The use of a genetic strategy to study the role of modulation of oxidative stress by uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes

Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil.