The association of mitochondrial content with prevalent and incident type 2 diabetes.

CONTEXT: It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive. OBJECTIVE: In this study, we assessed the heritability of mtDNA content in buccal cells and analyzed the association of mtDNA content in blood with prevalent and incident T2D. DESIGN AND SETTING: mtDNA content from cells from buccal and blood samples was assessed using a real-time PCR-based assay. Heritability of mtDNA content was estimated in 391 twins from the Netherlands Twin Register. The association with prevalent T2D was tested in a case control study from The Netherlands (n = 329). Incident T2D was analyzed using prospective samples from Finland (n = 444) and The Netherlands (n = 238). MAIN OUTCOME MEASURES: We measured the heritability of mtDNA content and the association of mtDNA content in blood with prevalent and incident T2D. RESULTS: A heritability of mtDNA content of 35% (19-48%) was estimated in the twin families. We did not observe evidence of an association between mtDNA content and prevalent or incident T2D and related traits. Furthermore, we observed a decline in mtDNA content with increasing age that was male specific (P = 0.001). CONCLUSION: In this study, we show that mtDNA content has a heritability of 35% in Dutch twins. There is no association between mtDNA content in blood and prevalent or incident T2D and related traits in our study samples.

Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study.

Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes mellitus (T2DM) using a two-stage design. In the first stage, we analyzed 62 tagging single nucleotide polymorphisms (SNPs) in the Hoorn study (n=999 participants) covering all common variation in 13 biological candidate genes. These 13 candidate genes were selected from four clusters regarded essential for correct mitochondrial protein synthesis and biogenesis: aminoacyl tRNA synthetases, translation initiation factors, tRNA modifying enzymes and mitochondrial DNA transcription and replication. SNPs showing evidence for association with T2DM were measured in second stage genotyping (n=10164 participants). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85-1.00), P=0.06. Moreover, in a large meta-analysis of three genome-wide association studies, this SNP was also not associated with T2DM (P=0.72). In conclusion, we did not find evidence for association of common variants in 13 nuclear-encoded mitochondrial proteins with T2DM.

Lessons that can be learned from patients with diabetogenic mutations in mitochondrial DNA: implications for common type 2 diabetes.

PURPOSE OF REVIEW: To discuss the role of mitochondria in the development of type 2 diabetes. RECENT FINDINGS: Some mutations in mitochondrial DNA are diabetogenic due to a gradual decline in insulin secretion by the pancreas. These mutations also result in abnormalities in lipid metabolism. A similar situation is seen in patients treated with nucleoside analogues as part of highly active antiretroviral therapy to suppress human immunodeficiency virus infection. These drugs induce a 30-50% reduction in mitochondrial DNA copy number in multiple tissues. Treated individuals develop a redistribution of body fat with concomitant development of markers of the metabolic syndrome and an elevated risk of developing type 2 diabetes. Studies have also shown the presence of reduced mitochondrial activity in muscle and adipose tissue in individuals with type 2 diabetes. SUMMARY: These observations suggest a pathogenic model for obesity-associated type 2 diabetes, in which mitochondrial activity in peripheral adipocytes is essential to keep triacylglycerol stored within these cells. Mitochondria protect the organism against fatty acid-induced insulin resistance and lipotoxicity to the pancreas. In adipocytes, mitochondria may remove fatty acids through uncoupled beta oxidation, whereas in muscle fatty acids, removal is largely driven by adenosine diphosphate production through physical activity.

Do we inherit or acquire mitochondrial dysfunction in the metabolic syndrome and Type 2 diabetes?

The rapid increase in the incidence of Type 2 diabetes mellitus as part of the metabolic syndrome in our current societies is largely the result of an increased caloric intake in combination with a sedentary lifestyle. Mitochondria are the organelles within our body that oxidize the constituents of our food, furthermore, they provide the energy for physical activity. An imbalance between energy supply and energy consumption at the mitochondrial level may be at the basis of the current epidemics of Type 2 diabetes. This review discusses underlying pathogenic mechanisms. In particular, it will focus on the contribution of mitochondrial dysfunction in muscle and adipose tissue and the issue to what extent genetic factors are primary determinants for a mitochondrial dysfunction.

New insights in the molecular pathogenesis of the maternally inherited diabetes and deafness syndrome.

The 3243A>G mutation in mitochondrial DNA (mtDNA) is a genetic variant that is associated with a high risk of developing diabetes during life. Enhanced aging of pancreatic beta-cells, a reduced capacity of these cells to synthesize large amounts of insulin,and a resetting of the ATP/ADP-regulated K-channel seem to be the pathogenic factors involved.

Molecular mechanisms of mitochondrial diabetes (MIDD).

Mitochondria provide cells with most of the energy in the form of adenosine triphosphate (ATP). Mitochondria are complex organelles encoded both by nuclear and mtDNA. Only a few mitochondrial components are encoded by mtDNA, most of the mt-proteins are nuclear DNA encoded. Remarkably, the majority of the known mutations leading to a mitochondrial disease have been identified in mtDNA rather than in nuclear DNA. In general, the idea is that these pathogenic mutations in mtDNA affect energy supply leading to a disease state. Remarkably, different mtDNA mutations can associate with distinct disease states, a situation that is difficult to reconcile with the idea that a reduced ATP production is the sole pathogenic factor. This review deals with emerging insight into the mechanism by which the A3243G mutation in the mitochondrial tRNA (Leu, UUR) gene associates with diabetes as major clinical expression. A decrease in glucose-induced insulin secretion by pancreatic beta-cells and a premature aging of these cells seem to be the main process by which this mutation causes diabetes. The underlying mechanisms and variability in clinical presentation are discussed.