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Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

  • Research Article
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Central European Journal of Biology

Abstract

Emerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

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References

  1. Kahn C.R., Insulin action, diabetogenes, and the cause of type II diabetes, Diabetes, 1994, 43, 1066–1084

    Article  PubMed  CAS  Google Scholar 

  2. DeFronzo R.A., Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes, Diabetes, 1997, 5, 177–269

    Google Scholar 

  3. Kahn B.B., Flier J.S., Obesity and insulin resistance, J Clin Invest, 2000, 106, 473–481

    Article  PubMed  CAS  Google Scholar 

  4. Maritim A.C., Sanders R.A., Watkins J.B., Diabetes, oxidative stress, and antioxidants: a review, J Biochem Mol Toxicol, 2003, 17, 24–38

    Article  PubMed  CAS  Google Scholar 

  5. Pablos M.I., Guerrero J.M., Ortiz G.G., Agapito M.T., ReiterBoth R.J., Melatonin and a putative nuclear melatonin receptor agonist CGP 52608 stimulate glutathione peroxidase and glutathione reductase activities in mouse brain in vivo, Neuroendocrinol Lett, 1997, 18, 49–58

    CAS  Google Scholar 

  6. Barlow-Walden L.R., Reiter R.J., Abe M., Pablos M., Menendez-Pelaez A., Chen L.D., et al., Melatonin stimulates brain glutathione peroxidase activity, Neurochem Int, 1995, 26, 497–502

    Article  PubMed  CAS  Google Scholar 

  7. Antolin I., Rodriquez C., Sainz R.M., Mayo J.C., Aria H., Kotler M., et al., Neurohormone melatonin prevent damage: effect on gene expression for antioxidative enzymes, FASEB J, 1996, 10, 882–890

    PubMed  CAS  Google Scholar 

  8. Okatani Y., Wakatsuki A., Kaneda C., Melatonin increases activities of glutathione peroxidase and superoxide dismutase in fetal rat brain, J Pineal Res, 2000, 28, 89–96

    Article  PubMed  CAS  Google Scholar 

  9. Forrest C.M., Mackay G.M., Stoy N., Stone T.W., Darlington L.G., Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin, Br J Clin Pharmacol, 2007, 64, 517–526

    Article  PubMed  CAS  Google Scholar 

  10. Kedziora-Kornatowska K., Szewczyk-Golec K., Czuczejko J., Pawluk H., van Marke de Lumen K., Kozakiewicz M., et al., Antioxidative effects of melatonin administration in elderly primary essential hypertension patients, J Pineal Res, 2008, 45, 312–317

    Article  PubMed  CAS  Google Scholar 

  11. Tamura H., Takasaki A., Miwa I., Taniguchi K., Maekawa R., Asada H., et al., Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate, J Pineal Res, 2008, 44, 280–287

    Article  PubMed  CAS  Google Scholar 

  12. Jang J.W., Lee J.K., Lee M.C., Piao M.S., Kim S.H., Kim H.S., Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model, J Neurol Sci, 2012, 323, 221–227

    Article  PubMed  CAS  Google Scholar 

  13. Hirai N., Kawano H., Hirashima O., Motoyama T., Moriyama Y., Sakamoto T., et al., Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C, Am J Physiol, 2000, 279, H1172–H1178

    CAS  Google Scholar 

  14. Jacob S., Ruus P., Hermann R., Tritschler H.J., Maerker E., Renn W., et al., Oral administration of RAC-α-lipoic acid modulates insulin sensitivity in patients with type 2 diabetes mellitus: a placebo-controlled pilot trial, Free Radic Biol Med, 1999, 27, 309–314

    Article  PubMed  CAS  Google Scholar 

  15. Caballero B., Vitamin E improves the action of insulin, Nutr Rev, 1993, 51, 339–340

    Article  PubMed  CAS  Google Scholar 

  16. Paolisso G., Di Maro G., Pizza G., D’Amore A., Sgambato S., Tesauro P., et al., Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics, Am J Physiol, 1992, 263, E435–E440

    PubMed  CAS  Google Scholar 

  17. Montilla P.L., Vargas J.F., Túnez I.F., Muñoz de Agueda M.C., Valdelvira M.E., Cabrera E.S., Oxidative stress in diabetes rats induced by streptozotocin: protective effects of melatonin, J Pineal Res, 1998, 25, 94–100

    Article  PubMed  CAS  Google Scholar 

  18. Nishida S., Segawa T., Murai I., Nakagawa S., Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity, J Pineal Res, 2002, 32, 26–33

    Article  PubMed  CAS  Google Scholar 

  19. Jomain-Baum M., Schramm V.L., Kinetic mechanism of phosphoenolpyruvate carboxykinase (GTP) from rat liver cytosol. Product inhibition, isotope exchange at equilibrium, and partial reactions, J Biol Chem, 1978, 253, 3648–3659

    PubMed  CAS  Google Scholar 

  20. Nakatani Y., Kaneto H., Kawamori D., Hatazaki M., Miyatsuka T., Matsuoka T.A., Modulation of the JNK pathway in liver affects insulin resistance status, J Biol Chem, 2004, 279, 45803–45809

    Article  PubMed  CAS  Google Scholar 

  21. Hariri N., Thibault L., High-fat diet-induced obesity in animal models, Nutr Res, 2010, 23, 270–299

    Article  CAS  Google Scholar 

  22. Golay A., Bobbioni E., The role of dietary fat in obesity, Int J Obes Relat Metab Disord, 1997, 3, S2–11

    Google Scholar 

  23. Boden G., Role of fatty acids in the pathogenesis of insulin resistance and NIDDM, Diabetes, 1997, 46, 3–10

    Article  PubMed  CAS  Google Scholar 

  24. Henry R.R., Impaired muscle fat metabolism: a cause or effect of visceral obesity? J Clin Invest, 1995, 95, 1427–1428

    Article  PubMed  CAS  Google Scholar 

  25. Lewis G.F., Carpentier A., Adeli K., Giacca A., Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes, Endocr Rev, 2002, 23, 201–229

    Article  PubMed  CAS  Google Scholar 

  26. McGarry J.D., Glucose-fatty acid interactions in health and disease, Am J Clin Nutr, 1998, 67, 500S–504S

    PubMed  CAS  Google Scholar 

  27. Thamer C., Machann J., Stefan N., Haap M., Schäfer S., Brenner S., High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention, Obesity (Silver Spring), 2007, 15, 531–538

    Article  Google Scholar 

  28. Lin C.Y., Chen P.C., Kuo H.K., Lin L.Y., Lin J.W., Hwang J.J., Effects of obesity, physical activity, and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance in the National Health and Nutrition Survey, Nutr Metab Cardiovasc Dis, 2010, 20, 713–719

    Article  PubMed  Google Scholar 

  29. Wolden-Hanson T., Mitton D.R., McCants R.L., Yellon S.M., Wilkinson C.W., Matsumoto A.M., et al., Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat, Endocrinology, 2000, 141, 487–497

    Article  PubMed  CAS  Google Scholar 

  30. Prunet-Marcassus B., Desbazeille M., Bros A., Louche K., Delagrange P., Renard P., et al., Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity, Endocrinology, 2003, 44, 5347–5352

    Article  Google Scholar 

  31. Cardinali D.P., Bernasconi P.A., Reynoso R., Toso C.F., Scacchi P., Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats, Int J Mol Sci, 2013, 14, 2502–2514

    Article  PubMed  CAS  Google Scholar 

  32. Faria J.A., Kinote A., Ignacio-Souza L.M., de Araújo T.M., Razolli D.S., Doneda D.L., et al., Melatonin acts through MT1/MT2 receptors to activate hypothalamic AKT and suppress hepatic gluconeogenesis in rats, Am J Physiol Endocrinol Metab, 2013, doi: 10.1152/ajpendo.00094.2013

    Google Scholar 

  33. Zanuto R., Siqueira-Filho M.A., Caperuto L.C., Bacurau R.F., Hirata E., Peliciari-Garcia R.A., et al., Melatonin improves insulin sensitivity independently of weight loss in old obese rats, J Pineal Res, 2013, doi: 10.1111/jpi.12056

    Google Scholar 

  34. Korkmaz A., Ma S., Topal T., Rosales-Corral S., Tan D.X., Reiter R.J., Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state, Mol Cell Endocrinol, 2012, 349, 128–137

    Article  PubMed  CAS  Google Scholar 

  35. Agil A., Rosado I., Ruiz R., Figueroa A., Zen N., Fernández-Vázquez G., Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats, J Pineal Res, 2012, 52, 203–210

    Article  PubMed  CAS  Google Scholar 

  36. Blair A.S., Hajduch E., Litherland G.J., Hundal H.S., Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress. Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways, J Biol Chem, 1999, 274, 36293–36299

    Article  PubMed  CAS  Google Scholar 

  37. Tirosh A., Potashnik R., Bashan N., Rudich A., Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation, J Biol Chem, 1999, 274, 10595–10602

    Article  PubMed  CAS  Google Scholar 

  38. Tirosh A., Rudich A., Potashnik R., Bashan N., Oxidative stress impairs insulin but not plateletderived growth factor signalling in 3T3-L1 adipocytes, Biochem J, 2001, 355, 757–763

    PubMed  CAS  Google Scholar 

  39. Evans J.L., Goldfine I.D., Maddux B.A., Grodsky G.M., Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes, Endocr Rev, 2002, 23, 599–622

    Article  PubMed  CAS  Google Scholar 

  40. Barthel A., Schmoll D., Novel concepts in insulin regulation of hepatic gluconeogenesis, Am J Physiol Endocrinol Metab, 2003, 285, E685–692

    PubMed  CAS  Google Scholar 

  41. Wan X.D., Yang W.B., Xia Y.Z., Wang J.F., Lu T., Wang X.M., Disruption of glucose homeostasis and induction of insulin resistance by elevated free fatty acids in human L02 hepatocytes, J Endocrinol Invest, 2009, 32, 454–459

    PubMed  CAS  Google Scholar 

  42. Manning B.D., Cantley L.C., AKT/PKB signaling: navigating downstream, Cell, 2007, 129, 1261–1274

    Article  PubMed  CAS  Google Scholar 

  43. Liu H.Y., Wen G.B., Han J., Hong T., Zhuo D., Liu Z., et al., Inhibition of gluconeogenesis in primary hepatocytes by stromal cell-derived factor-1 (SDF-1) through a c-Src/Akt-dependent signaling pathway, J Biol Chem, 2008, 283, 30642–30649

    Article  PubMed  CAS  Google Scholar 

  44. Altomonte J., Richter A., Harbaran S., Suriawinata J., Nakae J., Thung S.N., et al., Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice, Am J Physiol Endocrinol Metab, 2003, 285, E718–728

    PubMed  CAS  Google Scholar 

  45. Marzban L., Rahimian R., Brownsey R.W., McNeill J.H., Mechanisms by which bis(maltolato)oxovanadium(IV) normalizes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression in streptozotocindiabetic rats in vivo, Endocrinology, 2002, 143, 4636–4645

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College, Henan University of Science and Technology, 471003, Luoyang, China

    Xue-Dong Wan, San-Qiang Li & Shou-Min Xi

  2. Biochemistry Department of Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China

    Jian-Fei Wang, Yan-Chun Guo & Xi-Ming Wang

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  1. Xue-Dong Wan
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Correspondence to Xi-Ming Wang.

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Wan, XD., Li, SQ., Xi, SM. et al. Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats. cent.eur.j.biol. 8, 958–967 (2013). https://doi.org/10.2478/s11535-013-0211-z

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  • DOI: https://doi.org/10.2478/s11535-013-0211-z

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