Mitochondria and Diabetes

There is strong evidence of involvement of mitochondria in type 2 diabetes, causing or caused by insulin resistance of muscle, insulin secretion from the pancreas and in the complications of diabetes.

Typically, the number and size of mitochondria is reduced in the muscle of diabetics, there is reduced mitochondrial biogenesis and switching of metabolic substrate use that is linked directly to mitochondrial enzymes. Insulin secretion from the pancreatic islet cells requires ATP and altered functioning of mitochondria and the resulting increased oxidative stress of these cells is thought to play a major part in the reduced insulin release. The pyruvate dehydrogenase complex (PDH or PDC) is the key regulatory site in cellular metabolism. Perturbation of the regulation of the choice of glucose or fatty acids as energy source is a key part of diabetes, metabolic syndrome and obesity, while metabolic substrate switching from oxidative phosphorylation to glycolysis defines the cancer phenotype, linking diabetes with PDH.

Among the most convincing links between mitochondrial dysfunction and diabetes are the observed diabetic pathology of a point mutation in mtDNA encoding the tRNA for leucine, and the more recent finding that depletion of the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) caused much reduced insulin secretion from islet cells.

NNT is a mitochondrial inner membrane protein catalyzing the interconversion of NADH and NADPH within the matrix space of the organelle. It couples this reaction to proton translocation across the inner membrane. In the presence of an electrochemical proton gradient the production of NADPH is strongly favored. NADPH is required in the mitochondrial matrix to keep the ratio GSH:GSSG high via the NADPH dependent glutathione reductase. Thus NNT has an important role to play in defences against oxidative stress produced by the organelle.

A novel, unexpected role of NNT is in insulin secretion. The absence of NNT prevents glucose from closing the K+ATP channel and from opening the Ca++ channel in pancreatic beta cells. These defective beta cells also show a profound increase in ROS.

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