A possible association of pancreatic autoimmunity with mitochondrial diabetes, which is associated with pathogenetic mitochondrial DNA (mtDNA) abnormalities (1), has been controversial. The study by Kobayashi et al. (2) and our study (3) previously reported that islet cell antibody (ICA) was detected in, respectively, 42% (13 of 31) and 18% (2 of 11) of patients with mitochondrial diabetes associated with tRNA(UUR) mutation at position 3243 (MD3243). These results support an mtDNA abnormality associated with ICA-related pancreatic autoimmune abnormality. Kobayashi et al. (2) and we (4) also reported that 6.5% (2 of 31) and 0% (0 of 11), respectively, of MD3243 patients had GAD antibody (GADA), suggesting that GADA is not often detected in MD3243. We speculated that immunological background is somewhat different between autoimmune-associated mitochondrial diabetes and typical type 1 diabetes (4).

In 1996, we reported a family having mitochondrial diabetes associated with mitochondrial tRNA(UUR) mutation at position 3271 (MD3271) (5). The proband was treated with diet alone and had several manifestations that are common in MD3243. The details of his clinical pictures are described in our previous reports (5,6). When we studied him in 1996, at age 40 years, GADA was not detected (<0.3 units/ml). However, in 2001, the titer of GADA was found to be positive (4.4 units/ml; GADA is considered to be positive at >1.5, which is >3 SD above the mean of 100 normal controls), whereas his ICA remained negative (<1.25 Juvenile Diabetes Foundation units).

These findings are important for three reasons. First, this is the first report to provide evidence of pancreatic autoimmune disorder associated with mtDNA abnormality other than 3243 mtDNA mutation. Second, this case suggests that GADA can be detected with passage of time in mitochondrial diabetes. Third, the low titer of GADA and negative ICA suggest that the immunological background of MD3271 may be different from typical type 1 diabetes.

As for the mechanism by which GADA changes from negative to positive over time, several explanations could be possible. It has been hypothesized that mitochondrial dysfunction in pancreatic β-cells could produce hyperexpression of GAD (7). Myers et al. (8) reported that specific inhibition of mitochondrial respiration enhances the expression of GAD in both fetal mouse pancreatic tissue and hamster HIT-T15 cells. Furthermore, it is well known that with aging, mitochondrial function decreases and mtDNA mutations accumulate (911). Therefore, in mitochondrial diabetes, GADA could become positive because of the aging-related decline of mitochondrial function, which could be facilitated by the congenital handicap of having pathogenic mitochondrial DNA mutation. It might also be a result of the fluctuating feature of pancreatic autoimmune antibodies. Kobayashi et al. (12) reported that 5 of 49 ICA-positive patients with diabetes showed fluctuations of ICA reactivity during the observation period of ∼67 months.

In conclusion, this is the first report to suggest the association of a mtDNA bp 3271 mutation with GADA. This case should be closely followed in the future, especially for pancreatic autoimmunity and insulin secretion capacity.

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Address correspondence to Yoshihiko Suzuki, MD, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo, 108-0073 Japan. E-mail: drsuzuki@ba2.so-net.ne.jp.