Diabetes Mellitus with Mitochondrial Gene Mutations in Japan

Abstract

Diabetes mellitus due to the mitochondrial DNA 3243(A-G) mutation is reported to represent 0.5-1% of the general diabetic population in Japan. To further elucidate the clinical symptoms and course of diabetes mellitus with the 3243 mutation, we undertook a nationwide cross-sectional case-finding study and observational study of a genetically defined subject group. One hundred sixteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a higher maternal inheritance of diabetes or deafness, short stature, thin habitus, and early middle-aged onset of diabetes or deafness. Eighty-six percent of the patients required insulin therapy because of progressive insulin secretory defect. Although half of the patients had the phenotype of type 1 diabetes or slowly progressive type 1 diabetes, the patients lacked the presence of autoantibodies to glutamic acid decarboxylase. Diabetes in the mothers was characterized by early middle-aged onset, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic ratio of the 3243 mutation in leukocytes was low. The patients had mitochondria-related complications such as sensorineural deafness, cardiomyopathy, cardiac conductance disorders, encephalomyopathy, macular pattern dystrophy, and mental disorders. The patients also had advanced microvascular complications. Thus, this study has revealed that (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria-related complications and (2) insulin secretory ability is more severely impaired in the patients whose mothers were also diabetic.

The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes

“…In general, mDM is not associated with any congenital anomalies and is rarely associated with kidney cysts or hepatic adenomas . Human leukocyte antigen (HLA) polymorphisms associated with DM1 as well as autoantibodies (islet cell and GAD) (Glutamic Acid Decarboxylase Autoantibodies) have only been anecdotally reported in mDM .…”

High Prevalence of the COII/tRNALys Intergenic 9‐bp Deletion in Mitochondrial DNA of Taiwanese Patients with MELAS or MERRF Syndrome

“…In Taiwan, 4.3% of the patients with type II diabetes mellitus were found to harbor the A3243→G mutation of mtDNA 14. In Japan, the incidence of mitochondrial disease was high, and it was estimated that 0.5‐1.0% of the 6 million cases of diabetes were caused by the A3243→G mutation of mtDNA, and more than 100,000 subjects were affected by MELAS syndrome 15. The A3243→G mutation of mtDNA has been established as one of the important genetic factors involved in the pathogenesis of type II diabetes mellitus in Taiwan and Japan 3,15.…”

“…In Japan, the incidence of mitochondrial disease was high, and it was estimated that 0.5‐1.0% of the 6 million cases of diabetes were caused by the A3243→G mutation of mtDNA, and more than 100,000 subjects were affected by MELAS syndrome 15. The A3243→G mutation of mtDNA has been established as one of the important genetic factors involved in the pathogenesis of type II diabetes mellitus in Taiwan and Japan 3,15. However, there has been no satisfactory explanation for this relatively high prevalence of mitochondrial diabetes in the Taiwanese population.…”

Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus

“…Diabetes patients with the mtDNA 3243 A>G variant have a lower body mass index, a progressive impairment in insulin secretion (76) and are more likely to be treated with insulin (77). The mtDNA 3243 A>G variant is associated with various conditions, such as sensory neural hearing loss, cardiomyopathy (78), macular pattern dystrophy (79), progressive kidney disease (80), gastrointestinal symptoms (81,82), encephalomyopathy and mental disorders (83). Mechanisms for this wide variability of clinical manifestation are largely unknown.…”