Nicotinamide nucleotide transhydrogenase: a key role in insulin secretion.
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 knock down 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 beta cells. We hypothesize that Nnt mutations/deletion uncouple beta cell mitochondrial metabolism leading to less ATP production, enhanced KATP channel activity, and consequently impaired insulin secretion.
Freeman
Helen
H
Medical Research Council, Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, United Kingdom.
Shimomura
Kenju
K
Horner
Emma
E
Cox
Roger D
RD
Ashcroft
Frances M
FM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009250:NADP Transhydrogenases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D007328:Insulin; D024101:Mitochondrial Proteins; D015221:Potassium Channels; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D009250:NADP Transhydrogenases; D005947:Glucose; D002118:Calcium