Resveratrol attenuates excessive ethanol exposure-induced ,B-cell senescence in rats: A critical role for the NAD + /SIRT1-p38MAPK/p16 pathway

Resveratrol has been found to improve ethanol-induced diabetes. Although pancreatic ,B-cell senescence-induced ,B-cell mass loss plays a critical role in the progression of diabetes, the exact mechanism by which resveratrol improves ethanol-triggered ,B-cell senescence and its role in ethanol-induced diabetes remains unknown. Male Sprague-Dawley rats were fed either control or ethanol liquid diets containing 2.4 g/kg.bw ethanol with or without 100 mg/kg.bw resveratrol for 22 weeks. Resveratrol decreased the ethanol-induced augmentation in senescence-associated ,B-galactosidase (SA ,B-gal)-positive area and attenuated reduction in ,B-cell mass, which were based on elevated levels of SIRT1 and proliferation marker Ki67 and reduced levels of senescence associated markers (p-p38MAPK and p16INK4a). Similarly, resveratrol rescued the reduction in NAD + /NADH ratio and SIRT1 and inhibited the upregulation of p-p38MAPK and p16INK4a in ethanol-treated INS-1 cells. Furthermore, supplementation with NAD+ inducer nicotinamide mononucleotide, SIRT1 activator SRT1720 or p38MAPK inhibitor SB203580 effectively reversed ethanol-induced ,B-cell senescence, while supplementation with SIRT1 inhibitor Ex527 or NAD+ inhibitor FK866 abrogated resveratrol-mediated antisenescence effects in INS-1 cells. Together, our results indicate that resveratrol improves ethanol triggered ,B-cell senescence and consequently recovers ,B-cell mass loss by inhibiting p38MAPK/p16 pathway through an NAD + /SIRT1 dependent pathway. (c) 2020 Elsevier Inc. All rights reserved. Superscript/Subscript Available ABSTRACT Resveratrol has been found to improve ethanol-induced diabetes. Although pancreatic ,B-cell senescence-induced ,B-cell mass loss plays a critical role in the progression of diabetes, the exact mechanism by which resveratrol improves ethanol-triggered ,B-cell senescence and its role in ethanol-induced diabetes remains unknown. Male Sprague-Dawley rats were fed either control or ethanol liquid diets containing 2.4 g/kg.bw ethanol with or without 100 mg/kg.bw resveratrol for 22 weeks. Resveratrol decreased the ethanol-induced augmentation in senescence-associated ,B-galactosidase (SA ,B-gal)-positive area and attenuated reduction in ,B-cell mass, which were based on elevated levels of SIRT1 and proliferation marker Ki67 and reduced levels of senescence associated markers (p-p38MAPK and p16INK4a). Similarly, resveratrol rescued the reduction in NAD + /NADH ratio and SIRT1 and inhibited the upregulation of p-p38MAPK and p16INK4a in ethanol-treated INS-1 cells. Furthermore, supplementation with NAD+ inducer nicotinamide mononucleotide, SIRT1 activator SRT1720 or p38MAPK inhibitor SB203580 effectively reversed ethanol-induced ,B-cell senescence, while supplementation with SIRT1 inhibitor Ex527 or NAD+ inhibitor FK866 abrogated resveratrol-mediated antisenescence effects in INS-1 cells. Together, our results indicate that resveratrol improves ethanol triggered ,B-cell senescence and consequently recovers ,B-cell mass loss by inhibiting p38MAPK/p16 pathway through an NAD + /SIRT1 dependent pathway. (c) 2020 Elsevier Inc. All rights reserved.

Automated summary

Resveratrol has been shown to improve ethanol-induced diabetes possibly by inhibiting the p38MAPK/p16 pathway. Resveratrol attenuates ethanol-induced damage to pancreatic β-cells by modulating the expression levels of SIRT1 and other proteins.