Submitted on October 14, 2008
Revised on January 5, 2009
Accepted on January 13, 2009
Selective mtDNA mutation accumulation results in beta cell apoptosis and diabetes development
Kenneth G Bensch1, Justin Mott1, Shin-Wen Chang1, Polly A Hansen2, Michael A. Moxley3, Kari T. Chambers1, Wieke de Graaf1, Peter H Zassenhaus1, and John A. Corbett2*
1 Saint Louis University
2 University of Alabama at Birmingham
3 Saint Louis Univeristy School of Medicine
* To whom correspondence should be addressed. E-mail: corbettj{at}uab.edu.
To test the hypothesis that somatic mitochondrial DNA mutation accumulation predisposes mice to 
-cells loss and diabetes development, transgenic mice expressing a proofreading deficient mtDNA polymerase 
under control of the rat insulin-1 promoter were generated. At 6 weeks 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 -cell mass. Importantly, apoptosis of -cells is increased 7-fold in female and 11-fold in male transgenic mice as compared to littermate controls. These results are consistent with a causative role of somatic mitochondrial DNA mutation accumulation in the loss of -cell mass and diabetes development.
