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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:692.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity

Karsten Sydow; Carl E. Mondon; Joerg Schrader; Hakuoh Konishi; 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.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5406. 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.

We hypothesized that a reduction in the endogenous NOS inhibitor ADMA by overexpression of the DDAH enzyme would increase NO synthesis and thereby enhance insulin sensitivity. In response to a glucose load, the DDAH transgenic mouse manifested greater insulin sensitivity, mediated in part by enhanced hepatic or skeletal muscle response to insulin. ADMA may be a new target for treatment of insulin resistance.

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

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