Hesperidin prevents hyperglycemia in diabetic rats by activating the insulin receptor pathway

Peng,Peng; Jin,Juan; Zou,Guoliang; Sui,Yanbo; Han,Yubo; Zhao,Dapeng; Liu,Li

doi:10.3892/etm.2020.9485

Hesperidin prevents hyperglycemia in diabetic rats by activating the insulin receptor pathway

Authors:
- Peng Peng
- Juan Jin
- Guoliang Zou
- Yanbo Sui
- Yubo Han
- Dapeng Zhao
- Li Liu
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Affiliations: Graduate School, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, The First Department of Cardiovascular, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, Department of Nephropathy, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
Published online on: November 19, 2020 https://doi.org/10.3892/etm.2020.9485
Article Number: 53

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Abstract

Diabetes, a disease with high prevalence in China, is a major risk factor of cardiovascular disease. Hesperidin is a flavanone glycoside with anti‑hyperglycemic and anti‑hyperlipidemic activities. Therefore, the present study aimed to investigate the potential preventive effect of hesperidin against type 2 diabetes mellitus (T2DM) using a rat model of alloxan and high fat diet (HFD)‑induced insulin resistance. Male Sprague Dawley rats were orally administered with 100 mg/kg hesperidin or vehicle (sodium carboxy methyl cellulose) for 35 days. Insulin resistance was induced by feeding animals a HFD for 3 weeks (from day 7) and then with an alloxan injection on day 28. Results from the in vivo study demonstrated that hesperidin improved fasting serum glucose (from 19.8 to 10.6 mmol/l) without changing the fasting insulin level, suggesting that hesperidin prevented the development of insulin resistance and diabetes by improving insulin sensitivity. In the oral glucose tolerance test, the development of impaired glucose tolerance was also prevented by hesperidin treatment. Hesperidin was found to regulate glycolysis and gluconeogenesis by enhancing the activity of glucokinase, inducing the phosphorylation of insulin receptor (IR) and phosphoinositide‑dependent kinase 1 (PDK1), while decreasing the activity of glucose‑6‑phosphatase and phosphoenolpyruvate carboxykinase in the liver. In a cell‑based assay, hesperidin increased glucose uptake in primary rat adipocytes. Collectively, the present study identified the potent preventive effect of hesperidin against HFD‑induced insulin resistance by activating the IR/PDK1 pathway. The current results may provide a potential strategy lacking sides effects to improve metabolic health and reduce risks.

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1	Elizabeth MM, Alarcon-Aguilar J F, Clara OC, Escobar-Villanueva and Carmen M: Pancreatic β-cells and type 2 diabetes development. Curr Diabetes Rev. 13:108–121. 2017.PubMed/NCBI View Article : Google Scholar
2	American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care. 40 (Suppl 1):S11–S24. 2017.PubMed/NCBI View Article : Google Scholar
3	Xu Y, Wang L, He J, Bi Y, Li M, Wang T, Wang L, Jiang Y, Dai M, Lu J, et al: 2010 China Noncommunicable Disease Surveillance Group: Prevalence and control of diabetes in Chinese adults. JAMA. 310:948–959. 2013.PubMed/NCBI View Article : Google Scholar
4	Yang SH, Dou KF and Song WJ: Prevalence of diabetes among men and women in China. N Engl J Med. 362:2425–2426; author reply 2426. 2010.PubMed/NCBI View Article : Google Scholar
5	Wang L, Gao P, Zhang M, Huang Z, Zhang D, Deng Q, Li Y, Zhao Z, Qin X, Jin D, et al: Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 317:2515–2523. 2017.PubMed/NCBI View Article : Google Scholar
6	Yang L, Shao J, Bian Y, Wu H, Shi L, Zeng L, Li W and Dong J: Prevalence of type 2 diabetes mellitus among inland residents in China (2000-2014): A meta-analysis. J Diabetes Investig. 7:845–852. 2016.PubMed/NCBI View Article : Google Scholar
7	Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, et al: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 7:941–946. 2001.PubMed/NCBI View Article : Google Scholar
8	DeFronzo RA and Ferrannini E: Insulin resistance A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 14:173–194. 1991.PubMed/NCBI View Article : Google Scholar
9	Leto D and Saltiel AR: Regulation of glucose transport by insulin: Traffic control of GLUT4. Nat Rev Mol Cell Biol. 13:383–396. 2012.PubMed/NCBI View Article : Google Scholar
10	Pollak M: The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat Rev Cancer. 12:159–169. 2012.PubMed/NCBI View Article : Google Scholar
11	Zhang H, Tan C, Wang H, Xue S and Wang M: Study on the history of Traditional Chinese Medicine to treat diabetes. Eur J Integr Med. 2:41–46. 2010.
12	Calixto JB: Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents). Braz J Med Biol Res. 33:179–189. 2000.PubMed/NCBI View Article : Google Scholar
13	Valli G and Giardina EG: Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol. 39:1083–1095. 2002.PubMed/NCBI View Article : Google Scholar
14	Ong KC and Khoo HE: Insulinomimetic effects of myricetin on lipogenesis and glucose transport in rat adipocytes but not glucose transport translocation. Biochem Pharmacol. 51:423–429. 1996.PubMed/NCBI View Article : Google Scholar
15	Hsu FL, Liu IM, Kuo DH, Chen WC, Su HC and Cheng JT: Antihyperglycemic effect of puerarin in streptozotocin-induced diabetic rats. J Nat Prod. 66:788–792. 2003.PubMed/NCBI View Article : Google Scholar
16	Choi JS, Yokozawa T and Oura H: Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Med. 57:208–211. 1991.PubMed/NCBI View Article : Google Scholar
17	Shisheva A and Shechter Y: Quercetin selectively inhibits insulin receptor function in vitro and the bioresponses of insulin and insulinomimetic agents in rat adipocytes. Biochemistry. 31:8059–8063. 1992.PubMed/NCBI View Article : Google Scholar
18	Garg A, Garg S, Zaneveld LJ and Singla AK: Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 15:655–669. 2001.PubMed/NCBI View Article : Google Scholar
19	Jung UJ, Lee MK, Jeong KS and Choi MS: The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J Nutr. 134:2499–2503. 2004.PubMed/NCBI View Article : Google Scholar
20	Akiyama S, Katsumata S, Suzuki K, Nakaya Y, Ishimi Y and Uehara M: Hypoglycemic and hypolipidemic effects of hesperidin and cyclodextrin-clathrated hesperetin in Goto-Kakizaki rats with type 2 diabetes. Biosci Biotechnol Biochem. 73:2779–2782. 2009.PubMed/NCBI View Article : Google Scholar
21	Ahmed OM, Mahmoud AM, Abdelmoneim A and Ashour MB: Antidiabetic effects of hesperidin and naringin in type 2 diabetic rats. Diabetol Croat. 41:53–67. 2012.PubMed/NCBI View Article : Google Scholar
22	Shi X, Liao S, Mi H, Guo C, Qi D, Li F, Zhang C and Yang Z: Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules. 17:12868–12881. 2012.PubMed/NCBI View Article : Google Scholar
23	Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R and Goldstein BJ: Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes. 52:1355–1363. 2003.PubMed/NCBI View Article : Google Scholar
24	China Food and Drug Administration (CFDA): Technical standards for testing and assessment of health food. CFDA, 2003.
25	Davidson AL and Arion WJ: Factors underlying significant underestimations of glucokinase activity in crude liver extracts: Physiological implications of higher cellular activity. Arch Biochem Biophys. 253:156–167. 1987.PubMed/NCBI View Article : Google Scholar
26	Alegre M, Ciudad CJ, Fillat C and Guinovart JJ: Determination of glucose-6-phosphatase activity using the glucose dehydrogenase-coupled reaction. Anal Biochem. 173:185–189. 1988.PubMed/NCBI View Article : Google Scholar
27	Bentle LA and Lardy HA: Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. J Biol Chem. 251:2916–2921. 1976.PubMed/NCBI
28	Nordlie RC and Foster JD: A retrospective review of the roles of multifunctional glucose-6-phosphatase in blood glucose homeostasis: Genesis of the tuning/retuning hypothesis. Life Sci. 87:339–349. 2010.PubMed/NCBI View Article : Google Scholar
29	Liu Y, Li X, Xie C, Luo X, Bao Y, Wu B, Hu Y, Zhong Z, Liu C and Li M: Prevention effects and possible molecular mechanism of mulberry leaf extract and its formulation on rats with insulin-insensitivity. PLoS One. 11(e0152728)2016.PubMed/NCBI View Article : Google Scholar
30	Zhang Y, Dong H, Wang M and Zhang J: Quercetin isolated from Toona sinensis leaves attenuates hyperglycemia and protects hepatocytes in high-carbohydrate/high-fat diet and alloxan induced experimental diabetic mice. J Diabetes Res. 2016(8492780)2016.PubMed/NCBI View Article : Google Scholar
31	Wallace TM, Levy JC and Matthews DR: Use and abuse of HOMA modeling. Diabetes Care. 27:1487–1495. 2004.PubMed/NCBI View Article : Google Scholar
32	Geloneze B, Vasques AC, Stabe CF, Pareja JC, Rosado LE, Queiroz EC and Tambascia MA: BRAMS Investigators. HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome: Brazilian Metabolic Syndrome Study (BRAMS). Arq Bras Endocrinol Metabol. 53:281–287. 2009.PubMed/NCBI View Article : Google Scholar
33	Wei W and Wu XM: Li: Experimental Methodology of Pharmacology. 4th edition. People's Medical Publishing House, Beijing, 2010 (In Chinese).
34	DeFronzo RA: Lilly lecture 1987. The triumvirate: Beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 37:667–687. 1988.PubMed/NCBI View Article : Google Scholar
35	Reaven GM: Pathophysiology of insulin resistance in human disease. Physiol Rev. 75:473–486. 1995.PubMed/NCBI View Article : Google Scholar
36	Iynedjian PB, Gjinovci A and Renold AE: Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J Biol Chem. 263:740–744. 1988.PubMed/NCBI
37	Massillon D, Chen W, Barzilai N, Prus-Wertheimer D, Hawkins M, Liu R, Taub R and Rossetti L: Carbon flux via the pentose phosphate pathway regulates the hepatic expression of the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase genes in conscious rats. J Biol Chem. 273:228–234. 1998.PubMed/NCBI View Article : Google Scholar
38	Lochhead PA, Salt IP, Walker KS, Hardie DG and Sutherland C: 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 49:896–903. 2000.PubMed/NCBI View Article : Google Scholar
39	Al-Quraishy S, Dkhil MA and Abdel Moneim AE: Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. Int J Nanomedicine. 10:6741–6756. 2015.PubMed/NCBI View Article : Google Scholar
40	Govers R: Cellular regulation of glucose uptake by glucose transporter GLUT4. Adv Clin Chem. 66:173–240. 2014.PubMed/NCBI View Article : Google Scholar
41	Natali A and Ferrannini E: Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: A systematic review. Diabetologia. 49:434–441. 2006.PubMed/NCBI View Article : Google Scholar
42	Dhanya R, Arun KB, Nisha VM, Syama HP, Nisha P, Santhosh Kumar TR and Jayamurthy P: Preconditioning L6 muscle cells with naringin ameliorates oxidative stress and increases glucose uptake. PLoS One. 10(e0132429)2015.PubMed/NCBI View Article : Google Scholar
43	Zygmunt K, Faubert B, MacNeil J and Tsiani E: Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun. 398:178–183. 2010.PubMed/NCBI View Article : Google Scholar
44	Yang Y, Wolfram J, Boom K, Fang X, Shen H and Ferrari M: Hesperetin impairs glucose uptake and inhibits proliferation of breast cancer cells. Cell Biochem Funct. 31:374–379. 2013.PubMed/NCBI View Article : Google Scholar
45	Ganugapati J, Baldwa A and Lalani S: Molecular docking studies of banana flower flavonoids as insulin receptor tyrosine kinase activators as a cure for diabetes mellitus. Bioinformation. 8:216–220. 2012.PubMed/NCBI View Article : Google Scholar
46	Cohen P, Alessi DR and Cross DAE: PDK1, one of the missing links in insulin signal transduction? FEBS Lett. 410:3–10. 1997.PubMed/NCBI View Article : Google Scholar