Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.cmet.2005.10.008

Type

Journal article

Journal

Cell Metab

Publication Date

01/2006

Volume

3

Pages

35 - 45

Keywords

Adenosine Triphosphate, Animals, Calcium, Cell Line, Female, Glucose, Glucose Intolerance, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Obese, Mitochondrial Proteins, NADP Transhydrogenases, Potassium Channels, RNA, Small Interfering, Reactive Oxygen Species