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

Oxidative stress has been demonstrated to play an essential role in the destruction of pancreatic β-cells without infiltrating inflammatory cells in mice with type 1 diabetes (1). Recently, it was reported that a nucleotide substitution in mitochondrial DNA, a C-to-A transversion at nucleotide position 5178 within the NADH dehydrogenase subunit 2 gene, resulting in a Leu→Met substitution (Mt5178A), is related to longevity and that individuals with Mt5178C are more susceptible to adult-onset diseases than those with Mt5178A (2). Mt5178C/A genotype may influence oxidative damage to mitochondrial DNA. Myers et al. (3) recently reported that the specific inhibition of mitochondrial oxidative phosphorylation induced hyperexpression of GAD in pancreatic β-cells. Inhibitors of NADH-ubiquinone oxidoreductase (complex I) seemed to be particularly effective in increasing the expression of GAD. Therefore, we hypothesized that the Mt5178C genotype is related to type 1 diabetes, especially autoimmune-related diabetes.

A total of 385 patients with type 1 diabetes (154 males, 231 females; current mean age 30.7 ± 5.5 years; onset age 14.4 ± 6.8 years; mean ± SD) diagnosed under the age of 30 were randomly recruited from outpatients attending the Diabetes Center at Tokyo Women’s Medical University. The subjects were diagnosed with type 1 diabetes according to the guideline of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (4). At the time of this study, all patients were ketosis-prone, and insulin treatment had been started immediately after the onset of type 1 diabetes. The mean BMI was 21.1 ± 0.5 kg/m². The mean daily insulin dose was 1.01 ± 0.23 IU · 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 served as control subjects. The Mt5178A/C genotype was analyzed by use of PCR and restriction fragment-length polymorphism with AluI digestion (2).

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

Next, the relation of mitochondrial genotype to the presence of pancreatic β-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 within 3 months after the onset of the disease. Sera within 2 weeks after the onset were tested for insulin autoantibody (IAA). The ratio of C-to-A was significantly higher in the patients who were positive for GAD antibody, IA-2 antibody, or IAA (Abs+) than in the patients who were negative for all three (Abs−) (Table 1).

Our present observation suggests that mitochondria with the Mt5178C genotype are susceptible to enhanced oxidative stress to pancreatic β-cells, resulting in activation of autoimmune mechanisms leading to the development of type 1 diabetes.