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

¹ Robarts Research Institute, London, Ontario, Canada
² Department of Medicine, Epidemiology, and Biostatistics, University of Western Ontario, London, Ontario, Canada

Address correspondence to Robert A. Hegele, 100 Perth Dr., London, Ontario, Canada N6A5K8. E-mail: hegele{at}robarts.ca

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-1. 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 ² 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.

References

1. Owen KR, Stride A, Ellard S, Hattersley AT: Etiological investigation of diabetes in young adults presenting with apparent type 2 diabetes. Diabetes Care 26:2088–2093, 2003[Abstract/Free Full Text]
   
2. Hosszufalusi N, Vatay A, Rajczy K, Prohaszka Z, Pozsonyi E, Horvath L, Grosz A, Gero L, Madacsy L, Romics L, Karadi I, Fust G, Panczel P: Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 26:452–457, 2003[Abstract/Free Full Text]
   
3. Behme MT, Mahon JL, Dupre J: Autoantibodies and HLA susceptibility markers in Canadian first-degree relatives of patients with type 1 diabetes. Ann NY Acad Sci 958:228–231, 2002[Abstract/Free Full Text]
   
4. Bingley PJ, Bonifacio E, Mueller PW: Diabetes Antibody Standardization Program: first assay proficiency evaluation. Diabetes 52:1128–1136, 2003[Abstract/Free Full Text]
   
5. Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980, 2001[Free Full Text]
   
6. Cao H, Shorey S, Robinson J, Metzger DL, Stewart L, Cummings E, Hegele RA: GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY). Hum Mutat 20:478–479, 2002
   

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This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McKinney, J. Articles by Hegele, R. A. Search for Related Content PubMed PubMed Citation Articles by McKinney, J. Articles by Hegele, R. A. Social Bookmarking                What's this?