Glucose intolerance in C57Bl/6 mice has been associated with mutations in the
nicotinamide nucleotide transhydrogenase (Nnt) gene. It has been proposed that the absence of NNT from mitochondria leads to increased mitochondrial
reactive oxygen species production and subsequent activation of
uncoupling protein 2 (UCP2). Activation of UCP2 has been suggested to uncouple electron transport from
ATP synthesis in pancreatic beta cell mitochondria thereby decreasing
glucose tolerance due to decreased insulin secretion through lower
ATP/
ADP ratios. The hypothesis tested in this paper is that UCP2 function is required for the dysregulation of
glucose homeostasis observed in NNT ablated mice. Single and double Nnt and Ucp2 knockout mouse lines were used to measure
glucose tolerance, whole animal energy balance and biochemical characteristics of mitochondrial uncoupling. As expected,
glucose tolerance was diminished in mice lacking NNT. This was independent of UCP2 as it was observed either in the presence or absence of UCP2. The range of metabolic parameters examined in the mice and the
proton conductance of isolated mitochondria remained unaltered in this double NNT and UCP2 knockout model. Ablation of UCP2 did not itself affect
glucose tolerance and therefore previous observations of increased
glucose tolerance of mice lacking UCP2 were not confirmed. We conclude that the decreased
glucose tolerance in Nnt knockout mice observed in our experiments does not require UCP2.