title: L-Citrulline increases hepatic sensitivity to insulin by reducing the phosphorylation of serine 1101 in insulin receptor substrate-1.
abstract: BACKGROUND
  Insulin resistance is characterized by deficient responses to insulin in its target tissues. In the present study, we examined the effects of L-Citrulline (L-Cit) on insulin sensitivity and signaling cascades in rat hepatoma H4IIE cells and SHRSP.Z-Leprfa/IzmDmcr rats.
  
  
  METHODS
  H4IIE cells were pretreated in the presence or absence of 250 μM L-Cit in serum-free medium and then incubated in the presence or absence of 0.1 nM insulin. Rats were allocated into 2 groups; a control group (not treated) and L-Cit group (2 g/kg/day, L-Cit) and treated for 8 weeks.
  
  
  RESULTS
  L-Cit enhanced the insulin-induced phosphorylation of Akt in H4IIE cells. Moreover, the inhibited expression of Dex/cAMP-induced PEPCK mRNA by insulin was enhanced by the L-Cit treatment. The phosphorylation of tyrosine, which is upstream of Akt, in insulin receptor substrate-1 (IRS-1) was increased by the L-Cit treatment. The L-Cit-induced enhancement in insulin signaling was not related to the binding affinity of insulin to the insulin receptor or to the expression of the insulin receptor, but to a decrease in the phosphorylation of serine 1101 in IRS-1. These results were also confirmed in animal experiments. In the livers of L-Cit-treated rats, PI3K/Akt signaling was improved by decreases in the phosphorylation of serine 1101.
  
  
  CONCLUSIONS
  We herein demonstrated for the first time the beneficial effects of L-Cit on improved insulin resistance associated with enhanced insulin sensitivity. These results may have clinical applications for insulin resistance and the treatment of type-2 diabetes.
authors.affiliation: School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, 663-8179, Nishinomiya, Hyogo, Japan. hisa4403@mukogawa-u.ac.jp.
authors.forename: Hisae
authors.initials: H
authors.lastname: Yoshitomi
authors.affiliation: School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, 663-8179, Nishinomiya, Hyogo, Japan. peachmomo6@hotmail.com.
authors.forename: Maki
authors.initials: M
authors.lastname: Momoo
authors.affiliation: Key Laboratory of Pu-erh Tea Science, Yunnan Agricultural University, 650201, Kunming, China. ma.xiao.edu@gmail.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: College of Life Science, Jilin University, 130012, Changchun, China. huangyewei2011@gmail.com.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Protein Chemical Co., LTD, 1000011, Tokyo, Japan. suguro@prochemi.ne.jp.
authors.forename: Shiori
authors.initials: S
authors.lastname: Suguro
authors.affiliation: Protein Chemical Co., LTD, 1000011, Tokyo, Japan. yamagishi@prochemi.ne.jp.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Yamagishi
authors.affiliation: School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, 663-8179, Nishinomiya, Hyogo, Japan. gaoming@mukogawa-u.ac.jp.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
mesh_terms: D000818:Animals; D002956:Citrulline / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012694:Serine / Q000378:metabolism*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D002956:Citrulline; D012694:Serine