Mirtazapine may show anti-hyperglycemic effect by decreasing GLUT2 through leptin and galanin expressions in the liver of type 1 diabetic rats

Document Type: Original Article

Authors

1 Eskisehir Osmangazi University, Faculty of Medicine, Department of Histology and Embryology, Eskisehir, Turkey

2 Okan University, Faculty of Medicine, Department of Histology and Embryology, Istanbul, Turkey

Abstract

Objective(s): The aim of this study was to explore the molecular mechanism of mirtazapine with respect to energy metabolism in Streptozotocin-induced diabetic liver of rats by immunohistochemistry and Western blot.
Materials and Methods: Twenty-one male Sprague-Dawley rats were assigned into 3 groups including control, type 1 diabetes mellitus (T1DM) group (55 mg/kg Streptozocin, IP) and T1DM+mirtazapine (20 mg/kg,PO) group. At the end of the experiment, blood glucose levels were measured and liver tissues were stained by Periodic acid–Schiff. Moreover, leptin and glucose transporter 2 (GLUT2) proteins were analyzed by western blot and immunohistochemistry; however, galanin were analyzed only by immunohistochemistry.
Results: At the end of the study, in diabetes group, blood glucose level, GLUT2 and galanin expressions increased, while leptin expression decreased when compared to control group. Mirtazapine treatment restored the decreased leptin expression, and the increased blood glucose level and galanine expression to the level of the control group. It also decreased the GLUT2 expression even below the control group.
Conclusion: We concluded that mirtazapine may show its anti-hyperglycemic effect by decreasing GLUT2 through altering the leptin and galanin expression in the liver of type 1 diabetic rats. Mirtazapine can be used as an antidepressant for T1DM patients and as a drug to reduce blood glucose level in T1DM.

Keywords

Main Subjects


1. Kalra SP. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Peptides 2009; 30:1957-1963.
2. Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail ISB. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int 2014; 2014:801269-801287.
3. Prabakaran D, Ashokkumar N. Protective effect of esculetin on hyperglycemia-mediated oxidative damage in the hepatic and renal tissues of experimental diabetic rats. Biochim 2013; 95:366-373.
4. Schilling C, Gilles M, Blum WF, Daseking E, Colla M, Weber-Hamann B, et al. Leptin plasma concentrations increase during antidepressant treatment with amitriptyline and mirtazapine, but not paroxetine and venlafaxine: leptin resistance mediated by antihistaminergic activity? J Clin Psychopharmacol 2013; 33:99-103.
5. Ozsoy S, Besirli A, Abdulrezzak U, Basturk M. Serum ghrelin and leptin levels in patients with depression and the effects of treatment. Psychiatry Investig 2014; 11:167-172.
6. Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci 2013; 7:51-63.
7. Tatemoto K, Rökaeus Å, Jörnvall H, McDonald TJ, Mutt V. Galanin—a novel biologically active peptide from porcine intestine. FEBS lett 1983; 164:124-128.
8. Fang PH, Yu M, Ma YP, Li J, Sui YM, Shi MY. Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neurosci Bull 2011; 27:407-412.
9. Lang R, Kofler B. The galanin peptide family in inflammation. Neuropeptides 2011; 45:1-8.
10. Mitsukawa K, Lu X, Bartfai T. Galanin, galanin receptors and drug targets. Cell Mol Life Sci 2008; 65:1796-1805.
11. Nergiz S, Altınkaya ÖS, Küçük M, Yüksel H, Sezer SD, Kurt Ömürlü İ, et al. Circulating galanin and IL-6 concentrations in gestational diabetes mellitus. Gynecol Endocrinol 2014; 30:236-240.
12. Zhang Z, Fang P, Shi M, Zhu Y, Bo P. Elevated galanin may predict the risk of type 2 diabetes mellitus for development of Alzheimer’s disease. Mech Ageing Dev 2015; 150:20-26.
13. Augustin R. The protein family of glucose transport facilitators: It’s not only about glucose after all. IUBMB life 2010; 62:315-333.
14. De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 2014; 63:2262-2272.
15. De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement 2014; 10:26-32.
16. Laimer M, Kramer-Reinstadler K, Rauchenzauner M, Lechner-Schoner T, Strauss R, Engl J, et al. Effect of mirtazapine treatment on body composition and metabolism. J Clin Psychiatry 2006; 67:421-424.
17. Can OD, Ozkay UD, Dikmen M, Ucel UI. Beneficial effect of mianserin in experimentallyinduced chronic hyperglycemia: evidence of increased Ins1 mRNA expression. Klinik Psikofarmakol Bulteni 2015; 25:113-114.
18. Wang W, Wang C, Ding XQ, Pan Y, Gu TT, Wang MX, et al. Quercetin and allopurinol reduce liver thioredoxin‐interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol 2013; 169:1352-1371.
19. Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012; 83:650-659.
20. Popovic DS, Sekerus V. Levels of different adipocytokines in chronic complications of type 1 diabetes mellitus. Integr Obes Diabetes 2016; 2:255-261.
21. Fang P, Yu M, Shi M, Zhang Z, Sui Y, Guo L, et al. Galanin peptide family as a modulating target for contribution to metabolic syndrome. Gen Com Endocrinol 2012; 179:115-120.
22. Kuteeva E, Wardi T, Hökfelt T, Ögren SO. Galanin enhances and a galanin antagonist attenuates depression-like behaviour in the rat. Eur Neuropsychopharmacol 2007; 17:64-69.
23. Kuteeva E, Wardi T, Lundström L, Sollenberg U, Langel Ü, Hökfelt T, et al. Differential role of galanin receptors in the regulation of depression-like behavior and monoamine/stress-related genes at the cell body level. Neuropsychopharmacology 2008; 33:2573-2585.
24. Kuteeva E, Hökfelt T, Wardi T, Ogren S. Galanin, galanin receptor subtypes and depression-like behaviour. Cell Mol Life Sci 2008; 65:1854-1863.
25. Lundström L, Elmquist A, Bartfai T, Langel Ü. Galanin and its receptors in neurological disorders. Neuromolecular Med 2005; 7:157-180.
26. Agasse F, Xapelli S, Coronas V, Christiansen SH, Rosa AI, Sardá-Arroyo L, et al. Galanin promotes neuronal differentiation in murine subventricular zone cell cultures. Stem Cells Dev 2013; 22:1693-1708.
27. Yu M, Fang P, Shi M, Zhu Y, Sun Y, Li Q, et al. Galanin receptors possibly modulate the obesity-induced change in pain threshold. Peptides 2013; 44:55-59.
28. Fang P, Yu M, Guo L, Bo P, Zhang Z, Shi M. Galanin and its receptors: a novel strategy for appetite control and obesity therapy. Peptides 2012; 36:331-339.
29. Zhang Z, Gu C, Fang P, Shi M, Wang Y, Peng Y, et al. Endogenous galanin as a novel biomarker to predict gestational diabetes mellitus. Peptides 2014; 54:186-189.
30. Fang P, Min W, Sun Y, Guo L, Shi M, Bo P, et al. The potential antidepressant and antidiabetic effects of galanin system. Pharmacol Biochem Behav 2014; 120:82-87.
31. Rathinam A, Pari L. Myrtenal ameliorates hyperglycemia by enhancing GLUT2 through Akt in the skeletal muscle and liver of diabetic rats. Chem-Biol Interact 2016; 256:161-166.
32. Lima-Fontes M, Costa R, Rodrigues I, Soares R. Xanthohumol restores hepatic glucolipid metabolism balance in type 1 diabetic wistar rats. J Agric Food Chem 2017; 65:7433-7439.
33. German JP, Thaler JP, Wisse BE, Oh-i S, Sarruf DA, Matsen ME, et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinol 2010; 152:394-404.
34. Toftegaard C, Knigge U, Kjær A, Warberg J. The role of hypothalamic histamine in leptin-induced suppression of short-term food intake in fasted rats. Regul Pept 2003; 111:83-90.
35. Schmid DA, Wichniak A, Uhr M, Ising M, Brunner H, Held K, et al. Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine. Neuropsychopharmacology 2006; 31:832-844.
36. Marroquí L, Gonzalez A, Ñeco P, Caballero-Garrido E, Vieira E, Ripoll C, et al. Role of leptin in the pancreatic β-cell: effects and signaling pathways. J Mol Endocrinol 2012; 49:9-17.
37. Fagerholm V, Haaparanta M, Scheinin M. α2‐Adrenoceptor regulation of blood glucose homeostasis. Basic Clin Pharmacol 2011; 108:365-370.
38. Anderwald C, Müller Gn, Koca G, Fürnsinn C, Waldhäusl W, Roden M. Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2. Mol Endocrinol 2002; 16:1612-1628.
39. Ceddia R, Lopes G, Souza H, Borba-Murad G, William W, Bazotte R, et al. Acute effects of leptin on glucose metabolism of in situ rat perfused livers and isolated hepatocytes. Int J Obes Relat Metab Disord 1999; 23:1207-1212.
40. Zhao AZ, Shinohara MM, Huang D, Shimizu M, Eldar-Finkelman H, Krebs EG, et al. Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem 2000; 275:11348-11354.
41. Szanto I, Kahn CR. Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Pro Natl Acad Sci U S A 2000; 97:2355-2360.
42. Raman P, Donkin SS, Spurlock ME. Regulation of hepatic glucose metabolism by leptin in pig and rat primary hepatocyte cultures. Am J Physiol Regul Integr Comp Physiol 2004; 286:206-216.
43. Brabant G, Müller G, Horn R, Anderwald C, Roden M, Nave H. Hepatic leptin signaling in obesity. FASEB J 2005; 19:1048-1050.
44. Nemecz M, Preininger K, Englisch R, Fürnsinn C, Schneider B, Waldhäusl W, et al. Acute effect of leptin on hepatic glycogenolysis and gluconeogenesis in perfused rat liver. Hepatology 1999; 29:166-172.
45. Denroche HC, Levi J, Wideman RD, Sequeira RM, Huynh FK, Covey SD, et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 2011; 60:1414-1423.
46. Wang M, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 2010; 107:4813-4819.