Diabetes mellitus is now established as one of the greatest healthcare problems of the industrialised world, affecting approximately 7% of the US population. Genetic defects of beta cell function are increasingly being recognised and account for a small but significant proportion of patients who present with diabetes.

The association between mitochondrial disease and diabetes is now well established for the m.3243A >G point mutation, in some populations accounting for up to 3% of all cases of diabetes. Diabetes has also been reported in large-scale single deletions of mitochondrial DNA (mtDNA) and other point mutations in mitochondrial tRNA genes, such as m.14709T > C.

In addition, mutations of nuclear encoded mitochondrial genes affecting mtDNA replication and repair have been identified in mitochondrial diabetes. Less clearly understood are the factors that determine the clinical phenotype for any particular genotype. For example, the m.3243A > G point mutation can give rise to different phenotypes including: asymptomatic; maternally inherited diabetes and deafness; chronic progressive external ophthalmoplegia; or a syndrome known as mitochondrial encephalomyopathy, lactic acidosis and stroke like-episodes. The high metabolic requirement of the tissues involved and the level of mutated to wild-type mtDNA (heteroplasmy) in the tissue are important. However, these alone cannot explain the phenotypic variability and our understanding of the tendency of certain mutations to cause disease in particular tissues remains poor. Furthermore, in vivo assessment of heteroplasmy is extremely difficult in tissues such as pancreas. When post-mortem investigations have been undertaken, the level of mutant heteroplasmy in surviving islet beta cells has been surprisingly low. While this probably reflects selective loss of beta cells containing a high proportion of mutated mtDNA, this is by no means certain.

Understanding the mechanisms and natural history of diabetes in patients with mitochondrial disease is extremely important when it comes to providing patients and their families with prognostic advice. Here we present a large longitudinal clinical study of diabetes in patients with mitochondrial disease using data collected over the last 25 years. Comparison is made between different genotypes, in terms of onset, progression and complication rate of diabetes. In addition, mutant heteroplasmy levels in tissues such as blood, urine and muscle are reviewed to assess their predictive value for onset and progression of diabetes.

The aims of this study were (1) to determine the prevalence and rate of progression in diabetes secondary to mitochondrial DNA (mtDNA) mutations; and (2) to determine whether percentage heteroplasmy predicts clinical outcome in patients carrying the m.3243A > G mutation.

Methods 
We prospectively assessed 242 patients attending a specialist neuromuscular clinic using a validated mitochondrial disease rating scale. Retrospective clinical data on these patients from up to 25 years of follow-up were also included. Percentage heteroplasmy in blood, urine and muscle was determined for the m.3243A > G group and correlated against clinical features.

Results 
Patients carrying the m.3243A > G mutation formed the largest group of patients with diabetes (31/81 patients). The highest prevalence of diabetes was in the m.12258C > A group (2/2 patients), the lowest in the multiple mtDNA deletions group (3/43 patients). The earliest age of onset was in the m.3243A > G group (37.9 years) with the highest age of presentation in the multiple deletion group (56.3 years). Of patients presenting with m.3243A > G, 12.9% required insulin; an additional 32.3% progressed to insulin requirement over a mean of 4.2 years after presentation. Percentage heteroplasmy in blood, urine or muscle did not predict progression of diabetes or risk of developing complications. Early age of presentation with diabetes did predict poor clinical outcome.

Conclusions/Interpretation 
Although patients carrying the m.3243A > G mutation account for the majority of cases of diabetes secondary to mtDNA mutations, several other genotypes are also associated with the development of diabetes, some with high penetrance. All show a gradual progression to insulin requirement. Percentage heteroplasmy is a poor predictor of severity of diabetes in the m.3243A > G group.

Keywords 
Diabetes - Genotype - Heteroplasmy - Mitochondria - Mutations - Prevalence - Progression

R. G. Whittaker, A. M. Schaefer, R. McFarland, R. W. Taylor, M. Walker and D. M. Turnbull

R. G. Whittaker
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(1)  Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
(2)  Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

References
1. National Institutes of Health (2005) National diabetes statistics fact sheet: general information and national estimates on diabetes in the United States, 2005. Department of Health and Human Services, National Institutes of Health, Bethesda, MD
2. Ohkubo K, Yamano A, Nagashima M et al (2001) Mitochondrial gene mutations in the tRNA(Leu(UUR)) region and diabetes: prevalence and clinical phenotypes in Japan. Clin Chem 47:1641–1648
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