L-Citrulline increases hepatic sensitivity to insulin by reducing the phosphorylation of serine 1101 in insulin receptor substrate-1

BMC Complementary and Alternative Medicine

Ming Gao⁴  Yoshie Yamagishi³  Shiori Suguro³  Yewei Huang¹  Xiao Ma²  Maki Momoo⁴  Hisae Yoshitomi⁴ 

[1] College of Life Science, Jilin University, Changchun, China;Key Laboratory of Pu-erh Tea Science, Yunnan Agricultural University, Kunming, 650201, China;Protein Chemical Co., LTD, Tokyo, 1000011, Japan;School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya, 663-8179, Hyogo, Japan

关键词: H4IIE cells;    SHRSP.Z-Leprfa/IzmDmcr rat;    Insulin receptor substrate-1;    L-citrulline;    Insulin resistance;   

Others  :  1217071
DOI  :  10.1186/s12906-015-0706-4

 received in 2014-10-28, accepted in 2015-06-01,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Yoshitomi et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

【 参考文献 】

• [1]Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia. 2002; 45(11):1475-83.
• [2]Watson RT, Kanzaki M, Pessin JE. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev. 2004; 25(2):177-204.
• [3]Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007; 87(2):507-20.
• [4]Rimando AM, Perkins-Veazie PM. Determination of citrulline in watermelon rind. J Chromatogr A. 2005; 17; 1078(1–2):196-200.
• [5]Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, Leste-Lasserre T et al.. Leucine supplementation protects from insulin resistance by regulating adiposity levels. PLoS One. 2013; 25;8(9):e74705.
• [6]Prada PO, Hirabara SM, de Souza CT, Schenka AA, Zecchin HG, Vassallo J et al.. L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity. Diabetologia. 2007; 50(9):1949-59.
• [7]Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J et al.. L-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci U S A. 2005; 20; 102(38):13681-6.
• [8]Logie L, Ruiz-Alcaraz AJ, Schofield CJ, Hundal HS, Feuerstein GZ, Brady JD et al.. Generation, validation and humanisation of a novel insulin resistant cell model. Biochem Pharmacol. 2010; 80(7):1042-9.
• [9]Hanson RW, Reshef L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem. 1997; 66:581-611.
• [10]Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002; 31; 296(5573):1655-7.
• [11]Sata M, Nagai R. Phosphatidylinositol 3-kinase: a key regulator of vascular tone? Circ Res. 2002; 23; 91(4):273-5.
• [12]Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 13; 414(6865):799-806.
• [13]Hall RK, Granner DK. Insulin regulates expression of metabolic genes through divergent signaling pathways. J Basic Clin Physiol Pharmacol. 1999; 10(2):119-33.
• [14]Zick Y. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol. 2001; 11(11):437-41.
• [15]Sykiotis GP, Papavassiliou AG. Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. Mol Endocrinol. 2001; 15(11):1864-9.
• [16]Sun XJ, Goldberg JL, Qiao LY, Mitchell JJ. Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. Diabetes. 1999; 48(7):1359-64.
• [17]Liu YF, Herschkovitz A, Boura-Halfon S, Ronen D, Paz K, Leroith D et al.. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance. Mol Cell Biol. 2004; 24(21):9668-81.
• [18]Herschkovitz A, Liu YF, Ilan E, Ronen D, Boura-Halfon S, Zick Y. Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. J Biol Chem. 2007; 22; 282(25):18018-27.
• [19]Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ et al.. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002; 13; 277(50):48115-21.
• [20]Rui L, Mathews LS, Hotta K, Gustafson TA, Carter-Su C. Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Mol Cell Biol. 1997; 17(11):6633-44.
• [21]Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE et al.. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A. 2001; 10; 98(8):4640-5.
• [22]Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005; 87(1):99-109.
• [23]Hiraoka-Yamamoto J, Nara Y, Yasui N, Onobayashi Y, Tsuchikura S, Ikeda K. Establishment of a new animal model of metabolic syndrome: SHRSP fatty (fa/fa) rats. Clin Exp Pharmacol Physiol. 2004; 31(1–2):107-9.
• [24]Zick Y. Role of Ser/Thr kinases in the uncoupling of insulin signaling. Int J Obes Relat Metab Disord. 2003; 27 Suppl 3:S56-60.
• [25]Felig P. Amino acid metabolism in man. Annu Rev Biochem. 1975; 44:933-55.
• [26]Tremblay F, Brûlé S, Hee Um S, Li Y, Masuda K, Roden M et al.. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2007; 28; 104(35):14056-61.
• [27]Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev. 2006; 24(3–4):275-90.
• [28]McKnight JR, Satterfield MC, Jobgen WS, Smith SB, Spencer TE, Meininger CJ et al.. Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health. Amino Acids. 2010; 39(2):349-57.