title: Dysregulation of glucose homeostasis in nicotinamide nucleotide transhydrogenase knockout mice is independent of uncoupling protein 2.
abstract: 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.
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK. n.parker@ucl.ac.uk
authors.forename: Nadeene
authors.initials: N
authors.lastname: Parker
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Vidal-Puig
authors.forename: Vian
authors.initials: V
authors.lastname: Azzu
authors.forename: Martin D
authors.initials: MD
authors.lastname: Brand
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007473:Ion Channels / Q000502:physiology*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000502:physiology*; D009250:NADP Transhydrogenases / Q000502:physiology*; D011522:Protons; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D011522:Protons; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D009250:NADP Transhydrogenases; D005947:Glucose