Effect of Resveratrol Administration on Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion

Effect of Resveratrol Administration on Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion

Effect of Resveratrol Administration on Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion

The Metabolic Syndrome is a high prevalence disease worldwide. About a quarter of the adult population suffers the disease. Resveratrol is a substance found in many plants, including grapes, nuts and wine, but it's also found in Polygonum cuspidatum. There is evidence that resveratrol consumption has beneficial effects on glucose and lipids metabolism, blood pressure and body weight. The aim of this study was to evaluate the effect of resveratrol on metabolic syndrome, insulin sensitivity and insulin secretion. The investigators hypothesis was that the administration of resveratrol modifies the metabolic syndrome, insulin sensitivity and insulin secretion.

A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome in accordance with the International Diabetes Federation (IDF). Waist circumference, glucose, insulin levels, lipid profile, creatinine and acid uric were evaluated after a 75 g of dextrose load. 12 received resveratrol, 500 mg, three times per day (1500 mg) before meals during 3 months. The remaining 12 patients received placebo with the same prescription. Area Under the Curve of glucose and insulin was calculated as well as total insulin secretion (insulinogenic index), first-phase of insulin secretion (Stumvoll index) and insulin sensitivity (Matsuda index). This protocol was approved by a local ethics committee and written informed consent was obtained from all volunteers. Results are presented as mean and standard deviation. Intra and inter group differences were tested using the Wilcoxon signed-rank and Mann-Whitney U-test respectively; p≤0.05 was considered significant.

Resveratrol capsules of 500 mg three times per day before meals with a total dosis of 1500 mg per day.

Calcined magnesia capsules, 500 mg, three times per day before meals with a total dose per day of 1500 mg

The triglycerides were evaluated at baseline and week 12 with enzymatic-colorimetric techniques and the entered values reflect the triglycerides level at week 12

The c-HDL levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the c-HDL level at week 12

The fasting glucose levels were evaluated at baseline and week 12 with enzymatic/colorimetric techniques and the entered values reflect the fasting glucose level at week 12

The systolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the systolic blood pressure at week 12

The first phase of insulin secretion was calculated at baseline and week 12 with Stumvoll index and the entered values reflect the first phase of insulin secretion at week 12

The total insulin secretion was calculated at baseline and week 12 with insulinogenic index and the entered values reflect the total insulin secretion at week 12

The insulin sensitivity was calculated at baseline and week 12 with Matsuda index and the entered values reflect the insulin sensitivity at week 12

Waist circumference was evaluated at baseline and at week 12 with a flexible tape and the entered values reflect the waist circumference measure at week 12

The diastolic blood pressure was evaluated at baseline and week 12 with a digital sphygmomanometer and the entered values reflect the diastolic blood pressure at week 12

The weight was measured at baseline, week 4, week 8 and week 12 with a bioimpedance balance and the entered values reflect the weight at week 12

The Body Mass index was calculated at baseline and at week 12 with the Quetelet index and the entered values reflect the body mass index at week 12

The total cholesterol was estimated by standardized techniques at baseline and week 12 and the entered values reflect the total cholesterol level at week 12

The c-LDL levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the c-LDL levels at week 12

The creatinine levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the creatinine levels at week 12

The uric acid levels were measured at baseline and at week 12 with standardized techniques and the entered values reflect the uric acid levels at week 12

Inclusion Criteria: Patients both sexes Age between 30 and 50 years Metabolic Syndrome according to the IDF criteria Waist circumference Man ≥90 cm Woman ≥80 cm And two of the following criteria: High density lipoprotein Man ≤40 mg/dL Woman ≤50 mg/dL Fasting glucose ≥100 mg/dL Triglycerides ≥150 mg/dL Blood pressure ≥130/85 mmHg Informed consent signed Exclusion Criteria: Women with confirmed or suspected pregnancy Women under lactation and/or puerperium Hypersensibility to resveratrol Physical impossibility for taking pills Known uncontrolled renal, hepatic, heart or thyroid diseased Previous treatment for the metabolic syndrome components Body Mass Index ≥39.9 kg/m2 Fasting glucose ≥126 mg/dL Triglycerides ≥500 mg/dL Total cholesterol ≥240 mg/dL Low density lipoprotein (c-LDL) ≥190 mg/dL Blood Pressure ≥140/90 mmHg

Intstituto de Terapeútica Experimental y Clínica. Centro Universitario de Ciencias de la Salud. Universidad de Guadalajara

Beaudeux JL, Nivet-Antoine V, Giral P. Resveratrol: a relevant pharmacological approach for the treatment of metabolic syndrome? Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):729-36. doi: 10.1097/MCO.0b013e32833ef291.

Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol. 2010 Jun 10;635(1-3):1-8. doi: 10.1016/j.ejphar.2010.02.054. Epub 2010 Mar 19.

Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006 Jun;5(6):493-506. doi: 10.1038/nrd2060. Epub 2006 May 26.

Timmers S, Auwerx J, Schrauwen P. The journey of resveratrol from yeast to human. Aging (Albany NY). 2012 Mar;4(3):146-58. doi: 10.18632/aging.100445.

Kroon PA, Iyer A, Chunduri P, Chan V, Brown L. The Cardiovascular Nutrapharmacology of Resveratrol: Pharmacokinetics, Molecular Mechanisms and Therapeutic Potential. Curr Med Chem. 2010;17(23):2442-55. doi: 10.2174/092986710791556032.

Baur JA. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev. 2010 Apr;131(4):261-9. doi: 10.1016/j.mad.2010.02.007. Epub 2010 Feb 26.

Szkudelski T, Szkudelska K. Anti-diabetic effects of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:34-9. doi: 10.1111/j.1749-6632.2010.05844.x.

Zhang J. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J. 2006 Aug 1;397(3):519-27. doi: 10.1042/BJ20050977.

Rivera L, Moron R, Zarzuelo A, Galisteo M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009 Mar 15;77(6):1053-63. doi: 10.1016/j.bcp.2008.11.027. Epub 2008 Dec 3.

Hung LM, Chen JK, Huang SS, Lee RS, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000 Aug 18;47(3):549-55. doi: 10.1016/s0008-6363(00)00102-4.

Yu C, Shin YG, Chow A, Li Y, Kosmeder JW, Lee YS, Hirschelman WH, Pezzuto JM, Mehta RG, van Breemen RB. Human, rat, and mouse metabolism of resveratrol. Pharm Res. 2002 Dec;19(12):1907-14. doi: 10.1023/a:1021414129280.

Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004 Dec;32(12):1377-82. doi: 10.1124/dmd.104.000885. Epub 2004 Aug 27.

Aumont V, Krisa S, Battaglia E, Netter P, Richard T, Merillon JM, Magdalou J, Sabolovic N. Regioselective and stereospecific glucuronidation of trans- and cis-resveratrol in human. Arch Biochem Biophys. 2001 Sep 15;393(2):281-9. doi: 10.1006/abbi.2001.2496.

Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011 Aug;55(8):1129-41. doi: 10.1002/mnfr.201100143. Epub 2011 Jun 20.

Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. doi: 10.1038/nature05354. Epub 2006 Nov 1.

Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr. 2010 Jul;92(1):5-15. doi: 10.3945/ajcn.2009.28435. Epub 2010 May 12.

Baile CA, Yang JY, Rayalam S, Hartzell DL, Lai CY, Andersen C, Della-Fera MA. Effect of resveratrol on fat mobilization. Ann N Y Acad Sci. 2011 Jan;1215:40-7. doi: 10.1111/j.1749-6632.2010.05845.x.

Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Arias N, Andres-Lacueva C, Portillo MP. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab (Lond). 2011 May 10;8(1):29. doi: 10.1186/1743-7075-8-29.

Bruckbauer A, Zemel MB, Thorpe T, Akula MR, Stuckey AC, Osborne D, Martin EB, Kennel S, Wall JS. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond). 2012 Aug 22;9(1):77. doi: 10.1186/1743-7075-9-77.

Ramadori G, Gautron L, Fujikawa T, Vianna CR, Elmquist JK, Coppari R. Central administration of resveratrol improves diet-induced diabetes. Endocrinology. 2009 Dec;150(12):5326-33. doi: 10.1210/en.2009-0528. Epub 2009 Oct 9.

Szkudelski T. Resveratrol-induced inhibition of insulin secretion from rat pancreatic islets: evidence for pivotal role of metabolic disturbances. Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E901-7. doi: 10.1152/ajpendo.00564.2006. Epub 2007 Jun 19.

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec 15;127(6):1109-22. doi: 10.1016/j.cell.2006.11.013. Epub 2006 Nov 16.

Penumathsa SV, Thirunavukkarasu M, Zhan L, Maulik G, Menon VP, Bagchi D, Maulik N. Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signalling pathway in diabetic myocardium. J Cell Mol Med. 2008 Dec;12(6A):2350-61. doi: 10.1111/j.1582-4934.2008.00251.x. Erratum In: J Cell Mol Med. 2010 Oct;14(10):2539.

Dao TM, Waget A, Klopp P, Serino M, Vachoux C, Pechere L, Drucker DJ, Champion S, Barthelemy S, Barra Y, Burcelin R, Seree E. Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control. PLoS One. 2011;6(6):e20700. doi: 10.1371/journal.pone.0020700. Epub 2011 Jun 6.

Brasnyo P, Molnar GA, Mohas M, Marko L, Laczy B, Cseh J, Mikolas E, Szijarto IA, Merei A, Halmai R, Meszaros LG, Sumegi B, Wittmann I. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011 Aug;106(3):383-9. doi: 10.1017/S0007114511000316. Epub 2011 Mar 9.

Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1307-12. doi: 10.1093/gerona/glr235. Epub 2012 Jan 4.

Szkudelski T. Resveratrol inhibits insulin secretion from rat pancreatic islets. Eur J Pharmacol. 2006 Dec 15;552(1-3):176-81. doi: 10.1016/j.ejphar.2006.09.046. Epub 2006 Sep 27.