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Type 2 diabetes mellitus is in most cases a disease state associated with too much eating and too little physical exercise. Genetic factors determine the susceptibility to develop this disease. Whole body insulin resistance is an early marker of the disease process.1 Hyperglycaemia develops subsequently when an accelerated decline in β-cell function emerges.2,3,4 Type 2 diabetes mellitus is often accompanied by other co-morbidities such as hypertension, dyslipidaemia and a low-grade inflammation. Together, they constitute metabolic syndrome.2 A mitochondrial dysfunction resulting from the presence of 3243A>G mutations in mitochondrial DNA (mtDNA) is associated with the syndrome of maternally inherited diabetes and deafness (MIDD). Glucose intolerance develops around midlife due to the development of gradual pancreatic failure leading to insulinopaenia. This gradual, irreversible loss of pancreatic β-cell function resembles the situation seen during the development of type 2 diabetes mellitus.5
A mitochondrial dysfunction has pronounced effects on lipid metabolism. For example, carriers of the 3243A>G mutation tend to be protected from becoming obese. In some patients, remodelling of adipose tissue also occurs, resulting in the development of lipomas.6-8 Furthermore, in individuals undergoing highly active antiretroviral therapy (HAART), which also affects mitochondrial function by interference of the applied nucleoside analogues with mtDNA polymerase, a characteristic remodelling of body fat is sometimes seen. Also HAART is associated with elevated risk for developing metabolic syndrome and type 2 diabetes mellitus.9-11 Together, these observations point to a tight relationship between mitochondrial activity, triglyceride metabolism and the risk of developing metabolic syndrome and type 2 diabetes mellitus.
One of the main functions of mitochondria is to remove fatty acids (FAs) by β-oxidation. This process can take place in all cell types relevant for glucose homeostasis, including muscle, liver and adipocytes. During this process, FAs are oxidised in the mitochondrial matrix by nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD), yielding acetyl-co-enzyme A (CoA), which is further degraded to CO2 by the citric acid cycle. The resulting NADH and FADH2 need to be regenerated to NAD+ and FAD by the respiratory chain so that additional FA molecules can be oxidised. To do so, the respiratory chain needs a supply of adenosine diphosphate (ADP) that becomes converted into adenosine triphosphate (ATP) by the respiratory chain activity. In order to oxidise large amounts of FAs, ATP needs to be continuously reconverted into ADP. This reconversion takes place at a high rate in contracting muscle. Only when mitochondria are in the uncoupled state, can regeneration of NAD+ and FADH occur without the need for ADP regeneration. The released energy is then converted into heat. FAs have, like uncoupling protein 1 (UCP1), the capability to induce mitochondrial uncoupling. At high concentrations of FAs, however, mitochondrial function declines because of the toxic effects of FAs.12,13