Maturity-Onset Diabetes of the Young (MODY) Mutation in Type 2 Diabetes and Latent Autoimmune Diabetes of the Adult

Owen et al. (1) reported etiologic heterogeneity among 268 subjects with type 2 diabetes, of whom ∼10% had autoantibodies and ∼1% had mutations in HNF1A (MODY3) encoding hepatic nuclear factor-1α. We hypothesized that maturity-onset diabetes of the young (MODY) gene mutations would also be found in subjects with latent autoimmune diabetes of the adult (LADA) (2). We studied 37 Canadian subjects diagnosed with LADA (of whom 20 were female) and 54 control subjects with type 2 diabetes (of whom 28 were female). LADA was diagnosed when a type 2 diabetic patient concurrently had positive autoantibodies against GAD and/or the intracytoplasmatic domain of tyrosine phosphatase–like protein, insulinoma-associated protein (IA)-2, using validated assays (sensitivity:specificity of 86:92% for anti-GAD and 64:86% for anti–IA-2, respectively [3,4]). Type 2 diabetic control subjects were negative for autoantibodies by the same assays. Using Student’s t test (for means ± SD of quantitative traits) or χ² analysis (for discrete traits), the LADA subjects were found to be younger (44.4 ± 14.3 vs. 51.6 ± 12.6 years, P = 0.011) and leaner (BMI 28.7 ± 6.5 vs. 32.8 ± 6.7 kg/m², P = 0.005), and despite a tendency toward shorter disease duration (24.8 ± 23.8 vs. 34.8 ± 27.7 months, P = 0.07), were more likely to receive insulin (59.5 vs. 22.1%, P = 0.0003) than type 2 diabetic control subjects. Because most MODY mutations occur within HNF1A (MODY3) or GCK (MODY2) encoding glucokinase (5), we then tested our hypothesis by sequencing the promoter, exons, and >100 nucleotides flanking each intron-exon boundary of HNF1A and GCK as described (6) from genomic DNA of all 91 subjects (>500 kilobases sequenced in total). No subject had a MODY3 mutation. However, each group had one heterozygote for the MODY2 GCK IVS3 −8G>A mutation (6), i.e., 2.7% of subjects in the LADA group versus 1.9% of type 2 diabetic control subjects (P = 0.65, NS). This mutation was absent in 250 nondiabetic control subjects. Thus, a small proportion of subjects with either LADA or type 2 diabetes can also have a MODY gene mutation.