Liraglutide improves hepatic insulin resistance via the canonical Wnt signaling pathway

Qin,Yu; Chen,Min; Yang,Yan; Zhou,Xin‑Rong; Shao,Shi‑Ying; Wang,Dao‑Wen; Yuan,Gang

doi:10.3892/mmr.2018.8737

Liraglutide improves hepatic insulin resistance via the canonical Wnt signaling pathway

Authors:
- Yu Qin
- Min Chen
- Yan Yang
- Xin‑Rong Zhou
- Shi‑Ying Shao
- Dao‑Wen Wang
- Gang Yuan
View Affiliations

Affiliations: Department of Internal Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Geriatrics, The First Hospital of Jiangxia, Wuhan, Hubei 430030, P.R. China
Published online on: March 14, 2018 https://doi.org/10.3892/mmr.2018.8737
Pages: 7372-7380

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Liraglutide, a modified form of glucagon‑like peptide‑1 (GLP‑1), is used in the treatment of diabetes mellitus. However, the underlying mechanism by which liraglutide improves liver insulin resistance remains to be elucidated. The proto‑oncogene Wnt (Wnt) signaling pathway has been reported to be associated with glucose and lipid metabolism. Using in vivo and in vitro models of diabetes and insulin resistance, it was investigated whether the beneficial effects of liraglutide on liver glucose metabolism are mediated by the Wnt signaling pathway. The results of the present study demonstrate that body weight, fasting blood glucose, insulin levels and the homeostasis model assessment for insulin resistance were markedly decreased in db/db mice treated with liraglutide compared with control mice. Liraglutide also improved liver morphology and reduced the accumulation of lipid droplets. Furthermore, the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was downregulated, whereas the expression of phosphorylated forkhead box O1, Wnt signaling pathway‑associated molecules, β‑catenin, transcription factor 7‑like 2 and phosphorylated glycogen synthase kinase-3β was upregulated in the liver of mice treated with liraglutide. In the in vitro study, increased gluconeogenesis and decreased glucose uptake rates were observed in insulin resistant hepatocytes; treatment with liraglutide significantly reversed this effect. Furthermore, transfection of insulin resistant hepatocytes with β‑catenin small interfering RNA attenuated the effects of liraglutide, suggesting that liraglutide improves insulin resistance via activating the β‑catenin/Wnt signaling pathway. The results of the present study suggest a novel mechanism underlying liraglutide‑mediated improvements in insulin resistance in the liver. The Wnt signaling pathway may be a potential therapeutic target for the treatment of altered hepatic physiology in insulin resistance.

View Figures

View References

1	Baggio LL and Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology. 132:2131–2157. 2007. View Article : Google Scholar : PubMed/NCBI
2	Chiang YT, Ip W and Jin T: The role of the Wnt signaling pathway in incretin hormone production and function. Front Physiol. 3:2732012. View Article : Google Scholar : PubMed/NCBI
3	Salehi M, Aulinger B, Prigeon RL and D'Alessio DA: Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes. Diabetes. 59:1330–1337. 2010. View Article : Google Scholar : PubMed/NCBI
4	Zander M, Madsbad S, Madsen JL and Holst JJ: Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: A parallel-group study. Lancet. 359:824–830. 2002. View Article : Google Scholar : PubMed/NCBI
5	Ding X, Saxena NK, Lin S, Gupta NA and Anania FA: Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 43:173–181. 2006. View Article : Google Scholar : PubMed/NCBI
6	Fan R, Kang Z, He L, Chan J and Xu G: Exendin-4 improves blood glucose control in both young and aging normal non-diabetic mice, possible contribution of beta cell independent effects. PLoS One. 6:e204432011. View Article : Google Scholar : PubMed/NCBI
7	Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK and Anania FA: Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 51:1584–1592. 2010. View Article : Google Scholar : PubMed/NCBI
8	Lee J, Hong SW, Chae SW, Kim DH, Choi JH, Bae JC, Park SE, Rhee EJ, Park CY, Oh KW, et al: Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One. 7:e313942012. View Article : Google Scholar : PubMed/NCBI
9	Thompson MD and Monga SP: WNT/beta-catenin signaling in liver health and disease. Hepatology. 45:1298–1305. 2007. View Article : Google Scholar : PubMed/NCBI
10	Ackers I and Malgor R: Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases. Diab Vasc Dis Res. Nov 1–2017.(Epub ahead of print). PubMed/NCBI
11	Shao W, Wang D, Chiang YT, Ip W, Zhu L, Xu F, Columbus J, Belsham DD, Irwin DM, Zhang H, et al: The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis. Diabetes. 62:789–800. 2013. View Article : Google Scholar : PubMed/NCBI
12	Jin T and Liu L: The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. Mol Endocrinol. 22:2383–2392. 2008. View Article : Google Scholar : PubMed/NCBI
13	Akiyama T: Wnt/beta-catenin signaling. Cytokine Growth Factor Rev. 11:273–282. 2000. View Article : Google Scholar : PubMed/NCBI
14	Xiong X, Shao W and Jin T: New insight into the mechanisms underlying the function of the incretin hormone glucagon-like peptide-1 in pancreatic β-cells: The involvement of the Wnt signaling pathway effector β-catenin. Islets. 4:359–365. 2012. View Article : Google Scholar : PubMed/NCBI
15	Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, et al: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 38:320–323. 2006. View Article : Google Scholar : PubMed/NCBI
16	da Silva Xavier G, Mondragon A, Sun G, Chen L, McGinty JA, French PM and Rutter GA: Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice. Diabetologia. 55:2667–2676. 2012. View Article : Google Scholar : PubMed/NCBI
17	Boj SF, van Es JH, Huch M, Li VS, José A, Hatzis P, Mokry M, Haegebarth A, van den Born M, Chambon P, et al: Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell. 151:1595–1607. 2012. View Article : Google Scholar : PubMed/NCBI
18	Kaur K, Vig S, Srivastava R, Mishra A, Singh VP, Srivastava AK and Datta M: Elevated hepatic miR-22-3p expression impairs gluconeogenesis by silencing the Wnt-responsive transcription factor Tcf7. Diabetes. 64:3659–3669. 2015. View Article : Google Scholar : PubMed/NCBI
19	Ip W, Shao W, Song Z, Chen Z, Wheeler MB and Jin T: Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis. Diabetes. 64:1923–1932. 2015. View Article : Google Scholar : PubMed/NCBI
20	Gustafson B and Smith U: WNT signalling is both an inducer and effector of glucagon-like peptide-1. Diabetologia. 51:1768–1770. 2008. View Article : Google Scholar : PubMed/NCBI
21	Liu Z and Habener JF: Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 283:8723–8735. 2008. View Article : Google Scholar : PubMed/NCBI
22	Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF and Turner RC: Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28:412–419. 1985. View Article : Google Scholar : PubMed/NCBI
23	Zhang Z, Li B, Meng X, Yao S, Jin L, Yang J, Wang J, Zhang H, Zhang Z, Cai D, et al: Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress. Sci Rep. 6:208482016. View Article : Google Scholar : PubMed/NCBI
24	Yin J, Hu R, Chen M, Tang J, Li F, Yang Y and Chen J: Effects of berberine on glucose metabolism in vitro. Metabolism. 51:1439–1443. 2002. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Tikhanovich I, Cox J and Weinman SA: Forkhead box class O transcription factors in liver function and disease. J Gastroenterol Hepatol. 28 Suppl 1:S125–S131. 2013. View Article : Google Scholar
27	Desouza CV, Gupta N and Patel A: Cardiometabolic effects of a new class of antidiabetic agents. Clin Ther. 37:1178–1194. 2015. View Article : Google Scholar : PubMed/NCBI
28	van Can J, Sloth B, Jensen CB, Flint A, Blaak EE and Saris WH: Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 38:784–793. 2014. View Article : Google Scholar : PubMed/NCBI
29	Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B and Sjöholm A: Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 287:E1209–E1215. 2004. View Article : Google Scholar : PubMed/NCBI
30	Alcántara AI, Morales M, Delgado E, López-Delgado MI, Clemente F, Luque MA, Malaisse WJ, Valverde I and Villanueva-Peñacarrillo ML: Exendin-4 agonist and exendin(9–39)amide antagonist of the GLP-1(7–36)amide effects in liver and muscle. Arch Biochem Biophys. 341:1–7. 1997. View Article : Google Scholar : PubMed/NCBI
31	Su H, He M, Li H, Liu Q, Wang J, Wang Y, Gao W, Zhou L, Liao J, Young AA and Wang MW: Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice. PLoS One. 3:e28922008. View Article : Google Scholar : PubMed/NCBI
32	Cho YM, Fujita Y and Kieffer TJ: Glucagon-like peptide-1: Glucose homeostasis and beyond. Annu Rev Physiol. 76:535–559. 2014. View Article : Google Scholar : PubMed/NCBI
33	Redondo A, Trigo MV, Acitores A, Valverde I and Villanueva-Peñacarrillo ML: Cell signalling of the GLP-1 action in rat liver. Mol Cell Endocrinol. 204:43–50. 2003. View Article : Google Scholar : PubMed/NCBI
34	Nerurkar PV, Nishioka A, Eck PO, Johns LM, Volper E and Nerurkar VR: Regulation of glucose metabolism via hepatic forkhead transcription factor 1 (FoxO1) by Morinda citrifolia (noni) in high-fat diet-induced obese mice. Br J Nutr. 108:218–228. 2012. View Article : Google Scholar : PubMed/NCBI
35	Ip W, Shao W, Chiang YT and Jin T: The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. 303:E1166–E1176. 2012. View Article : Google Scholar : PubMed/NCBI
36	Liu H, Fergusson MM, Wu JJ, Rovira II, Liu J, Gavrilova O, Lu T, Bao J, Han D, Sack MN and Finkel T: Wnt signaling regulates hepatic metabolism. Sci Signal. 4:ra62011. View Article : Google Scholar : PubMed/NCBI
37	Hino S, Tanji C, Nakayama KI and Kikuchi A: Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol. 25:9063–9072. 2005. View Article : Google Scholar : PubMed/NCBI
38	Norton L, Fourcaudot M, Abdul-Ghani MA, Winnier D, Mehta FF, Jenkinson CP and Defronzo RA: Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia. 54:3132–3142. 2011. View Article : Google Scholar : PubMed/NCBI
39	Hoogeboom D, Essers MA, Polderman PE, Voets E, Smits LM and Burgering BM: Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J Biol Chem. 283:9224–9230. 2008. View Article : Google Scholar : PubMed/NCBI
40	Arai T, Kano F and Murata M: Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells. Genes Cells. 20:340–357. 2015. View Article : Google Scholar : PubMed/NCBI
41	Patel V, Joharapurkar A, Gandhi T, Patel K, Dhanesha N, Kshirsagar S, Dhote V, Detroja J, Bahekar R and Jain M: Omeprazole improves the anti-obesity and antidiabetic effects of exendin-4 in db/db mice (−4 db/db)*. J Diabetes. 5:163–171. 2013. View Article : Google Scholar : PubMed/NCBI
42	Yi F, Sun J, Lim GE, Fantus IG, Brubaker PL and Jin T: Cross talk between the insulin and Wnt signaling pathways: Evidence from intestinal endocrine L cells. Endocrinology. 149:2341–2351. 2008. View Article : Google Scholar : PubMed/NCBI
43	Sun J, Wang D and Jin T: Insulin alters the expression of components of the Wnt signaling pathway including TCF-4 in the intestinal cells. Biochim Biophys Acta. 1800:344–351. 2010. View Article : Google Scholar : PubMed/NCBI