Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity

Karsten Sydow, Carl E. Mondon, Joerg Schrader, Hakuoh Konishi, John P. Cooke

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)692-697
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Arteriosclerosis
  • Asymmetrical dimethylarginine
  • Dimethylarginine dimethylaminohydrolase
  • Glucose
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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