RETRACTED: Nicotinamide nucleotide transhydrogenase: A key role in insulin secretion (Retracted article. See vol. 19, pg. 344, 2014)

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. QTL mapping identified Nicotinamide Nucleotide Transhydrogenase (Nnt), a nuclear-encoded mitochondrial protein thought to be involved in free radical detoxification, as a candidate gene. To investigate its functional role, we used siRNA to knockdown Nnt in insulin-secreting MIN6 cells. This produced a dramatic reduction in insulin secretion and the rise in [Ca2+](i) evoked by glucose, but not tolbutamide. We identified two ENU-induced point mutations in Nnt (N68K, G745D). Nnt mutant mice were glucose intolerant and secreted less insulin during a glucose tolerance test. Isolated islets showed impaired insulin secretion in response to glucose, but not to tolbutamide, and glucose failed to enhance ATP levels. Glucose utilization and production of reactive oxygen species were increased in Nnt 0 cells. We hypothesize that Nnt mutations/deletion uncouple p cell mitochondrial metabolism leading to less ATP production, enhanced K-ATP channel activity, and consequently impaired insulin secretion.