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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (6) : 688-696    https://doi.org/10.1007/s11684-018-0662-8
RESEARCH ARTICLE
Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway in KKAy mice
Xiaoqing Li, Xinxin Li(), Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, Xiaohui Ma
Department of Pharmacology and Toxicology, Tasly Pharmaceutical Co., Ltd., Tianjin 300410, China
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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     
Corresponding Author(s): Xinxin Li   
Just Accepted Date: 24 October 2018   Online First Date: 13 November 2018    Issue Date: 03 December 2018
 Cite this article:   
Xiaoqing Li,Xinxin Li,Genbei Wang, et al. Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway in KKAy mice[J]. Front. Med., 2018, 12(6): 688-696.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0662-8
https://academic.hep.com.cn/fmd/EN/Y2018/V12/I6/688
Fig.1  Effect on the BWs and food and water intake levels of the diabetic model mice. (A) BW of mice during treatment in each group; (B) Daily food intake levels of the mice during treatment in each group; (C) Daily water intake levels of the mice during treatment in each group. The data are expressed as mean±SD (n=10). ## P<0.01 vs. control group. *P<0.05 vs. model group.
Fig.2  Effect on the FBG of the diabetic model mice. Data are expressed as mean±SD (n=10). *P<0.05 vs. model group.
Fig.3  Effect on the OGTT of the diabetic model mice. (A) Results of OGTT in each group in the 8th week; (B) AUC of the OGTT for the groups in the 8th week. Data are expressed as mean±SD (n=10). ## P<0.01 vs. control group. *P<0.05, **P<0.01 vs. model group.
Fig.4  Changes in the IR for each group. (A–C) represents the level of serum FIN, FBG, and HOMA–IR index for each group. The data are expressed as mean±SD (n=10). ## P<0.01 vs. control group. *P<0.05, **P<0.01 vs. model group.
Fig.5  Effect on the serum AST &ALT of the diabetic model mice (A) and liver index (B). Data are expressed as mean±SD (n=10). ## P<0.01 vs. control group. *P<0.05 vs. model group.
Fig.6  Pathological observation of the liver tissues of diabetic model mice. H&E staining of the liver (original magnification 100×). White arrows: normal liver cells. Black arrows: steatotic vacuole. n=6.
Fig.7  Effect on the expression of the PI3K/Akt pathway-related proteins in the skeletal muscle. (A) Representative image of Western blot; M, model; Con, control; X-L, XKQ low; X-M, XKQ medium; X-H, XKQ high. (B−E) Protein expression levels of IRS-1, PI3K, p-Akt, and GLUT4. Data are expressed as mean±SD (n=3). ## P<0.01 vs. control group. *P<0.05, **P<0.01 vs. model group.
1 Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414(6865): 782–787
https://doi.org/10.1038/414782a pmid: 11742409
2 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33(Suppl 1): S62–S69
https://doi.org/10.2337/dc10-S062 pmid: 20042775
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
https://doi.org/10.1007/s11892-015-0602-9 pmid: 25944304
4 Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106(2): 165–169
https://doi.org/10.1172/JCI10582 pmid: 10903329
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
https://doi.org/10.4239/wjd.v5.i2.128 pmid: 24748926
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
https://doi.org/10.2337/dc09-S302 pmid: 19875544
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
https://doi.org/10.1172/JCI7535 pmid: 10675357
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
https://doi.org/10.1128/MCB.25.5.1596-1607.2005 pmid: 15713620
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
https://doi.org/10.1006/bbrc.1993.2111 pmid: 8396927
10 Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 2017; 13(9): 509–520
https://doi.org/10.1038/nrendo.2017.56 pmid: 28621339
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
pmid: 24374436
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
https://doi.org/10.1371/journal.pone.0090137 pmid: 24598864
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
https://doi.org/10.1038/srep10344 pmid: 25989216
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
https://doi.org/10.1016/j.metabol.2008.01.013 pmid: 18442638
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
https://doi.org/10.2337/db06-0006 pmid: 16873688
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
https://doi.org/10.1152/ajpendo.00211.2007 pmid: 17971514
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
https://doi.org/10.3748/wjg.14.876 pmid: 18240344
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
https://doi.org/10.1016/j.metabol.2009.06.009 pmid: 19767038
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
pmid: 15066220
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
https://doi.org/10.1016/j.metabol.2008.08.013 pmid: 19059538
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
https://doi.org/10.1126/science.296.5573.1655 pmid: 12040186
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
https://doi.org/10.1074/jbc.271.49.31372 pmid: 8940145
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
https://doi.org/10.1016/j.bbagen.2012.10.016 pmid: 23104384
33 Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106(2): 165–169
https://doi.org/10.1172/JCI10582 pmid: 10903329
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
https://doi.org/10.7326/0003-4819-141-12-200412210-00011 pmid: 15611492
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
https://doi.org/10.2337/dc07-0349 pmid: 17519430
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
https://doi.org/10.3390/molecules21101336 pmid: 27754444
38 Galbo T, Shulman GI. Lipid-induced hepatic insulin resistance. Aging (Albany NY) 2013; 5(8): 582–583
https://doi.org/10.18632/aging.100585 pmid: 23929893
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