Prevention and treatment of diabetes with resveratrol in a non-obese mouse model of type 1 diabetes

Abstract

Aims/hypothesis We recently found that activation of the type III histone deacetylase sirtuin 1 suppresses T cell immune responses. Here we sought to determine the therapeutic potential of the sirtuin 1 activator resveratrol in the treatment of diabetes in the NOD mouse model of type 1 diabetes and the mechanisms underlying such potential. Methods NOD mice were fed or subcutaneously injected with resveratrol and evaluated for development of diabetes. Splenocytes from resveratrol-treated and control mice were analysed by gene array. The altered expression of inflammatory genes induced by resveratrol was validated and the role of changed gene expression in prevention of diabetes was determined. Results Resveratrol administration potently prevented and treated type 1 diabetes in NOD mice. Gene array analysis indicated a dramatic decrease in expression of Ccr6, which encodes chemokine (C-C motif) receptor (CCR) 6, in the splenocytes from resveratrol-treated mice. CCR6 abundance on IL-17-producing cells and CD11b+F4/80hi macrophages was inhibited by resveratrol treatment. Interestingly, CCR6+ IL-17-producing cells and CD11b+F4/80hi macrophages accumulated in the spleens and pancreatic lymph nodes, but their presence in the pancreas was reduced, suggesting that resveratrol blocks their migration from peripheral lymphoid organs to the pancreas. Indeed, the migration of splenocytes toward media containing chemokine (C-C motif) ligand 20 (CCL20) was impaired by resveratrol treatment. CCL20 peptides, which block CCR6 binding to CCL20, inhibited development of type 1 diabetes. Conclusions/interpretation Inhibition of CCR6-mediated migration of inflammatory cells by resveratrol may provide a powerful approach for treatment of type 1 diabetes and possibly of other inflammatory diseases.

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster

“…Resveratrol affects activities of a number of proteins involved in aging, such as sirtuins and PGC-1α, to exert beneficial effects on health and lifespan (Pirola and Frojdo 2008). Numerous studies have revealed health benefits of resveratrol supplementation, including delayed decline of age-related cognitive function, improved pancreatic β-cell function, and reduced cardiac hypertrophy in rodent models (Pearson et al 2008;Lee et al 2011;Chan et al 2008;Baur 2010). However, the effect of resveratrol on lifespan and the underlying mechanisms remain controversial.…”

Long-term treatment with resveratrol attenuates oxidative stress pro-inflammatory mediators and apoptosis in streptozotocin-nicotinamide-induced diabetic rats

“…Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a polyphenolic phytoalexin found in different plants such as grapes, peanuts and berries, has several beneficial properties such as lifespan extending, antioxidant, anti-inflammatory, anticancer, anticoagulant, cardioprotective and vasoprotective effects (Szkudelska and Szkudelski 2010;Csiszar 2011;Lee et al 2011). In regard to the central role of oxidative stress and proinflammatory cytokines in the pathogenesis of diabetes, in the recent years, numerous investigations have focused on the role of resveratrol in prevention or treatment of diabetes complications (Szkudelska and Szkudelski 2010;Csiszar 2011;Sharma et al 2011).…”

“…In regard to the central role of oxidative stress and proinflammatory cytokines in the pathogenesis of diabetes, in the recent years, numerous investigations have focused on the role of resveratrol in prevention or treatment of diabetes complications (Szkudelska and Szkudelski 2010;Csiszar 2011;Sharma et al 2011). In this regard, it has been reported that short-term treatment with resveratrol (2-8 weeks) has beneficial antidiabetic effects, mainly via reduction in blood glucose, lipid peroxidation, circulatory proinflammatory cytokines and apoptosis levels with concomitant enhancement of antioxidants defenses (Kumar 2007;Sharma et al 2009Sharma et al , 2011Palsamy and Subramanian 2010;Zhang et al 2010;Lee et al 2011). On the other hand, to date, no serious side effects were reported for long-term resveratrol treatment in healthy subjects during in vitro and in vivo studies (Cottart et al 2010).…”

c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4+ T-Cell Differentiation and Allergic Lung Inflammation

“…Upon stimulation with anti-CD3 or anti-CD3 plus anti-CD28 antibodies, the proliferation of stimulated cells was determined by [ 3 H]thymidine incorporation assay. The cytokine production levels in the culture supernatants of cultured cells were examined by enzyme-linked immunosorbent assay (ELISA) as described previously (19). For intracellular cytokine staining, activated or polarized T cells were restimulated with phorbol myristate acetate (PMA; 10 ng/ml) plus ionomycin (1 M) in the presence of 10 mg/ml brefeldin A for 4 h. Cells were fixed and permeabilized, and intracellular staining with anti-IFN-␥-fluorescein isothiocyanate (FITC) and IL-4-phycoerythrin (PE) was performed as described previously (15).…”