Abstract
Aims
The anti-inflammatory effects of the polyphenol resveratrol in patients with type 2 diabetes mellitus (T2DM) are controversial. Its role on pentraxin 3 (PTX3) concentrations, a human acute phase protein, has never been evaluated. Our aim was to determine whether a two-dosage resveratrol supplementation (500 and 40 mg/day) has an impact on PTX3 values in T2DM patients from a double-blind randomized placebo-controlled trial. Variations in total antioxidant status (TAS) were evaluated too.
Methods
A total of 192 T2DM patients were randomized to receive resveratrol 500 mg/day (Resv 500 arm), resveratrol 40 mg/day (Resv 40 arm) or placebo for 6 months. At baseline and at the trial end, PTX3 and TAS values were determined.
Results
A dose-dependent increase in PTX3 concentrations of 4.7% (Resv 40 arm) and 26.3% (Resv 500 arm), and 8.0% reduction after placebo were found. Adjusted mean differences of change versus placebo were 0.16 (95% CI 0.01–0.32) and 0.25 (0.09–0.42) in the Resv 40 and Resv 500 arms, respectively. At subgroup analyses, lower diabetes duration, aspirin, alcohol use, younger age, female gender, smoking (Resv 500 arm) and female gender and aspirin use (Resv 40 arm) were associated with higher PTX3 increments. A dose-dependent increment in TAS values in the resveratrol arms (1.4 and 6.4% for Resv 40 and Resv 500, respectively), and a reduction in placebo arm (−8.9%) were observed. Adjusted mean differences of change were 28.5 (95% CI 10.1–46.8) and 44.8 (25.4–64.1) in the Resv 40 and Resv 500 arms, respectively.
Conclusion
Resveratrol supplementation increased PTX3 and TAS levels in a dose-dependent manner in T2DM patients. At present, potential clinical implications of these results remain unclear.
ClinicalTrials.gov Identifier
NCT02244879.
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Abbreviations
- BMI:
-
Body mass index
- CV:
-
Cardiovascular
- CVs:
-
Coefficients of variations
- CRP:
-
C-reactive protein
- HbA1c:
-
Glycated hemoglobin
- IL-1:
-
Interleukin-1
- IL-6:
-
Interleukin-6
- PTX3:
-
Pentraxin 3
- SIRT:
-
Sirtuin
- TAS:
-
Total antioxidant status
References
Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomás-Barberán FA, García-Conesa MA, Espín JC (2013) Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharmac Des 19:6064–6093
Ponzo V, Soldati L, Bo S (2014) Resveratrol: a supplementation for men or for mice? J Transl Med 12:158
Novelle MG, Wahl D, Diéguez C, Bernier M, de Cabo R (2015) Resveratrol supplementation: where are we now and where should we go? Ageing Res Rev 21:1–15
Visioli F (2014) The resveratrol fiasco. Pharmacol Res 90:87
Bo S, Ciccone G, Castiglione A et al (2012) Antiinflammatory and Antioxidant Effects of Resveratrol in Healthy Smokers. Curr Med Chem 20:1323–1331
Fujitaka K, Otani H, Jo F et al (2011) Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res 31:842–847
Poulsen MM, Vestergaard PF, Clasen BF et al (2013) High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 62:1186–1195
Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI (2013) Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition 29:178–183
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:E1–E8
Timmers S, Konings E, Bilet L et al (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 14:612–622
Tomé-Carneiro J, Gonzálvez M, Larrosa M et al (2012) One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol 110:356–363
Tomé-Carneiro J, Larrosa M, Yáñez-Gascón MJ et al (2013) One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res 72:69–82
van der Made SM, Plat J, Mensink RP (2015) Resveratrol does not influence metabolic risk markers related to cardiovascular health in overweight and slightly obese subjects: a randomized, placebo-controlled crossover trial. PLoS one 10:e0118393
Bo S, Ponzo V, Ciccone G et al (2016) Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial. Pharmacol Res 111:896–905
Vilahur G, Badimon L (2015) Biological actions of pentraxins. Vasc Pharmacol 73:38–44
Norata CD, Marchesi P, Pirillo A et al (2008) Long pentraxin 3, a key component of innate immunity, is modulated by high-density lipoproteins in endothelial cells. Arterioscler Thromb Vasc Biol 28:925–931
Foo SS, Reading PC, Jaillon S, Mantovani A, Mahalingam S (2015) Pentraxins and collectins: friend or foe during pathogen invasion? Trends Microbiol 23:799–811
Fornai F, Carrizzo A, Ferrucci M et al (2015) Brain diseases and tumorigenesis: the good and bad cops of pentraxin 3. Int J Biochem Cell Biol 69:70–74
Daigo K, Mantovani A, Bottazzi B (2014) The yin-yang of long PTX3 in inflammation and immunity. Immunol Lett 161:38–43
Witasp A, Rydén M, Carrero JJ et al (2013) Elevated circulating levels and tissue expression of pentraxin 3 in uremia: a reflection of endothelial dysfunction. PLoS one 8:e63493
Yasunaga T, Ikeda S, Koga S et al (2014) Plasma pentraxin 3 is a more potent predictor of endothelial dysfunction than high-sensitive C-reactive protein. Int Heart J 55:160–164
Carrizzo A, Lenzi P, Procaccini C et al (2015) Pentraxin 3 induces vascular endothelial dysfunction through a p-selectin/matrix metalloproteinase-1 pathway. Circulation 131:1495–1505
Liu S, Qu X, Liu F, Wang C (2014) Pentraxin 3 as a prognostic biomarker in patients with systemic inflammation or infection. Med Inflammat ID 421429
Jenny NS, Arnold AM, Kuller LH, Tracy RP, Psaty BM (2009) Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 29:594–599
Latini R, Maggioni AP, Peri G et al (2004) Lipid assessment trial italian network (LATIN) investigators. Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction. Circulation 110:2349–2354
Salio M, Chimenti S, De Angelis N et al (2008) Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation 117:1055–1064
Rodriguez-Grande Swana M, Nguyen L, Englezou P et al (2014) The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury. J Cereb Blood Flow Metab 34:480–488
Ravizza T, Moneta D, Bottazzi B et al (2001) Dynamic induction of the long pentraxin PTX3 in the CNS after limbic seizures: evidence for a protective role in seizure-induced neurodegeneration. Neuroscience 105:43–53
Bottazzi B, Inforzato A, Messa M et al (2016) The pentraxins PTX3 and SAP in innate immunity, regulation of inflammation and tissue remodeling. J Hepatol 64:1416–1427
Ogawa T, Kawano Y, Imamura T et al (2010) Reciprocal contribution of pentraxin 3 and C-reactive protein to obesity and metabolic syndrome. Obesity 18:1871–1874
Barazzoni R, Aleksova A, Carriere C et al (2013) Obesity and high waist circumference are associated with low circulating pentraxin 3 in acute coronary syndrome. Cardiovasc Diabetol 12:167
Witasp A, Carrero JJ, Michaëlsson K et al (2014) Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss. Obesity 22:1373–1379
Miyazaki T, Chiuve S, Sacks FM, Ridker PM, Libby P, Aikawa M (2014) Plasma pentraxin 3 levels do not predict coronary events but reflect metabolic disorders in patients with coronary artery disease in the CARE Trial. PLoS one 9:e94073
Osorío-Conles O, Guitart M, Chacón MR et al (2011) Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity. Am J Physiol Endocrinol Metab 301:E1254–E1261
Barazzoni R, Palmisano S, Gortan Cappellari G et al (2016) Gastric bypass—induced weight loss alters obesity-associated patterns of plasma pentraxin-3 and systemic inflammatory markers. Surg Obes Relat Dis 12:23–32
Santilli F, Guagnano MT, Innocenti P et al (2016) Pentraxin 3 and platelet activation in obese patients after gastric banding. Circ J 80:502–511
Nakamura A (2015) Is pentraxin 3 a biomarker, a player, or both in the context of coronary atherosclerosis and metabolic factors? Heart Vessels 30:752–761
Yilmaz MI, Axelsson J, Sonmez A et al (2009) Effect of renin angiotensin system blockade on pentraxin 3 levels in type-2 diabetic patients with proteinuria. Clin J Am Soc Nephrol 4:535–541
Yang HS, Woo JE, Lee SJ, Park SH, Woo JM (2014) Elevated plasma pentraxin 3 levels are associated with development and progression of diabetic retinopathy in korean patients with type 2 diabetes mellitus. Investig Ophthalmol Vis Sci 55:5989–5997
Salcini C, Atasever-Arslan B, Sunter G et al (2016) High plasma pentraxin 3 levels in diabetic polyneuropathy patients with nociceptive pain. Tohoku J Exp Med 239:73–79
Wang R, Zhang J, Hu W (2016) Association of serum pentraxin 3 concentrations with diabetic nephropathy. J Investig Med 64:1124–1127
Seman NA, Abu Seman N, Witasp A et al (2013) Evolution of the association of plasma pentraxin 3 levels with type 2 diabetes and diabetic nephropathy in a Malay population. J Diabetes Res ID 298019
Sun H, Tian J, Xian W, Xie T, Yang X (2015) Pentraxin 3 attenuates renal damage in diabetic nephropathy by promoting M2 macrophage differentiation. Inflammation 38:1739–1747
Bonavita E, Gentile S, Rubino M et al (2015) PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160:700–714
Klouche M, Peri G, Knabbe C et al (2004) Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells. Atherosclerosis 175:221–228
Suzuki D, Toyoda M, Kimura M et al (2013) Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus. Intern Med 52:1029–1034
Lontchi-Yimagou E, Sobngwi E, Matsha TE, Kengne AP (2013) Diabetes mellitus and inflammation. Curr Diabetes Rep 13:435–444
Jaillon S, Peri G, Delneste Y et al (2007) The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 204:793–804
Whiting PH, Kalansooriya A, Holbrook I, Haddad F, Jennings PE (2008) The relationship between chronic glycaemic control and oxidative stress in type 2 diabetes mellitus. Br J Biomed Sci 65:71–74
Chang YC, Chuang LM (2010) The role of oxidative stress in the pathogenesis of type 2 diabetes: from molecular mechanism to clinical implication. Am J Transl Res 2:316–331
Crujeiras AB, Díaz-Lagares A, Carreira MC, Amil M, Casanueva FF (2013) Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity, type 2 diabetes mellitus and breast cancer. Free Rad Res 47:243–256
Bode LM, Bunzel D, Huch M et al (2013) In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am J Clin Nutr 97:295–309
Acknowledgements
This study was supported by the Ministry of Health (Ricerca Sanitaria Finalizzata 2010; Grant Number RF-2010-2313155) and by the Ministry of Education, University and Research (PRIN 2010-2011 (Grant Number 2010JCWWKM_006). The sponsors had no involvement in the study design, in the collection, in analysis and interpretation of data, in the writing of the report and in the decision to submit the article for publication.
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The study protocol was approved by the local ethics committee. All procedures were in agreement with the principles of the 1964 Helsinki Declaration and its later amendments.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
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Informed consent was obtained from all patients for being included in the study.
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Bo, S., Ponzo, V., Evangelista, A. et al. Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial. Acta Diabetol 54, 499–507 (2017). https://doi.org/10.1007/s00592-017-0977-y
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DOI: https://doi.org/10.1007/s00592-017-0977-y