Etiology of Early-Onset Type 2 Diabetes in Indians: Islet Autoimmunity and Mutations in Hepatocyte Nuclear Factor 1α and Mitochondrial Gene

Abstract

Abstract Context: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available. Objective: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1α (HNF1α) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology. Design: This was an observational cohort study. Setting: The setting was an outpatient diabetes clinic in a teaching hospital. Patients: Ninety-six consecutive young patients with T2DM (onset, ≤30 yr) were included in the study. Interventions: Glutamic acid decarboxylase and insulinoma antigen 2 antibodies, mitochondrial A3243G mutation, and the common HNF1α mutation P291fsinsC were measured in all patients. The entire HNF1α gene was studied for mutations in 32 subjects with onset less than 25 yr or with normal weight. The common HNF1α A98V polymorphism was studied in 91 patients. Results: The patients were clinically heterogeneous, with 42% having a normal body mass index. Glutamic acid decarboxylase antibodies were present in three (3%) subjects and mitochondrial A3243G mutation in one (1%) subject. The P291fsinsC mutation was not detected in any patient. A MODY3 mutation (R200W) was detected in one patient (3%). In this family, diabetes cosegregated with the R200W mutation in the proband and his youngest brother but not in three paternal uncles. The Val 98 allele was associated with T2DM (allele frequency, 0.14 vs. 0.03 in controls; odds ratio, 5.2; P < 0.001). Conclusions: Despite a significant proportion of young Indian patients with T2DM having normal weight, islet autoimmunity, A3243G mitochondrial, and HNF1α gene mutations were infrequent.