Selective mtDNA mutation accumulation results in beta-cell apoptosis and diabetes development. Am J Physiol Endocrinol Metab 2009 Apr;296(4):E672-80
Date
01/23/2009Pubmed ID
19158322Pubmed Central ID
PMC2670628DOI
10.1152/ajpendo.90839.2008Scopus ID
2-s2.0-65649145174 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
To test the hypothesis that somatic mitochondrial (mt)DNA mutation accumulation predisposes mice to beta-cell loss and diabetes development, transgenic mice expressing a proofreading-deficient mtDNA polymerase-gamma under the control of the rat insulin-1 promoter were generated. At 6 wk of age, mtDNA mutations reached 0.01% (1.05 mutations/10,000 bp) in islets isolated from transgenic mice. This mutational burden is associated with impaired glucose tolerance and a diabetes prevalence of 52% in male transgenic mice. Female transgenic mice maintain slightly elevated fasting glucose levels, mild glucose intolerance, and a diabetes prevalence of 14%. Diabetes in transgenic animals is associated with insulin insufficiency that results from a significant reduction in beta-cell mass. Importantly, apoptosis of beta-cells is increased 7-fold in female and 11-fold in male transgenic mice compared with littermate controls. These results are consistent with a causative role of somatic mtDNA mutation accumulation in the loss of beta-cell mass and diabetes development.
Author List
Bensch KG, Mott JL, Chang SW, Hansen PA, Moxley MA, Chambers KT, de Graaf W, Zassenhaus HP, Corbett JAAuthor
John A. Corbett PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
DNA Polymerase gamma
DNA, Mitochondrial
DNA-Directed DNA Polymerase
Diabetes Mellitus
Female
Glucose
Homeostasis
Insulin
Insulin-Secreting Cells
Male
Mice
Mice, Transgenic
Mutation
Organ Size
Promoter Regions, Genetic
Transgenes
