Changes in the pancreas of diabetic patients with the A-to-G mitochondrial DNA (mtDNA) mutation at nucleotide position 3243 base pair (bp) have not previously been described. The clinical phenotypes of diabetes associated with the mtDNA 3243 mutation range from NIDDM to IDDM. We sought the presence of the mutation and studied volume of β-, α-, and δ-cells, mitochondrial enzyme activity, and presence of apoptosis in diabetic pancreases obtained at autopsy. Pancreases were obtained from 16 patients with IDDM, from 18 patients with NIDDM, and from 11 nondiabetic patients. Mitochondrial enzyme activity was determined for cytochrome c oxidase (COX), the subunits of which are partially encoded by mtDNA, and for succinate dehy-drogenase (SDH), the subunits of which are solely encoded by nuclear DNA. The volumes of islet β-, α-, and δ-cells were estimated by computerized morphometry. Pancreatic cells were examined for apoptosis by an in situ end-labeling procedure. The mtDNA 3243 mutation was detected in 1 of 16 (6%) pancreases from the IDDM patients; none of the pancreases from 18 NIDDM patients and 11 nondiabetic patients had the mutation. The single patient with the mtDNA 3243 mutation was a 56-year-old woman with IDDM, aged 39 years at diabetes onset, whose mother was diagnosed with NIDDM. The patient had a history of secondary failure of oral hypoglycemie agents and had a marked decrease in the number of β-cells. The islet β-cells and non-β-cells of the patient showed extremely decreased COX enzyme activity. The islet cells in the patient showed a high activity when examined for SDH. Some pancreatic exocrine cells also showed decreased COX activity with high SDH activity. In IDDM, NIDDM, and nondiabetic patients without the mtDNA 3243 mutation, only weak staining for SDH of the islet cells showed. The percentage of heteroplasmy of the mtDNA 3243 mutation in pancreatic micropunched islet specimens was 63 ± 5% (mean ± SD) in the islets, 32 ± 3% in the exocrine pancreas, and 8 ± 1% in peripheral polymorphonuclear cells. Apoptotic cells were not observed in the IDDM pancreas in the patient with the mtDNA 3243 mutation. The fact that higher levels of mutated mtDNA at 3243 bp were found in affected islets rather than in other tissue suggests that the distribution of the mutant may determine the effect on islet function. A characteristic decrease in the mitochondrial enzyme with COX activity and accelerated SDH activity of the affected islets may provide new insights into the pathogenesis of mitochondrial diabetes.
In Situ Characterization of Islets in Diabetes With a Mitochondrial DNA Mutation at Nucleotide Position 3243
- Views Icon Views
- PDF LinkPDF
- Share Icon Share
Tetsuro Kobayashi, Koji Nakanishi, Hirofumi Nakase, Hiroshi Kajio, Minoru Okubo, Toshio Murase, Kinori Kosáka; In Situ Characterization of Islets in Diabetes With a Mitochondrial DNA Mutation at Nucleotide Position 3243. Diabetes 1 October 1997; 46 (10): 1567–1571. https://doi.org/10.2337/diacare.46.10.1567
Download citation file: