Mitochondrial Diabetes

Molecular Mechanisms and Clinical Presentation

  1. J. Antonie Maassen12,
  2. Leen. M. ‘t Hart1,
  3. Einar van Essen3,
  4. Rob J. Heine2,
  5. Giel Nijpels2,
  6. Roshan S. Jahangir Tafrechi1,
  7. Anton K. Raap1,
  8. George M.C. Janssen1 and
  9. Herman H.P.J. Lemkes3
  1. 1Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, the Netherlands
  2. 2Institute for Research in Extramural Medicine and Department of Endocrinology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
  3. 3Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, Leiden, the Netherlands
  1. Address correspondence and reprint requests to J. Antonie Maassen, Department of Molecular Cell Biology, LUMC, Wassenaarseweg 72, 2333 AL Leiden, Netherlands. E-mail: j.a.maassen{at}


Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic β-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic β-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.


  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Les Laboratoires Servier.

    • Accepted May 30, 2003.
    • Received March 10, 2003.
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