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

To discuss the role of mitochondria in the development of type 2 diabetes.

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.

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.