| |||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 4, 2007
Accepted on January 17, 2008
From the Division of Cardiovascular Medicine (K.S., C.E.M., H.K., J.P.C.), Stanford University School of Medicine, Stanford, Calif; the Department of Cardiology (K.S.), Hamburg University Heart Center, Hamburg, Germany; and the Department of Medicine I (J.S.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
* To whom correspondence should be addressed. E-mail: john.cooke{at}stanford.edu.
Objective—Previous studies suggest that nitric oxide (NO) may modulate insulin-induced uptake of glucose in insulin-sensitive tissues. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We hypothesized that a reduction in endogenous ADMA would increase NO synthesis and thereby enhance insulin sensitivity.
Methods and Results—To test this hypothesis we used a transgenic mouse in which we overexpressed human dimethylarginine dimethylaminohydrolase (DDAH-I). The DDAH-I mice had lower plasma ADMA at all ages (22 to 70 wk) by comparison to wild-type (WT) littermates. With a glucose challenge, WT mice showed a prompt increase in ADMA, whereas DDAH-I mice had a blunted response. Furthermore, DDAH-I mice had a blunted increase in plasma insulin and glucose levels after glucose challenge, with a 50% reduction in the insulin resistence index, consistent with enhanced sensitivity to insulin. In liver, we observed an increased Akt phosphorylation in the DDAH-I mice after i.p. glucose challenge. Incubation of skeletal muscle from WT mice ex vivo with ADMA (2 µmol/L) markedly suppressed insulin-induced glycogen synthesis in fast-twitch but not slow-twitch muscle.
Conclusions—These findings suggest that the endogenous NOS inhibitor ADMA reduces insulin sensitivity, consistent with previous observations that NO plays a role in insulin sensitivity.
|
ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2008 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |