Swimming training alleviated insulin resistance through Wnt3a/β-catenin signaling in type 2 diabetic rats

Document Type: Original Article


Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou 221002, Jiangsu, China


Objective(s): Increasing evidence suggests that regular physical exercise improves type 2 diabetes mellitus (T2DM). However, the potential beneficial effects of swimming on insulin resistance and lipid disorder in T2DM, and its underlying mechanisms remain unclear.
Materials and Methods: Rats were fed with high fat diet and given a low dosage of Streptozotocin (STZ) to induce T2DM model, and subsequently treated with or without swimming exercise. An 8-week swimming program (30, 60 or 120 min per day, 5 days per week) decreased body weight, fasting blood glucose and fasting insulin.
Results: Swimming ameliorated lipid disorder, improved muscular atrophy and revealed a reduced glycogen deposit in skeletal muscles of diabetic rats. Furthermore, swimming also inhibited the activation of Wnt3a/β-catenin signaling pathway, decreased Wnt3a mRNA and protein level, upregulated GSK3β phosphorylation activity and reduced the expression of β-catenin phosphorylation in diabetic rats.
Conclusion: The trend of the result suggests that swimming exercise proved to be a potent ameliorator of insulin resistancein T2DM through the modulation of Wnt3a/β-catenin pathway and therefore, could present a promising therapeutic measure towards the treatment of diabetes and its relatives.


1.Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480.

2.Brøns C, Grunnet LG. Mechanisms in endocrinology: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander? Eur J Endocrinol. 2017; 176:R67-R78.

3.Pachori AS, Madan M, Nunez Lopez YO, Yi F, Meyer C, Seyhan AA. Reduced skeletal muscle secreted frizzled-related protein 3 is associated with inflammation and insulin resistance. Obesity 2017; 25:697-703.

4.Xi XH, Wang Y, Li J, Wang FW, Tian GH, Yin MS, Mu YL, Chong ZZ. Activation of Wnt/β-catenin/GSK3β signaling during the development of diabetic cardiomyopathy. Cardiovasc Pathol 2015; 24:179-186.

5.Wang J, Zhao J, Zhang J, Luo X, Gao K, Zhang M, Li L, Wang C, Hu D. Association of canonical Wnt/β-Catenin pathway and type 2 diabetes: genetic epidemiological study in Han Chinese. Nutrients 2015; 7:4763-4777.

6.Liu X, Chen D, Wu Z, Li J, Li J, Zhao H, Liu T. Ghrelin inhibits high glucose-induced 16HBE cells apoptosis by regulating Wnt/β-catenin pathway. Biochem Biophys Res Commun 2016; 477:902-907.

7.Figeac F, Uzan B, Faro M, Chelali N, Portha B, Movassat J. Neonatal growth and regeneration of beta-cells are regulated by the Wnt/beta-catenin signaling in normal and diabetic rats. Am J Physiol Endocrinol Metab 2010; 298:E245-256.

8.Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci USA2007; 104:6247–6252.

9.Astrom MB, Feigh M and Pedersen BK. Persistent lowgrade inflammation and regular exercise. Front Biosci (Schol Ed) 2010; 2:96-105.

10.Qin L, Yao ZQ, Chang Q, Zhao YL, Liu NN, Zhu XS, Liu QQ, Wang LF, Yang AG, Gao CF, Li JT. Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis. Oncotarget 2017; 8:7391-7404.

11.Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/ exercise and type 2 diabetes. Diabetes Care2004; 27:2518-2539.

12.Capaldo B, Gastaldelli A, Antoniello S, Auletta M, Pardo F, Ciociaro D, Guida R, Ferrannini E, Saccà L. Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans. Diabetes 1999; 48: 958-966.

13.DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009; 32: S157-163.

14.Patel TP, Rawal K, Bagchi AK, Akolkar G, Bernardes N, Dias Dda S, Gupta S, Singal PK. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Heart Fail Rev 2016; 21:11-23.

15.Hashemipour S, Esmailzadehha N, Hamid H, Oveisi S, Yakhchaliha P, Ziaee A. Association of metabolic syndrome components with insulin resistance in normal weight population: the Qazvin Metabolic Diseases study. J Endocrinol Invest 2015;38:1111-1115.

16.Hayakawa T, Takamura T, Abe T, Kaneko S. Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese. Metabolism 2007; 56:44-48.

17.Popovic DS, Del Prato S. 1h post-load blood glucose for detection of individuals at increased risk of diabetes and cardiovascular disease. Diabetes Res ClinPract 2016; 120:184-185.

18.Wang J, Stančáková A, Soininen P, Kangas AJ, Paananen J, Kuusisto J, Ala-Korpela M, Laakso M. Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population-based study of 9399 Finnish men. J Intern Med 2012;272:562-572.

19.Qi J, Yang B, Ren C, Fu J, Zhang J. Swimming exercise alleviated insulin resistance by regulating tripartite motif family protein 72 expression and AKT signal pathway in Sprague-Dawley rats fed with high-fat diet. J Diabetes Res 2016; 2016:1564386.

20.da Rocha GL, Crisp AH, de Oliveira MR, da Silva CA, Silva JO, Duarte AC, Sene-Fiorese M, Verlengia R. Effect of high intensity interval and continuous swimming training on body mass adiposity level and serum parameters in high-fat diet fed rats. ScientificWorldJournal 2016; 2016:2194120.

21.Barel M 1, Perez OA, Giozzet VA, Rafacho A, Bosqueiro JR, do Amaral SL. Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment. Eur J ApplPhysiol 2010; 108: 999-1007.

22.vanDijk JW, Tummers K, Stehouwer CD, Hartgens F, van Loon LJ. Exercise therapy in type 2 diabetes: is daily exercise required to optimize glycemic control? Diabetes Care 2012; 35: 948–954.

23.Yfanti C, Nielsen AR, Akerström T, Nielsen S, Rose AJ, Richter EA, Lykkesfeldt J, Fischer CP, Pedersen BK. Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training. Am J Physiol Endocrinol Metab 2011; 300: E761-770.

24.Palm DC, Rohwer JM, Hofmeyr JH. Regulation of glycogen synthase from mammalian skeletal muscle--a unifying view of allosteric and covalent regulation. FEBS J 2013; 280:2-27.

25.Rudrappa SS, Wilkinson DJ, Greenhaff PL, Smith K, Idris I, Atherton PJ. Human skeletal muscle disuse atrophy: effects on muscle protein synthesis, breakdown, and insulin resistance-aqualitative review. Front Physiol 2016;7:361.

26.Onat. A Metabolic syndrome: nature, therapeutic solutions and options. Expert Opin Phar-macother 2011; 12:1887-1900.

27.Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 2005; 280:10290-10297.

28.Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, Wasserman DH. Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice. Diabetes 2011; 60:416-426.

29.Kang L, Mokshagundam S, Reuter B, Lark DS, Sneddon CC, Hennayake C, Williams AS, Bracy DP, James FD, Pozzi A, Zent R, Wasserman DH. Integrin-linked kinase in muscle is necessary for the development of insulin resistance in diet-induced obese mice. Diabetes 2016; 65:1590-1600.

30.Schinner S. Wnt-signalling and the metabolic syndrome. Horm Metab Res 2009; 41:159-163.

31.Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl AcadSci USA 2007; 104:6247-6252.

32.Gaudio A, Privitera F, Battaglia K, Torrisi V, Sidoti MH, Pulvirenti I, Canzonieri E, Tringali G, Fiore CE. Sclerostin levels associated with inhibition of the Wnt/β-catenin signaling and reduced bone turnover in type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97:3744-3750.

33.Sakamoto K, Arnolds DE, Ekberg I,Thorell A, Goodyear LJ. Exercise regulates Akt and glycogen synthase kinase-3 activities in human skeletal muscle. Biochem Biophys Res Commun2004; 319:419-425.