Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes

José P. Silva, Martin Köhler, Caroline Graff, Anders Oldfors, Mark A. Magnuson, Per Olof Berggren, Nils Göran Larsson

Research output: Contribution to journalArticle

329 Scopus citations

Abstract

Mitochondrial dysfunction is an important contributor to human pathology1-4 and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus5,6. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic β-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance8,9. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of β-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca2+-signalling and lowered insulin release in response to glucose stimulation. We observed reduced β-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant β-cells initially display reduced stimulus-secretion coupling, later followed by β-cell loss. This animal model reproduces the β-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.

Original languageEnglish (US)
Pages (from-to)336-340
Number of pages5
JournalNature genetics
Volume26
Issue number3
DOIs
StatePublished - Nov 20 2000

ASJC Scopus subject areas

  • Genetics

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    Silva, J. P., Köhler, M., Graff, C., Oldfors, A., Magnuson, M. A., Berggren, P. O., & Larsson, N. G. (2000). Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nature genetics, 26(3), 336-340. https://doi.org/10.1038/81649