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Liraglutide Improves Hepatic Insulin Resistance Via the Canonical Wnt Signaling Pathway

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Liraglutide Improves Hepatic Insulin Resistance Via the Canonical Wnt Signaling Pathway 7372 MOLECULAR MEDICINE REPORTS 17: 7372-7380, 2018 Liraglutide improves hepatic insulin resistance via the canonical Wnt signaling pathway YU QIN1,2*, MIN CHEN3*, YAN YANG1, XIN-RONG ZHOU1, SHI-YING SHAO1, DAO-WEN WANG1 and GANG YUAN1 1Department of Internal Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030; 2Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000; 3Department of Geriatrics, The First Hospital of Jiangxia, Wuhan, Hubei 430030, P.R. China Received March 7, 2017; Accepted November 23, 2017 DOI: 10.3892/mmr.2018.8737 Abstract. Liraglutide, a modified form of glucagon-like attenuated the effects of liraglutide, suggesting that liraglutide peptide-1 (GLP-1), is used in the treatment of diabetes mellitus. improves insulin resistance via activating the β-catenin/Wnt However, the underlying mechanism by which liraglutide signaling pathway. The results of the present study suggest a improves liver insulin resistance remains to be elucidated. novel mechanism underlying liraglutide-mediated improve- The proto-oncogene Wnt (Wnt) signaling pathway has been ments in insulin resistance in the liver. The Wnt signaling reported to be associated with glucose and lipid metabolism. pathway may be a potential therapeutic target for the treatment Using in vivo and in vitro models of diabetes and insulin of altered hepatic physiology in insulin resistance. resistance, it was investigated whether the beneficial effects of liraglutide on liver glucose metabolism are mediated by the Introduction Wnt signaling pathway. The results of the present study demon- strate that body weight, fasting blood glucose, insulin levels Glucagon-like peptide-1 (GLP-1) is an incretin hormone and the homeostasis model assessment for insulin resistance encoded by the glucagon GCG gene (1). GLP-1 is secreted were markedly decreased in db/db mice treated with liraglu- from the gastrointestinal tract into the circulation in response tide compared with control mice. Liraglutide also improved to nutrient ingestion (1,2). GLP-1 stimulates insulin secretion liver morphology and reduced the accumulation of lipid drop- from β-cells and inhibits glucagon secretion from α-cells (3) lets. Furthermore, the expression of glucose-6-phosphatase and has previously been used for development of novel strate- and phosphoenolpyruvate carboxykinase was downregulated, gies to treat type 2 diabetes. In a clinical study involving patients whereas the expression of phosphorylated forkhead box O1, with type 2 diabetes, administering a subcutaneous infusion of Wnt signaling pathway-associated molecules, β-catenin, tran- GLP-1 for 6 weeks resulted in improved insulin sensitivity and scription factor 7-like 2 and phosphorylated glycogen synthase β-cell function (4). Ding et al (5) reported that GLP-1 decreased kinase-3β was upregulated in the liver of mice treated with the levels of serum glucose and improved insulin resistance. liraglutide. In the in vitro study, increased gluconeogenesis Exendin-4, a GLP-1 receptor agonist, has been reported to and decreased glucose uptake rates were observed in insulin inhibit the expression of glucose-6-phosphatase (G6Pase) resistant hepatocytes; treatment with liraglutide significantly and phosphoenolpyruvate carboxykinase (PEPCK) in the reversed this effect. Furthermore, transfection of insulin hepatocytes of young adult mice via an insulin-independent resistant hepatocytes with β-catenin small interfering RNA mechanism (6). Several studies have demonstrated that the GLP-1 receptor is a member of the 7 transmembrane family of G protein coupled receptors and is expressed in the human hepatocyte cell lines HepG2 and Huh7 as well as C57BL/6J mice with high-fat-diet-induced obesity (6-8). However, the Correspondence to: Dr Gang Yuan or Dr Dao-Wen Wang, exact mechanism underlying GLP-1-mediated improvement of Department of Internal Medicine, Tongji Hospital, Huazhong liver insulin resistance remains to be elucidated. University of Science and Technology, 1095 Jiefang Road, Wuhan, Evolutionarily conserved proto-oncogene Wnt (Wnt) Hubei 430030, P.R. China signaling pathways are present in multicellular eukaryotes and E-mail: [email protected] E-mail: [email protected] serve roles in embryonic development, morphogenesis, stem cell regulation, liver zonation and metabolism (9). Wnt genes *Contributed equally encode 19 Wnt proteins and are evolutionarily conversed (9). To date, two different Wnt signaling pathways have been identi- Key words: β-catenin, diabetes mellitus, glucagon-like peptide-1, fied, including the canonical and non‑canonical pathway (10). gluconeogenesis, liver The canonical Wnt signaling pathway components include the frizzled family of cell surface receptors, T-cell factor (TCF) family transcription factors, co-receptors and the downstream QIN et al: EFFECT OF LIRAGLUTIDE ON THE Wnt SIGNALING PATHWAY 7373 degradation complex containing axin/glycogen synthase Nanjing Medical College (Nanjing, China). C57BL/6 mice kinase (GSK)-3β/adenomatosis polyposis coli (APC) and were used as the control group. The mice were bred under β-catenin (11-13). Interactions between Wnt and frizzled recep- standard laboratory conditions and used for experimentation tors and/or co-receptors, including low-density lipoprotein when 6 weeks old. All animals were maintained in a tempera- receptor-related protein (LRP) 5 and 6, leads to the activation ture‑controlled environment (22‑24˚C; 50‑60% humidity) with of the intracellular protein disheveled (Dsh). These events a 12-h light/dark cycle and free access to drinking water and trigger an intracellular signaling cascade, which eventually normal chow (60, 15 and 25% calories from carbohydrates, fats results in phosphorylation and inactivation of glycogen synthase and proteins, respectively). All animal care and experimental kinase-3β (GSK3β), and decreased GSK3β-induced phosphory- procedures were approved by the Institutional Animal Care lation of β-catenin (14). Accumulation and nuclear translocation and Use Committee of Tongji Medical College, Huazhong of β-catenin, and increased levels of nuclear β-catenin lead to University of Science and Technology (Wuhan, China). Male the activation of over 60 Wnt-responsive genes via interactions db/db mice were divided into 2 groups: Saline and liraglutide with transcription factors, including TCF, TCF7, TCF7 like 1 (n=6/group) and received intraperitoneal injections of saline or (TCF7L1), TCF7L2 and lymphoid enhancer factor (LEF) (14). liraglutide (Novo Nordisk Pharmaceutical Co., Ltd., Tianjin, Genetic associations between TCF7L2 polymorphisms China) once daily at a concentration of 200 µg/kg body and type 2 diabetes has previously been reported in multiple weight for 8 weeks. Animals were monitored each 2 weeks for ethnic populations (15). Several studies have investigated alterations in body weight, plasma glucose and insulin. Every the role of the Wnt signaling pathway in the pathogenesis 2 weeks, the tail vein blood was harvested from the tail vein of diabetes (16-19). In TCF7L2 gene knockout mice, the and plasma was stored at ‑80˚C for further analysis. A Glucose number of pancreatic β‑cells was significantly reduced along Oxidase and Peroxidase Assay (GOD-POD) kit (Shanghai with the reduction of the deficiencies in insulin secretion Mingdian Bioengineering, Co., Ltd., Shanghai, China) and an and glucose tolerance (16). Liver‑specific TCF7L2 knockout Insulin ELISA kit (cat. no. EZHIASF-14K; EMD Millipore, mice demonstrated increased hepatic glucose production and Billerica, MA, USA) were used to quantify levels of glucose overexpression of liver-specific TCF4, leading to reduced and insulin, respectively. The homeostasis model assessment hepatic glucose levels (17). TCF7 knockdown in HepG2 cells for insulin resistance (HOMA-IR) was calculated using the resulted in increased gluconeogenic gene expression, whereas following equation: Fasting insulinxfasting glucose/22.5 (22). restoration of hepatic TCF7 levels decreased the expression of Animals were fasted overnight in the 8th week of the experi- gluconeogenic genes and reduced hepatic glucose output (18). ment and subsequently sacrificed by cervical dislocation. Liver Using the liver‑specific dominant‑negative TCF7L2 transgenic tissues were harvested, frozen in liquid nitrogen and stored mouse model LTCFDN, Ip et al (19) demonstrated that the at ‑80˚C until RNA and protein extraction. Wnt signaling pathway and its effector β-catenin/TCF serve a beneficial role in suppressing hepatic gluconeogenesis. Hematoxylin and eosin (H&E) staining. Liver tissues were GLP-1 has been demonstrated to directly activate the Wnt fixed in 10% formalin for 24 h at room temperature and signaling pathway (20). Liu and Habener (21) reported that embedded in paraffin. Paraffin blocks were cut using a GLP-1 and exendin-4 induced Wnt signaling in pancreatic microtome into 5‑µm sections. Following deparaffinization β-cells and INS-1 cells independent of GSK3β, as well as and dehydration, the sections were stained with 0.5% (w/v) increasing nuclear levels of β-catenin. These interactions led hematoxylin (5-10 min) and eosin (1-2 min; H&E staining) to transcriptional activation of genes associated with β-cell at room temperature. Histological slides were examined by proliferation via interacting with TCF7L2 (21). Furthermore, it light microscopy (magnification, x200). Histological features, has been demonstrated that lithium, a GSK3β inhibitor,
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