Journal Article

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

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

2000

Overview

Mitochondrial dysfunction is an important contributor to human pathology 1 , 2 , 3 , 4 and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5–1% of all types of diabetes mellitus 5 , 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 maintenance 8 , 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 Ca 2+ -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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adenosine Triphosphate - metabolism / Age Factors / Agriculture / Animal Genetics and Genomics / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Calcium - pharmacology / Calcium Channels, L-Type - metabolism / Cancer Research / Classical genetics, quantitative genetics, hybrids / Diabetes / Diabetes Mellitus - genetics / Diabetes Mellitus - pathology / Disease Models, Animal / Disease Progression / DNA, Mitochondrial - analysis / DNA-Binding Proteins / Electron Transport Complex IV - analysis / Exocytosis / Fundamental and applied biological sciences. Psychology / Gene Function / Gene Targeting / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Glucose - pharmacology / High Mobility Group Proteins / Human Genetics / Humans / Insulin - metabolism / Insulin Secretion / Integrases - metabolism / Ion Transport / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / letter / Mice / Mice, Transgenic / Mitochondrial DNA / Mitochondrial Proteins / Nuclear Proteins / Organ Specificity / Oxidative Phosphorylation / Pancreatic beta cells / Physiological aspects / Potassium Channels - metabolism / Recombinant Fusion Proteins - metabolism / Risk factors / Secretory Rate / Succinate Dehydrogenase - analysis / Tfam protein / Trans-Activators / Transcription Factors - deficiency / Transcription Factors - genetics / Transcription Factors - physiology / Transcription, Genetic / Transgenes / Vertebrata / Viral Proteins / Xenopus Proteins