on January 31, 2008
Published online before print January 31, 2008, doi: 10.1161/ATVBAHA.108.162073
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 4, 2007
Accepted on January 17, 2008
Dimethylarginine Dimethylaminohydrolase Overexpression Enhances Insulin Sensitivity
Karsten Sydow ;
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
This article has been cited by other articles:
 |
|
 |
|
  K. Hanai, T. Babazono, I. Nyumura, K. Toya, N. Tanaka, M. Tanaka, A. Ishii, and Y. Iwamoto Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1884 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Koh, P. C. Oh, and M. J. Quon Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res, March 1, 2009; 81(4): 649 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kobayashi, M. Oka, K. Maesato, R. Ikee, T. Mano, M. Hidekazu, and T. Ohtake Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients Clin. J. Am. Soc. Nephrol., September 1, 2008; 3(5): 1289 - 1295. [Abstract] [Full Text] [PDF]
|
|