Pterostilbene Ameliorates Streptozotocin-Induced Diabetes through Enhancing Antioxidant Signaling Pathways Mediated by Nrf2.

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (Nrf2) remains a master regulator of cytoprotective and antioxidant genes. In this study, we investigated the antidiabetic role of pterostilbene (PTS) in streptozotocin (STZ)-induced diabetic model through Nrf2-mediated antioxidant mechanisms. The ability of PTS to activate Nrf2 in MIN6 cells was assessed by dissociation of the Nrf2-Keap1 complex at different time points and by expression of ARE-driven downstream target genes of Nrf2. Immunoblot experiments examining Nrf2 activation and phosphorylation indicated that it conferred cytoprotection against STZ-induced cellular damage. In STZ-induced diabetic mice, PTS administration significantly decreased blood glucose levels through the improvement of insulin secretion. In addition, we also observed insulin-positive cells with recovered islet architecture in the pancreas of STZ-induced diabetic mice after treatment with PTS. The activation of Nrf2 and expression of its downstream target genes were observed upon PTS treatment, thereby reducing oxidative damage to pancreas. Furthermore, PTS treatment significantly reverted the abundance of key glucose metabolism enzymes, such as hexokinase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissue of STZ-induced diabetic mice. These results clearly indicate that PTS maintains glucose homeostasis, suggesting the possibility that it is a future candidate for use in diabetes management.