Diabetologia, 2015-04, Vol.58 (4), p.771-780
2015
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- Autor(en) / Beteiligte
- Titel
- Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure
- Ist Teil von
- Diabetologia, 2015-04, Vol.58 (4), p.771-780
- Ort / Verlag
- Berlin/Heidelberg: Springer Berlin Heidelberg
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Aim/hypothesis Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown. Methods We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1 )-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane. Results Crif1 beta−/− mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1 beta−/− mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1 beta−/− mice. Conclusions/interpretation Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1 beta−/− mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0012-186XeISSN: 1432-0428DOI: 10.1007/s00125-015-3506-yTitel-ID: cdi_proquest_miscellaneous_1661333166
- Format
- –
- Schlagworte
- Age Factors, Animals, Autophagy, Blood Glucose - metabolism, Cell Cycle Proteins - deficiency, Cell Cycle Proteins - genetics, Cell Line, Cells, Diabetes, Diabetes Mellitus - drug therapy, Diabetes Mellitus - genetics, Diabetes Mellitus - metabolism, Diabetes Mellitus - pathology, Disease Models, Animal, Disease Progression, Electrons, Genotype, Glucagon, Glucagon-Like Peptide-1 Receptor - agonists, Glucagon-Like Peptide-1 Receptor - metabolism, Glucose, Human Physiology, Hypoglycemic Agents - pharmacology, Hypotheses, Incretins - pharmacology, Insulin - blood, Insulin resistance, Insulin-Secreting Cells - drug effects, Insulin-Secreting Cells - metabolism, Insulin-Secreting Cells - ultrastructure, Internal Medicine, Laboratory animals, Medicine, Medicine & Public Health, Metabolic Diseases, Metabolism, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Mitochondria - ultrastructure, Mitochondrial DNA, Oxidative Phosphorylation, Pathogenesis, Peptides, Peptides - pharmacology, Phenotype, Proteins, Time Factors, Transcription factors, Transgenic animals, Transmission electron microscopy, Venoms - pharmacology