Abstract
Aims
Oxidative stress plays a pivotal role in the pathogenesis of type 2 diabetes (T2D). In vitro and animal studies have shown that resveratrol exerts an antioxidant effect, but clinical trials addressing this effect in patients with T2D are limited. The aim of this study was to determine whether resveratrol supplementation affects oxidative stress markers in a randomized, placebo-controlled, double-blind clinical trial.
Methods
A total of 48 patients with T2D randomly were assigned to receive 800 mg/day resveratrol or placebo for 2 months. Plasma total antioxidant capacity, malondialdehyde concentration, protein carbonyl and total thiol contents, intracellular superoxide anion (O2−·) and hydrogen peroxide (H2O2) in PBMCs, the expression of genes involved in oxidative stress responses (Nrf2, SOD, Cat, HO-1, RAGE, NOS) in PBMCs, and metabolic and anthropometric parameters were measured at the baseline and at the trial end.
Results
Compared with the placebo group, resveratrol reduced plasma protein carbonyl content and PBMCs O2−· level and significantly increased plasma total antioxidant capacity and total thiol content. Furthermore, the expression of Nrf2 and SOD was significantly increased after resveratrol consumption. Resveratrol had no significant effects on the metabolic and anthropometric parameters except for a significant reduction in weight, BMI, and blood pressure levels. Resveratrol was well tolerated, and no serious adverse event was occurred.
Conclusions
Our study demonstrated that 8 weeks of supplementation with 800 mg/day resveratrol has an antioxidant effect in the blood and PBMCs of patients with T2D.
Clinical Trial Registry number and website IRCT registration number: IRCT2015072523336N1 and http://en.search.irct.ir/view/24752.
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Change history
16 June 2018
Oxidative stress plays a pivotal role in the pathogenesis of type 2 diabetes (T2D). In vitro and animal studies have shown that resveratrol exerts an antioxidant effect, but clinical trials addressing this effect in patients with T2D are limited. The aim of this study was to determine whether resveratrol supplementation affects oxidative stress markers in a randomized, placebo-controlled, double-blind clinical trial.
Abbreviations
- BMI:
-
Body mass index
- Cat:
-
Catalase
- DCFH-DA:
-
Dichloro-dihydro-fluorescein diacetate
- DHE:
-
Dihydroethidium
- FBS:
-
Fasting blood sugar
- FRAP:
-
Ferric reducing ability of plasma
- HDL-C:
-
High-density lipoprotein cholesterol
- HO-1:
-
Heme oxygenase 1
- HOMA-IR:
-
Homeostasis model assessment of insulin resistance
- hsCRP:
-
High-sensitivity C-reactive protein
- LDL-C:
-
Low-density lipoprotein cholesterol
- MDA:
-
Malondialdehyde
- NOS:
-
Nitric oxide synthases
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- PBMCs:
-
Peripheral blood mononuclear cells
- RAGE:
-
Receptor of advanced glycation end product
- ROS:
-
Reactive oxygen species
- SOD:
-
Superoxide dismutase
- TAC:
-
Total antioxidant capacity (TAC)
- T2D:
-
Type 2 diabetes
- WC:
-
Waist circumference
References
Brasnyó P, Sümegi B, Winkler G, Wittmann I (2013) Resveratrol and oxidative stress in diabetes mellitus. In: Preedy V (ed) Diabetes: oxidative stress and dietary antioxidants. Elsevier Inc., Amsterdam
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103(2):137–149. https://doi.org/10.1016/j.diabres.2013.11.002
Ilechukwu C, Ebenebe U, Ubajaka C, Ilika A, Emelumadu O, Nwabueze S (2014) The role of oxidative stress in diabetes mellitus: a 24-year review. Afrimedic J 5(1):1–7
Francisqueti FV, Chiaverini LC, Santos KC et al (1992) The role of oxidative stress on the pathophysiology of metabolic syndrome. Rev Assoc Med Bras 63(1):85–91. https://doi.org/10.1590/1806-9282.63.01.85
Folli F, Corradi D, Fanti P et al (2011) The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro-and macrovascular complications: avenues for a mechanistic-based therapeutic approach. Curr Diabetes Rev 7(5):313–324
Tiwari BK, Pandey KB, Abidi A, Rizvi SI (2013) Markers of oxidative stress during diabetes mellitus. J Biomark, Art id 378790
Martín-Gallán P, Carrascosa A, Gussinyé M, Domínguez C (2003) Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications. Free Radic Biol Med 34(12):1563–1574. https://doi.org/10.1016/s0891-5849(03)00185-0
Timmers S, de Ligt M, Phielix E et al (2016) Resveratrol as add-on therapy in subjects with well-controlled type 2 diabetes: a randomized controlled trial. Diabetes Care 39(12):2211–2217
Gawlik K, Naskalski J, Fedak D et al. (2015) Markers of antioxidant defense in patients with type 2 diabetes. Oxid Med Cell Longev 2016:2352361
Javkhedkar AA, Quiroz Y, Rodriguez-Iturbe B et al (2015) Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 308(10):R840–R846. https://doi.org/10.1152/ajpregu.00308.2014
Jimenez-Osorio AS, Picazo A, Gonzalez-Reyes S, Barrera-Oviedo D, Rodriguez-Arellano ME, Pedraza-Chaverri J (2014) Nrf2 and redox status in prediabetic and diabetic patients. Int J Mol Sci 15(11):20290–20305. https://doi.org/10.3390/ijms151120290
Gerszon J, Rodacka A, Puchała M (2014) Antioxidant properties of resveratrol and its protective effects in neurodegenerative diseases. Adv Cell Biol. https://doi.org/10.2478/acb-2014-0006
Smoliga JM, Baur JA, Hausenblas HA (2011) Resveratrol and health—a comprehensive review of human clinical trials. Mol Nutr Food Res 55(8):1129–1141. https://doi.org/10.1002/mnfr.201100143
Gülçin İ (2010) Antioxidant properties of resveratrol: a structure—activity insight. Innov Food Sci Emerg Technol 11(1):210–218. https://doi.org/10.1016/j.ifset.2009.07.002
de la Lastra CA, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Portland Press Limited, London
Wood LG, Wark PA, Garg ML (2010) Antioxidant and anti-inflammatory effects of resveratrol in airway disease. Antioxid Redox Signal 13(10):1535–1548
Movahed A, Nabipour I, Lieben Louis X et al (2013) Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Altern Med eCAM 2013:851267. https://doi.org/10.1155/2013/851267
Thazhath SS, Wu T, Bound MJ et al (2016) Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial. Am J Clin Nutr 103(1):66–70
Chakraborty A, Chowdhury S, Bhattacharyya M (2011) Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract 93(1):56–62
Ghorbani M, Vatannejad A, Khodadadi I, Amiri I, Tavilani H (2016) Protective effects of glutathione supplementation against oxidative stress during cryopreservation of human spermatozoa. Cryoletters 37(1):34–40
Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329(1):23–38
Schmatz R, Perreira LB, Stefanello N et al (2012) Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats. Biochimie 94(2):374–383. https://doi.org/10.1016/j.biochi.2011.08.005
Soufi FG, Mohammad-nejad D, Ahmadieh H (2012) Resveratrol improves diabetic retinopathy possibly through oxidative stress–nuclear factor κB—apoptosis pathway. Pharmacol Rep 64(6):1505–1514
Mecocci P, Polidori MC (1822) Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta 5:631–638. https://doi.org/10.1016/j.bbadis.2011.10.006
Ndiaye M, Philippe C, Mukhtar H, Ahmad N (2011) The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch Biochem Biophys 508(2):164–170. https://doi.org/10.1016/j.abb.2010.12.030
Shradha B, Sisodia S (2010) Diabetes, dyslipidemia, antioxidant and status of oxidative stress. Intern J Res Ayurveda Pharm 1(1):33–42
Carrizzo A, Forte M, Damato A et al (2013) Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem Toxicol 61:215–226. https://doi.org/10.1016/j.fct.2013.07.021
Leonard SS, Xia C, Jiang B-H et al (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun 309(4):1017–1026
Ghanim H, Sia CL, Abuaysheh S et al (2010) An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab 95(9):E1–E8. https://doi.org/10.1210/jc.2010-0482
De Groote D, Van Belleghem K, Deviere J, Van Brussel W, Mukaneza A, Amininejad L (2012) Effect of the intake of resveratrol, resveratrol phosphate, and catechin-rich grape seed extract on markers of oxidative stress and gene expression in adult obese subjects. Ann Nutr Metab 61(1):15–24. https://doi.org/10.1159/000338634
Buonocore D, Lazzeretti A, Tocabens P et al (2012) Resveratrol-procyanidin blend: nutraceutical and antiaging efficacy evaluated in a placebocontrolled, double-blind study. Clin Cosmet Investig Dermatol 5:159–165. https://doi.org/10.2147/CCID.S36102
Losa G (2003) Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. Eur J Clin Investig 33(9):818–823
Bo S, Ciccone G, Castiglione A et al (2013) Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem 20(10):1323–1331
Imamura H, Yamaguchi T, Nagayama D, Saiki A, Shirai K, Tatsuno I (2017) Resveratrol ameliorates arterial stiffness assessed by cardio-ankle vascular index in patients with type 2 diabetes mellitus. Int Heart J 58(4):577–583
Samsamikor M, Daryani NE, Asl PR, Hekmatdoost A (2016) Resveratrol supplementation and oxidative/anti-oxidative status in patients with ulcerative colitis: a randomized, double-blind, placebo-controlled pilot study. Arch Med Res 47(4):304–309
Bhatt JK, Nanjan MJ (2013) Resveratrol supplementation in patients with type 2 diabetes mellitus: a prospective, open label, randomized controlled trial. Int Res J Pharm 4(8):245–249. https://doi.org/10.7897/2230-8407.04849
Brasnyo P, Molnar GA, Mohas M et al (2011) Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr 106(3):383–389. https://doi.org/10.1017/S0007114511000316
Hausenblas HA, Schoulda JA, Smoliga JM (2015) Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus—systematic review and meta-analysis. Mol Nutr Food Res 59(1):147–159. https://doi.org/10.1002/mnfr.201400173
Sahebkar A (2013) Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 71(12):822–835. https://doi.org/10.1111/nure.12081
Elgebaly A, Radwan IA, AboElnas MM et al (2017) Resveratrol supplementation in patients with non-alcoholic fatty liver disease: systematic review and meta-analysis. J Gastrointest Liver Dis 26(1):59–67. https://doi.org/10.15403/jgld.2014.1121.261.ely
Méndez-del Villar M, González-Ortiz M, Martínez-Abundis E, Pérez-Rubio KG, Lizárraga-Valdez R (2014) Effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord 12(10):497–501
Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A (2014) Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res 34(10):837–843. https://doi.org/10.1016/j.nutres.2014.09.005
Kim S, Jin Y, Choi Y, Park T (2011) Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem Pharmacol 81(11):1343–1351
Lasa A, Churruca I, Eseberri I, Andrés-Lacueva C, Portillo MP (2012) Delipidating effect of resveratrol metabolites in 3T3-L1 adipocytes. Mol Nutr Food Res 56(10):1559–1568
Wang S, Liang X, Yang Q et al (2015) Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) α1. Int J Obes 39(6):967–976
Yang JY, Della-Fera MA, Rayalam S et al (2008) Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci 82(19–20):1032–1039. https://doi.org/10.1016/j.lfs.2008.03.003
Hu P, Zhao L, Chen J (2015) Physiologically achievable doses of resveratrol enhance 3T3-L1 adipocyte differentiation. Eur J Nutr 54(4):569–579. https://doi.org/10.1007/s00394-014-0738-4
Lagouge M, Argmann C, Gerhart-Hines Z et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122. https://doi.org/10.1016/j.cell.2006.11.013
Christenson J, Whitby SJ, Mellor D et al (2016) The effects of resveratrol supplementation in overweight and obese humans: a systematic review of randomized trials. Metab Syndr Relat Disord 14(7):323–333. https://doi.org/10.1089/met.2016.0035
Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomas-Barberan FA, Teresa Garcia-Conesa M, Carlos Espin J (2013) Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 19(34):6064–6093
Gummesson A, Nyman E, Knutsson M, Karpefors M (2017) Effect of weight reduction on glycated haemoglobin in weight loss trials in patients with type 2 diabetes. Diabetes Obes Metab 19(9):1295–1305. https://doi.org/10.1111/dom.12971
Liu Z, Song Y, Zhang X et al (2005) Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin Exp Pharm Physiol 32(12):1049–1054
Acknowledgements
We greatly appreciate the assistance provided by the staff of the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences. We also thank all volunteers for their participation in the study. This work was financially supported by grants from the Deputy of Research, Tehran University of Medical Sciences (Grant 94-01-30-28313), and from the Diabetes Research Center, Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences (Grant 1393-04-97-1879).
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SE conducted the research, analyzed the data or performed statistical analysis, and wrote the paper. HK conducted the research. ENE helped in patients recruitment. RM designed the research, analyzed the data or performed statistical analysis, and had primary responsibility for final content.
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The authors declare that they have no conflicts of interest with the contents of this article.
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The present study was approved by the Ethics Committee of Tehran University of Medical Sciences. The research was recorded in the Iranian Web site for registration of clinical trials (http://www.irct.ir: IRCT2015072523336N1).
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All participants gave written informed consent prior to entering the study.
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Seyyedebrahimi, S., Khodabandehloo, H., Nasli Esfahani, E. et al. The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Acta Diabetol 55, 341–353 (2018). https://doi.org/10.1007/s00592-017-1098-3
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DOI: https://doi.org/10.1007/s00592-017-1098-3