Resveratrol attenuates visfatin and vaspin genes expression in adipose tissue of rats with type 2 diabetes

Document Type : Original Article


1 Department of Clinical Biochemistry, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran

2 Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

3 Department of Molecular Medicine and Genetic, Medical School, Hamadan University of Medical Sciences, Hamadan, Iran

4 Chronic Diseases (Home Care) Research Center, Hamadan University of Medical Sciences, Hamadan, Iran


Objective(s): Visfatin and vaspin are secreted by adipose tissue and play key roles in glucose homeostasis and subsequently are potential targets for diabetes treatment. Resveratrol (RVS) corrects insulin secretion and improves insulin sensitivity. We investigated the RVS effects on serum antioxidants, insulin and glucose levels, also visfatin and vaspin genes expression in adipose tissue of streptozotocin-nicotinamide (STZ-NA) induced type 2 diabetic rats.
Materials and Methods: Diabetes was induced in Wistar rats (n=32) using STZ (60 mg/kg body weight) and NA (120 mg/kg body weight); rats were divided into 4 groups (n=8). Eight untreated normal rats were used as control group; four diabetic rat groups (2–5) were treated with 0, 1, 5 and 10 mg /kg body weight of RVS, respectively for 30 days. After treatment blood and adipose tissue were prepared from all animals. Serum glucose, insulin, HOMA index, total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Visfatin and vaspin genes expression in adipose tissue were evaluated using real-time PCR.
Results: RVS reduced blood glucose significantly and increased insulin level, resulting in insulin sensitivity improvement. Furthermore RVS increased weight and TAC, while reducing serum MDA in the diabetic groups. Visfatin gene expression increased in the diabetic group, and RVS treatment reduced it. Vaspin gene expression was reduced in RVS receiving diabetic groups.
Conclusion: The results indicated that RVS has potential hypoglycemic effect, probably by increasing insulin level and changing gene expression of visfatin and vaspin. Moreover RVS showed antioxidant effects through reduction in peroxidiation products and augmented antioxidant capacity.


1. Organization WH. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: WHO; 2006.p.1-50.
2. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6:772-783.
3. Trayhurn P. Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 2005; 184:285-293.
4. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 2005; 307:426-430.
5. Flier JS, Maratos-Flier E. Biology of obesity. In: Wiener C, Fauci AS, Braunwald E, Kasper D, Hauser Sl, Longo DL et al. editors.  Harrison's principle of internal medicine. 17th ed. Philadelphia: The Mcgraw-Hill companies Inc; 2008. p. 262-263.
6. Ognjanovic S, Bao S, Yamamoto S, Garibay-Tupas J, Samal B, Bryant-Greenwood G. Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes.J Mol Endocrinol 2001; 26:107-117.
7. Berndt J, Klöting N, Kralisch S, Kovacs P, Fasshauer M, Schön MR, et al. Plasma visfatin concentrations and fat depot–specific mRNA expression in humans. Diabetes 2005; 54:2911-2916.
8. Dogru T, Sonmez A, Tasci I, Bozoglu E, Yilmaz MI, Genc H, et al. Plasma visfatin levels in patients with newly diagnosed and untreated type 2 diabetes mellitus and impaired glucose tolerance. Diabetes Res Clin Pract 2007; 76:24-29.
9. Gettins PG. Serpin structure, mechanism, and function. Chem Rev 2002; 102:4751-804.
10. Law R, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, et al. An overview of the serpin superfamily. Genome Biol 2006; 7:216.
11. Silverman GA, Bird PI, Carrell RW, Coughlin PB, Gettins PG, Irving JI, et al. The serpins are an expanding superfamily of structurally similar but funtionally diverse proteins: Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001; 276:33293-33296.
12. Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005; 102:10610-10615.
13. Wada J. Vaspin: a novel serpin with insulin-sensitizing effects. Expert Opin Investig Drug 2008; 17:327-333.
14. Burgess TA, Robich MP, Chu LM, Bianchi C, Sellke FW. Improving glucose metabolism with resveratrol in a swine model of metabolic syndrome through alteration of signaling pathways in the liver and skeletal muscle. Arch Surg 2011; 146:556-564.
15. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337-342.
16. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006; 127:1109-1122.
17. Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol 2010; 635:1-8.
18. Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B, Cseh J, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr 2011; 106:383-389.
19. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 2012; 32:537-541.
20. Movahed A, Nabipour I, Lieben Louis X, Thandapilly SJ, Yu L, Kalantarhormozi M, et al.
Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Alternat Med 2013; 2013:851267.
21. Chen WP, Chi TC, Chuang LM, Su MJ.Resveratrol enhances insulin secretion by blocking K (ATP) and K (V) channels of beta cells. Eur J Pharmacol 2007; 568:269-277. 
22.  Hambrock A, de Oliveira Franz CB, Hiller S, Grenz A, Ackermann S, Schulze DU, et al. Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner. J Biol Chem 2007; 282:3347-3356.
23. Derdemezis CS, Kiortsis DN, Tsimihodimos V, Petraki MP, Vezyraki P, Elisaf MS, et al. Effect of plant polyphenols on adipokine secretion from human SGBS adipocytes. Biochem Res Int 2011; 2011:285618.
24.  Schirmer H, Pereira TCB, Rico EP, Rosemberg DB, Bonan CD, Bogo MR, et al. Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver. Mol Biol Rep 2012; 39:3281-3289.
25. Sheela N, Jose MA, Sathyamurthy D, Kumar BN. Effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats. Iran J Kidney Dis 2013; 7:117-123.
26. LeDoux S, Woodley S, Patton N, Wilson G. Mechanisms of nitrosourea-induced β-cell damage: alterations in DNA. Diabetes 1986; 35:866-872.
27. Sandler S, Swenne I. Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro. Diabetologia 1983; 25:444-447.
28. Srinivasan K, Viswanad B, Asrat L, Kaul C, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 2005; 52:313-320.
29. Kante K, Reddy CS. Anti diabetic activity of Dolichos lablab (seeds) in Streptozotocin- Nicotinamide induced diabetic rats. Hygeia J D Med 2013; 5:32-40.
30. Kohn DF, Wixson SK, White WJ, Benson GJ, editors. Anesthesia and analgesia in laboratory animals. San Diego: Academic Press; 1997.
31. Rio DC, Ares M, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc 2010; 2010:pdb. prot5439.
32. Katsuki A, Sumida Y, Gabazza EC, Murashima S, Furuta M, Araki-Sasaki R, et al. Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes Care 2001; 24:362-365.
33. Benzie IF, Strain J. Ferric reducing/antioxidant power assay: Direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol 1999; 299:15-27.
34. Yagi K. A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 1976; 15:212-216.
35. Kobayashi K, Inoguchi T. Adipokines: therapeutic targets for metabolic syndrome. Curr Drug Targets 2005; 6:525-9.
36. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance.Mol Endocrinol 2008; 22:1023-1031.
37. Mohammadi A, Gholamhoseinian A, Fallah H. Zataria multiflora increases insulin sensitivity and PPARγ gene expression in high fructose fed insulin resistant rats. Iran J Basic Med Sci 2014; 17:263–270.
38. Hambrock A, de Oliveira Franz CB, Hiller S, Grenz A, Ackermann S, Schulze DU, et al. Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner. J Biol Chem 2007; 282:3347--3356.
39. Sharma S, Misra CS, Arumugam S, Roy S, Shah V, Davis JA, et al. Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type‐2 diabetes. Phytother Res 2011; 25:67-73.
40. Palsamy P, Subramanian S. Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother. 2008; 62:598-605.
41. Rivera L, Morón R, Zarzuelo A, Galisteo M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem pharmacol 2009; 77:1053-1063.
42. Su H-C, Hung L-M, Chen J-K. Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 2006; 290:E1339-E46.
43. Rezaei Farimani A, Goodarzi MT, Saidijam M, Yadgar Azari R, Asadi S, Zarei S, et al. The effect of resveratrol supplementation on the SNARE proteins expression in adipose tissue of stroptozotocin-nicotinamide induced type 2 diabetic rats. Iran J Med Sci 2015; 40:248-255
44. Prasad K. Oxidative stress as a mechanism of diabetes in diabetic BB prone rats: effect of secoisolariciresinol diglucoside (SDG). Mol Cell Biochem 2000; 209:89-96.
45. Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, Gharbi N, Kamoun A, et al. Protective effect of resveratrol on ethanol-induced lipid peroxidation in rats. Alcohol 2006; 41:236-239.
46. Opara EC, Abdel-Rahman E, Soliman S, Kamel WA, Souka S, Lowe JE, et al. Depletion of total antioxidant capacity in type 2 diabetes. Metabolism 1999; 48:1414-1417.
47. Franco JG, de Moura EG, Koury JC, Trotta PA, Cordeiro A, Souza LL, et al. Resveratrol reduces lipid peroxidation and increases sirtuin 1 expression in adult animals programed by neonatal protein restriction. J Endocrinol 2010; 207:319-328.
48. Li L, Yang G, Li Q, Tang Y, Yang M, Yang H, et al. Changes and relations of circulating visfatin, apelin, and resistin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects. Exp Clin Endocrinol Diabetes 2006; 114:544-548.
49. Palin M-F, Labrecque B, Beaudry D, Mayhue M, Bordignon V, Murphy BD. Visfatin expression is not associated with adipose tissue abundance in the porcine model. Domest Anim Endocrinol 2008;35:58-73.
50. Retnakaran R, Youn BS, Liu Y, Hanley AJ, Lee NS, Park JW, et al. Correlation of circulating full‐length visfatin (PBEF/NAMPT) with metabolic parameters in subjects with and without diabetes: a cross‐sectional study. Clin endocrinol (Oxf) 2008; 69:885-893.
51. Sandeep S, Velmurugan K, Deepa R, Mohan V. Serum visfatin in relation to visceral fat, obesity, and type 2 diabetes mellitus in Asian Indians. Metabolism 2007; 56:565-570.
52. Eseberri I, Lasa A, Churruca I, Portillo MP. Resveratrol metabolites modify adipokine expression and secretion in 3T3-L1 pre-adipocytes and mature adipocytes. PloS One 2013; 8:e63918.
53. Klöting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schön MR, et al. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun  2006; 339:430-436.
54. Klöting N, Kovacs P, Kern M, Heiker J, Fasshauer M, Schön M, et al. Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects. Diabetologia 2011; 54:1819-1823.
55. Li K, Li L, Yang M, Liu H, Liu D, Yang H, et al. Short-term continuous subcutaneous insulin infusion decreases the plasma vaspin levels in patients with type 2 diabetes mellitus concomitant with improvement in insulin sensitivity. Eur J Endocrinol 2011; 164:905-910.
56. Youn B-S, Klöting N, Kratzsch J, Lee N, Park JW, Song E-S, et al. Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 2008;57:372-377.