtype of NIDDM is characterized by a severe insulin secretory defect and by major hyperglycemia that progresses rapidly to overt diabetes. Microvascular complications of diabetes were frequently observed in the MODY3 subjects and the subjects with a late age of onset of NIDDM in this cohort. Both the duration and the severity of diabetes were independently associated with these complications.