A Mitochondrial Genotype Associated With the Development of Autoimmune-Related Type 1 Diabetes

doi:10.2337/diacare.25.11.2106

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Letters: Observations
Letter

A Mitochondrial Genotype Associated With the Development of Autoimmune-Related Type 1 Diabetes

Yasuko Uchigata, MD, PHD¹, Taisuke Okada, MD¹^,2, J.-S. Gong, MD³, Yoshiji Yamada, MD³, Yasuhiko Iwamoto, MD¹ and Massashi Tanaka, MD³

¹ Diabetes Center, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan
² Department of Pediatrics, Kochi Medical School, Kochi, Japan
³ Department of Gene Therapy, Gifu International Institute of Biotechonology, Gifu, Japan

Oxidative stress has been demonstrated to play an essentialrole in the destruction of pancreatic ß-cells withoutinfiltrating inflammatory cells in mice with type 1 diabetes(1). Recently, it was reported that a nucleotide substitutionin mitochondrial DNA, a C-to-A transversion at nucleotide position5178 within the NADH dehydrogenase subunit 2 gene, resultingin a Leu $->$ Met substitution (Mt5178A), is related to longevityand that individuals with Mt5178C are more susceptible to adult-onsetdiseases than those with Mt5178A (2). Mt5178C/A genotype mayinfluence oxidative damage to mitochondrial DNA. Myers et al.(3) recently reported that the specific inhibition of mitochondrialoxidative phosphorylation induced hyperexpression of GAD inpancreatic ß-cells. Inhibitors of NADH-ubiquinoneoxidoreductase (complex I) seemed to be particularly effectivein increasing the expression of GAD. Therefore, we hypothesizedthat the Mt5178C genotype is related to type 1 diabetes, especiallyautoimmune-related diabetes.

A total of 385 patients with type 1 diabetes (154 males, 231females; current mean age 30.7 ± 5.5 years; onset age14.4 ± 6.8 years; mean ± SD) diagnosed under theage of 30 were randomly recruited from outpatients attendingthe Diabetes Center at Tokyo Women’s Medical University.The subjects were diagnosed with type 1 diabetes according tothe guideline of the Expert Committee on the Diagnosis and Classificationof Diabetes Mellitus (4). At the time of this study, all patientswere ketosis-prone, and insulin treatment had been started immediatelyafter the onset of type 1 diabetes. The mean BMI was 21.1 ±0.5 kg/m². The mean daily insulin dose was 1.01 ± 0.23IU · kg^-1 · day^-1. A total of 469 healthy people(276 males, 193 females; current age 35.4 ± 6.4 years)who had no abnormality in glucose or lipid metabolism servedas control subjects. The Mt5178A/C genotype was analyzed byuse of PCR and restriction fragment-length polymorphism withAluI digestion (2).

The frequency of Mt5178C among patients with type 1 diabetes(264 of 385, 68.6%) was significantly higher than that amonghealthy control subjects (285 of 469, 60.8%) (P = 0.017; oddsratio 1.409; 95% CI 1.060–1.871). This finding suggeststhat Mt5178C is associated with genetic susceptibility to type1 diabetes. There was no association of Mt5178C with HLA-DR4,-DR9, -DQ3, or -DQ4 as representative HLA class II moleculesin Japanese patients with type 1 diabetes (5).

Next, the relation of mitochondrial genotype to the presenceof pancreatic ß-cell-specific autoantibodies was examined.Antibodies to GAD and to a receptor-type protein tyrosine phosphatase,designated IA-2, were assayed in a total of 180 subjects within3 months after the onset of the disease. Sera within 2 weeksafter the onset were tested for insulin autoantibody (IAA).The ratio of C-to-A was significantly higher in the patientswho were positive for GAD antibody, IA-2 antibody, or IAA (Abs+)than in the patients who were negative for all three (Abs-)(Table 1).

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Table 1— Frequency of Mt5178C and Mt5178A in 180 patients who were tested for GAD and IA-2 antibodies and IAA

Our present observation suggests that mitochondria with theMt5178C genotype are susceptible to enhanced oxidative stressto pancreatic ß-cells, resulting in activation ofautoimmune mechanisms leading to the development of type 1 diabetes.

Footnotes

Address correspondence to Yasuko Uchigata, Diabetes Center,Tokyo Women’s Medical University School of Medicine, 8-1Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: uchigata{at}dmc.twmu.ac.jp.

References

Takamura T, Kato I, Kimura N, Nakazawa T, Yonekura H, Takasawa S, Okamoto H: Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic ß cell develop insulin-dependent diabetes without insulitis. J Biol Chem 273:2493–2496, 1998[Abstract/Free Full Text]
Tanaka M, Gong JS, Zhang J, Yoneda M, Yagi K: Mitochondrial genotype associated with longevity. Lancet 351:185–186, 1998[Medline]
Myers MA, Georgiou HM, Byron S, Esposti MD: Inhibition of mitochondrial oxidative phosphorylation induces hyper-expression of glutamic acid decarboxylase in pancreatic islet cells. Autoimmunity 30:43–50, 1999[Medline]
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197, 1997[Medline]
Mizota M, Uchigata Y, Moriyama S, Tokunaga K, Matsunaga N, Miura J, Juji T, Omori Y: Age-dependent association of HLA-A24 in Japanese IDDM patients. Diabetologia 39:371–372, 1996[Medline]