Journal
ENDOCRINOLOGY
Volume 153, Issue 10, Pages 4666-4676Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2012-1296
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Funding
- German Federal Ministry of Education and Research by the Gerontosys 2 program
- German Diabetes Foundation
- Hertie foundation [1.01.1/07/001]
- EU-FP6 [MRTN-CT-2004-005693 EURO-RA]
- Deutsche Forschungsgemeinschaft (DFG)
- Forschungsforderung der Medizinischen Fakultat der Rostocker Universitat program [889018]
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Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic phenotypes. In this study, we used conplastic mouse strains to characterize the impact of a mtDNA mutation in the Atp8 gene on beta-cell function, reactive oxygen species (ROS) generation, beta-cell mass, and glucose metabolism in response to high-fat diet (HFD). In comparison with B6-mt(AKR) controls, the B6-mt(FVB) strain carries a point mutation of the mtDNA-coded Atp8 gene (ATP synthase), leading to a fragmentated mitochondrial phenotype. Isolated pancreatic islets from 3-month-old B6-mt(FVB) mice showed increased mitochondrial generation of ROS, reduced cellular ATP levels, reduced glucose-induced insulin secretion, higher susceptibility to palmitate stress, and pathological morphology of mitochondria. ROS generation in beta-cells was not affected by changes of the ambient glucose concentrations. Feeding a HFD for 3 months resulted in impaired glucose tolerance in B6-mt(FVB) mice but not in B6-mt(AKR) controls. In B6-mt(FVB) animals, glucose intolerance positively correlated with gain of body weight. Serum insulin levels and beta-cell mass significantly increased in B6-mt(FVB) mice after a 3-month HFD. The data indicate that the mutation in the Atp8 gene induces mitochondrial dysfunction in beta-cells with concomitant impairment of secretory responsiveness. This mitochondrial dysfunction induced a higher susceptibility to metabolic stressors, although this effect appeared not strictly linked to nutrient-induced ROS generation. The Atp8 gene mutation caused mitochondrial dysfunction, apparently stimulating an adaptive increase of beta-cell mass in response to HFD, whereas mitochondrial ROS might have had an supportive role. (Endocrinology 153: 4666-4676, 2012)
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