Polydatin prevents lipotoxicity-induced dysfunction in pancreatic β-cells by inhibiting endoplasmic reticulum stress and excessive autophagy

Background: Chronically elevated free fatty acid levels can adversely affect pancreatic beta-cells, leading to insulin resistance and eventually type 2 diabetes mellitus (T2DM). Polydatin (PD) from Polygonum cuspidatum has been shown to regulate blood lipid content and lower cholesterol levels. However, there have been no reports on the potential therapeutic effects and actions of PD on lipotoxicity in beta-cells. Purpose: This study aimed to investigate the protective effects of PD on palmitate (PA)-treated INS-1 insulinoma cells and diabetic mice. Methods: Cells were incubated with PA and varying concentrations of PD for 24 h. Viability assays, morphological observations, flow cytometric analysis, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to assess the effects of PD on PA-induced lipotoxicity. Western blotting was used to measure the endoplasmic reticulum stress (ERS) and the levels of autophagy-related factors after incubation with inducers and inhibitors of ERS and autophagy. Diabetic mice were treated with intragastric PD for 6 weeks followed by the measurement of their physiological and blood lipid indices and assessment of the results of histological and immunofluorescence analyses. Results: Treatment with PD after PA exposure enhanced insulin secretion and the expression of diabetes-associated genes. PD promoted beta-cell function by reducing the levels of proteins associated with ERS and autophagy while also attenuating ERS triggered by tunicamycin. PD also reduced tunicamycin-induced autophagy, indicating that it regulated ERS-mediated autophagy and reduced PA-induced cellular dysfunction. In addition, treatment of db/db mice with PD substantially reduced body weight gain, alleviated dyslipidemia, improved beta-cell function, and reduced insulin resistance. Conclusion: These results suggest that PD protects beta-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting ERS and preventing excessive autophagy. Our study provides a new basis for exploring the potential of PD against beta-cell lipotoxicity and T2DM.

Automated summary

This study demonstrates that polydatin (PD) protects beta-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting endoplasmic reticulum stress (ERS) and preventing excessive autophagy. PD treatment enhances insulin secretion and expression of diabetes-associated genes, promoting beta-cell function. In diabetic mice, PD reduces body weight gain, improves dyslipidemia, enhances beta-cell function, and reduces insulin resistance.