Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway in KKAy mice

Abstract

Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle.

Keywords

XKQ / type 2 diabetes mellitus / KKAy mice / PI3K/Akt pathway / diabetic liver disease

References

[1] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414(6865): 782–787

[2] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33(Suppl 1): S62–S69

[3] Yabe D, Seino Y, Fukushima M, Seino S. β cell dysfunction versus insulin resistance in the pathogenesis of type 2 diabetes in East Asians. Curr Diab Rep 2015; 15(6): 602

[4] Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106(2): 165–169

[5] Brunetti A, Chiefari E, Foti D. Recent advances in the molecular genetics of type 2 diabetes mellitus. World J Diabetes 2014; 5(2): 128–140

[6] DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009; 32(Suppl 2): S157–S163

[7] Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000; 105(3): 311–320

[8] Brachmann SM, Ueki K, Engelman JA, Kahn RC, Cantley LC. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol Cell Biol 2005; 25(5): 1596–1607

[9] Kanai F, Ito K, Todaka M, Hayashi H, Kamohara S, Ishii K, Okada T, Hazeki O, Ui M, Ebina Y. Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase. Biochem Biophys Res Commun 1993; 195(2): 762–768

[10] Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 2017; 13(9): 509–520

[11] Lin P, Zhou H. Relationship between insulin resistance, dyslipidemia and fatty liver in non-insulin-dependent diabetes mellitus. Guangzhou Med J (Guangzhou Yi Yao) 2001; 32(l): 41–42 (in Chinese)

[12] Yun X, Yao D, Han T. Clinical observation of Xiao ke Qing in treating 42 cases of type 2 diabetic patients. Gansu J Tradit Chin Med (Gansu Zhong Yi) 2002; 15(4): 37–38 (in Chinese)

[13] Li Y. Clinical observation of Xiaokeqing treating type 2 diabetes mellitus with relieving blood stasis. Dissertation. Liaoning: Liaoning University of Traditional Chinese Medicine, 2017 (in Chinese)

[14] Chen XM, Li NI, Jin HL, Sun WL. Studies of hypoglycemic effects of xiaokeqing. Chin Hosp Pharm J (Zhongguo Yi Yuan Yao Xue Za Zhi) 2005; 25(2): 126–128 (in Chinese)

[15] Qiu ZJ, Shi RS, Zhu XX, Chen Z. Experimental study on treatment of diabetes with Xiaokeqing soft extract. J Nanjing Univ Tradit Chin Med (Nanjing Zhong Yi Yao Da Xue Xue Bao) 2001; 17(3): 170–172 (in Chinese)

[16] Wang LQ, Wang X, Tong L, Li XW, Liu WY, Zhou SP, Sun H. Establishment of UPLC-PDA-ELSD fingerprints of Xiaokeqing Granules and determination of its five main constituents. Chin Tradit Herbal Drugs (Zhong Cao Yao) 2013; 44(24): 3482–3488 (in Chinese)

[17] Sellamuthu PS, Arulselvan P, Fakurazi S, Kandasamy M. Beneficial effects of mangiferin isolated from Salacia chinensis on biochemical and hematological parameters in rats with streptozotocin-induced diabetes. Pak J Pharm Sci 2014; 27(1): 161–167

[18] Lim J, Liu Z, Apontes P, Feng D, Pessin JE, Sauve AA, Angeletti RH, Chi Y. Dual mode action of mangiferin in mouse liver under high fat diet. PLoS One 2014; 9(3): e90137

[19] Na L, Zhang Q, Jiang S, Du S, Zhang W, Li Y, Sun C, Niu Y. Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial. Sci Rep 2015; 5(1): 10344

[20] Li CM, Gao YL, Li M, Han B, Liu ZF. Effects of timosaponins on blood glucose level in mice.  Pharm Clin Chin Materia Medica (Zhongguo Yao Li Yu Lin Chuang) 2005;21 (4):22–23 (in Chinese)

[21] Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008; 57(5): 712–717

[22] Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 2006; 55(8): 2256–2264

[23] Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 2008; 294(1): E148–E156

[24] Yi P, Lu FE, Xu LJ, Chen G, Dong H, Wang KF. Berberine reverses free-fatty-acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ. World J Gastroenterol 2008; 14(6): 876–883

[25] Chen Y, Li Y, Wang Y, Wen Y, Sun C. Berberine improves free-fatty-acid-induced insulin resistance in L6 myotubes through inhibiting peroxisome proliferator-activated receptor γ and fatty acid transferase expressions. Metabolism 2009; 58(12): 1694–1702

[26] Leng SH, Lu FE, Xu LJ. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin 2004; 25(4): 496–502

[27] Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, Wang YM, Shan N, Zhou ZX, Yang P, You XF, Li ZR, Si SY, Zhao LX, Pan HN, Jiang JD. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism 2009; 58(1): 109–119

[28] Chen G, Lu FE, Wang ZS, Yi P, Wang KF, Zou X. Correlation between the amelioration of insulin resistance and protein expression of PI3K and GLUT4 in type 2 diabetic rats treated with berberine. Chin Pharmacol Bull (Zhongguo Yao Li Xue Tong Bao) 2008; 24(8): 1007–1010 (in Chinese)

[29] Chen W, Li S, Jing X, Jia H, Wan Y, Che R. Research progress in animal models of type 2 diabetes KKAy mice. J Clin Med (Lin Chuang Yi Yao Wen Xian Za Zhi ) 2017; 4(54): 10681–10682 (in Chinese)

[30] Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296(5573): 1655–1657

[31] Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 1996; 271(49): 31372–31378

[32] Gandhi GR, Stalin A, Balakrishna K, Ignacimuthu S, Paulraj MG, Vishal R. Insulin sensitization via partial agonism of PPARg and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. Biochim Biophys Acta 2013; 1830(1): 2243–2255

[33] Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106(2): 165–169

[34] Chi YJ, Jing LI, Guan YF, Yang JC. PI3K/Akt signaling axis in regulation of glucose homeostasis. Chin J Biochem Mol Biol (Zhongguo Sheng Wu Hua Xue Yu Fen Zi Sheng Wu Xue Bao) 2010; 26(10): 879–885 (in Chinese)

[35] Tolman KG, Fonseca V, Tan MH, Dalpiaz A. Narrative review: hepatobiliary disease in type 2 diabetes mellitus. Ann Intern Med 2004; 141(12): 946–956

[36] Targher G, Bertolini L, Rodella S, Tessari R, Zenari L, Lippi G, Arcaro G. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007; 30(8): 2119–2121

[37] Zhu X, Bian H, Gao X. The potential mechanisms of berberine in the treatment of nonalcoholic fatty liver disease. Molecules 2016; 21(10): 1336

[38] Galbo T, Shulman GI. Lipid-induced hepatic insulin resistance. Aging (Albany NY) 2013; 5(8): 582–583

Acknowledgements

This study was financially supported by the National Key Special Project of Science and Technology for Innovation Drugs of China (No. 2013zx09402202).

Compliance with ethics guidelines

Xiaoqing Li, Xinxin Li, Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, and Xiaohui Ma declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature