Antidiabetic effects of a lipophilic extract obtained from flowers of Wisteria sinensis by activating Akt/GLUT4 and Akt/GSK3β
Background: Type 2 diabetes mellitus is primarily caused by insulin resistance (IR) in insulin-sensitive tissues, including liver, white adipose tissues (WAT), and skeletal muscles. Discovering nutritious foods with antidiabetic effects is of great significance. Numerous published reports indicated that protein kinase B (Akt) and glucose transporter 4 (GLUT4) play crucial roles in ameliorating IR and diabetic symptoms.
Objective: In the present study, antidiabetic effects and the potential mechanism of action of WS-PE (a lipophilic extract from edible flowers of Wisteria sinensis) were explored with L6 cells in vitro and in high-fat diet (HFD) + Streptozocin (STZ)-induced diabetic mice in vivo.
Design: In vivo, HFD + STZ-induced diabetic mice were used as diabetic models to investigate the potential antidiabetic and antidyslipidemic activities. In vitro, a novel GLUT4 translocation assay system was established to evaluate the potential effects of WS-PE on GLUT4 translocation. Western blot analysis was adopted to investigate the molecular mechanisms of WS-PE both in vivo and in vitro.
Results: In vitro, WS-PE increased glucose uptake by stimulating GLUT4 expression and translocation, which were regulated by Akt phosphorylation. In vivo, the WS-PE treatment ameliorated the hyperglycemia, IR, and dyslipidemia and reversed hepatic steatosis and pancreatic damage in diabetic mice. The WS-PE treatment increased GLUT4 expression by Akt activation in WAT and skeletal muscle. Akt activation stimulated GSK3β phosphorylation in liver and skeletal muscles, indicating that WS-PE showed regulatory effects on glycogen synthesis in liver and skeletal muscles.
Conclusion: These in vitro and in vivo results indicated that the WS-PE treatment exerted antidiabetic effects by activating Akt/GLUT4 and Akt/GSK3β.
- Zhu H, Chen B, Cheng Y, Zhou Y, Yan YS, Luo Q, et al. Insulin therapy for gestational diabetes mellitus does not fully protect offspring from diet-induced metabolic disorders. Diabetes 2019; 68(4): 696–708. doi: 10.2337/db18-1151
- Verma N, Usman K, Patel N, Jain A, Dhakre S, Swaroop A, et al. A multicenter clinical study to determine the efficacy of a novel fenugreek seed (Trigonella foenum-graecum) extract (Fenfuro) in patients with type 2 diabetes. Food Nutr Res 2016; 60: 32382. doi: 10.3402/fnr.v60.32382
- Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271–81. doi: 10.1016/j.diabres.2018.02.023
- Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103(2): 137–49. doi: 10.1016/j.diabres.2013.11.002
- Zafar A, Davies M, Azhar A, Khunti K. Clinical inertia in management of T2DM. Prim Care Diabetes 2010; 4(4): 203–7. doi: 10.1016/j.pcd.2010.07.003
- He ZX, Zhou ZW, Yang Y, Yang T, Pan SY, Qiu JX, et al. Overview of clinically approved oral antidiabetic agents for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2015; 42(2): 125–38. doi: 10.1111/1440-1681.12332
- Lv YB, Ming Q, Hao J, Huang Y, Chen H, Wang Q, et al. Anti-diabetic activity of canophyllol from Cratoxylum cochinchinense (Lour.) Blume in type 2 diabetic mice by activation of AMP-activated kinase and regulation of PPARgamma. Food Funct 2019; 10(2): 964-77. doi: 10.1039/c8fo02169d
- Yang XZ, Huang M, Yang J, Wang J, Zheng SJ, Ma XH, et al. Activity of isoliensinine in improving the symptoms of type 2 diabetic mice via activation of AMP-activated kinase and regulation of PPARgamma. J Agric Food Chem 2017; 65(33): 7168-78. doi: 10.1021/acs.jafc.7b01964
- Selvakumar G, Shathirapathiy G, Jainraj R, Yuvaraj Paul P. Immediate effect of bitter gourd, ash gourd, Knol-khol juices on blood sugar levels of patients with type 2 diabetes mellitus: a pilot study. J Tradit Complement Med 2017; 7(4): 526–31. doi: 10.1016/j.jtcme.2017.01.009
- Oboh G, Isaac AT, Akinyemi AJ, Ajani RA. Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside induced lipid peroxidation in rats’ pancreas by phenolic extracts of avocado pear leaves and fruit. Int J Biomed Sci 2014; 10(3): 208–16. Available from: www.ncbi.nlm.nih.gov/pubmed/25324703
- Crunkhorn S. Type 2 diabetes: broccoli extract lowers glucose levels. Nat Rev Drug Discov 2017; 16(8): 530. doi: 10.1038/nrd.2017.143
- Li Y, Deng C, Qiao Y, Zhao X, Zhou Q. Characterization of a new badnavirus from Wisteria sinensis. Arch Virol 2017; 162(7): 2125–9. doi: 10.1007/s00705-017-3322-4
- Mohamed MA, Hamed MM, Abdou AM, Ahmed WS, Saad AM. Antioxidant and cytotoxic constituents from Wisteria sinensis. Molecules 2011; 16(5): 4020–30. doi: 10.3390/molecules16054020
- Konoshima T, Takasaki M, Kozuka M, Tokuda H, Nishino H, Matsuda E, et al. Anti-tumor promoting activities of isoflavonoids from Wistaria brachybotrys. Biol Pharm Bull 1997; 20(8): 865–8. doi: 10.1248/bpb.20.865
- Tai BH, Trung TN, Nhiem NX, Ha do T, Van Men C, Duong VB, et al. A new flavan-3-ol and the anti-inflammatory effect of flavonoids from the fruit peels of Wisteria floribunda. J Asian Nat Prod Res 2011; 13(11): 1061–8. doi: 10.1080/10286020.2011.603306
- Atkinson BJ, Griesel BA, King CD, Josey MA, Olson AL. Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet-fed transgenic mice. Diabetes 2013; 62(7): 2249–58. doi: 10.2337/db12-1146
- Zheng SJ, Deng SH, Huang Y, Huang M, Zhao P, Ma XH, et al. Anti-diabetic activity of a polyphenol-rich extract from Phellinus igniarius in KK-Ay mice with spontaneous type 2 diabetes mellitus. Food Funct 2018; 9(1): 614-23. doi: 10.1039/c7fo01460k.
- Yang XZ, Yang J, Xu C, Huang M, Zhou Q, Lv JN, et al. Antidiabetic effects of flavonoids from Sophora flavescens EtOAc extract in type 2 diabetic KK-ay mice. J Ethnopharmacol 2015; 171:161-70. doi: 10.1016/j.jep.2015.05.043
- Lampson MA, Racz A, Cushman SW, McGraw TE. Demonstration of insulin-responsive trafficking of GLUT4 and vpTR in fibroblasts. J Cell Sci 2000; 113 (Pt 22): 4065–76. doi: 10.1097/00008506-199510000-00068
- Huang M, Deng SH, Han QQ, Zhao P, Zhou Q, Zheng SJ, et al. Hypoglycemic activity and the potential mechanism of the flavonoid rich extract from Sophora tonkinensis Gagnep. in KK-Ay mice. Front Pharmacol 2016; 7:288 doi: ARTN 288 10.3389/fphar.2016.00288
- Yang XZ, Deng SH, Huang M, Wang JL, Chen L, Xiong MR, et al. Chemical constituents from Sophora tonkinensis and their glucose transporter 4 translocation activities. Bioorg Med Chem Lett 2017; 27(6): 1463-6. doi: 10.1016/j.bmcl.2017.01.078
- Gurley JM, Ilkayeva O, Jackson RM, Griesel BA, White P, Matsuzaki S, et al. Enhanced GLUT4-dependent glucose transport relieves nutrient stress in obese mice through changes in lipid and amino acid metabolism. Diabetes 2016; 65(12): 3585–97. doi: 10.2337/db16-0709
- Al-Shaqha WM, Khan M, Salam N, Azzi A, Chaudhary AA. Anti-diabetic potential of Catharanthus roseus Linn. and its effect on the glucose transport gene (GLUT-2 and GLUT-4) in streptozotocin induced diabetic wistar rats. BMC Complement Altern Med 2015; 15: 379. doi: 10.1186/s12906-015-0899-6
- Ramachandran V, Saravanan R. Glucose uptake through translocation and activation of GLUT4 in PI3K/Akt signaling pathway by asiatic acid in diabetic rats. Hum Exp Toxicol 2015; 34(9): 884–93. doi: 10.1177/0960327114561663
- Zhang C, Jiang Y, Liu J, Jin M, Qin N, Chen Y, et al. AMPK/AS160 mediates tiliroside derivatives-stimulated GLUT4 translocation in muscle cells. Drug Des Devel Ther 2018; 12: 1581–7. doi: 10.2147/DDDT.S164441
- Deng B, Zhu X, Zhao Y, Zhang D, Pannu A, Chen L, et al. PKC and Rab13 mediate Ca(2+) signal-regulated GLUT4 traffic. Biochem Biophys Res Commun 2018; 495(2): 1956–63. doi: 10.1016/j.bbrc.2017.12.064
- Cogan KE, Carson BP, Patel B, Amigo-Benavent M, Jakeman PM, Egan B. Regulation of GLUT4 translocation in an in vitro cell model using postprandial human serum ex vivo. Exp Physiol 2019; 104(6): 800-807. doi: 10.1113/EP087356
- Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul 2017; 65: 5–15. doi: 10.1016/j.jbior.2017.06.003
- Han HS, Jeon H, Kang SC. Phellopterin isolated from Angelica dahurica reduces blood glucose level in diabetic mice. Heliyon 2018; 4(3): e00577. doi: 10.1016/j.heliyon.2018.e00577
- Abu Bakar Sajak A, Mediani A, Maulidiani, Ismail A, Abas F. Metabolite variation in lean and obese Streptozotocin (STZ)-induced diabetic rats via (1)H NMR-based metabolomics approach. Appl Biochem Biotechnol 2017; 182(2): 653–68. doi: 10.1007/s12010-016-2352-9
- Rathinam A, Pari L, Chandramohan R, Sheikh BA. Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal. J Physiol Biochem 2014; 70(4): 935–46. doi: 10.1007/s13105-014-0362-z
- Boland BB, Brown C, Jr, Boland ML, Cann J, Sulikowski M, Hansen G, et al. Pancreatic beta-cell rest replenishes insulin secretory capacity and attenuates diabetes in an extreme model of obese type 2 diabetes. Diabetes 2019; 68(1): 131–40. doi: 10.2337/db18-0304
- Apovian CM, Okemah J, O’Neil PM. Body weight considerations in the management of type 2 diabetes. Adv Ther 2019; 36(1): 44–58. doi: 10.1007/s12325-018-0824-8
- DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14(3): 173–94. doi: 10.2337/diacare.14.3.173.
- Sala M, Kroft LJ, Roell B, van der Grond J, Slagboom PE, Mooijaart SP, et al. Association of liver enzymes and computed tomography markers of liver steatosis with familial longevity. PLoS One 2014; 9(3): e91085. doi: 10.1371/journal.pone.0091085
- Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol 2002; 3(4): 267–77. doi: 10.1038/nrm782
- Wang J, Huang M, Yang J, Ma X, Zheng S, Deng S, et al. Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter. Food Nutr Res 2017; 61(1): 1364117. doi: 10.1080/16546628.2017.1364117
- Gurley JM, Griesel BA, Olson AL. Increased skeletal muscle GLUT4 expression in obese mice after voluntary wheel running exercise is posttranscriptional. Diabetes 2016; 65(10): 2911–9. doi: 10.2337/db16-0305
- Zhou L, Park SY, Xu L, Xia X, Ye J, Su L, et al. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice. Nat Commun 2015; 6: 5949. doi: 10.1038/ncomms6949
- Garneau L, Aguer C. Role of myokines in the development of skeletal muscle insulin resistance and related metabolic defects in type 2 diabetes. Diabetes Metab 2019; 45(6): 505-516. doi: 10.1016/j.diabet.2019.02.006
- Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci 2018; 14(11): 1483–96. doi: 10.7150/ijbs.27173
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This work is licensed under a Creative Commons Attribution 4.0 International License
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