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Arteriosclerosis, Thrombosis, and Vascular Biology
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on January 31, 2008

Arteriosclerosis, Thrombosis, and Vascular Biology. 2008
Published online before print January 31, 2008, doi: 10.1161/ATVBAHA.108.162073
A more recent version of this article appeared on April 1, 2008
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Submitted on January 4, 2007
Accepted on January 17, 2008

Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity

Karsten Sydow ; Carl E. Mondon ; Joerg Schrader ; Hakuoh Konishi ; and John P. Cooke *

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.


Key words: arteriosclerosis • nitric oxide • asymmetrical dimethylarginine • dimethylarginine dimethylaminohydrolase • glucose




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