A synthetic Nitraria alkaloid, isonitramine protects pancreatic beta-cell and attenuates postprandial hyperglycemia

Abstract

Objective. The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown. Methods. Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids. In this study, we investigated the and-diabetic potential of isonitramine in diabetes mellitus and its underlying molecular mechanism in carbohydrate catabolism in vitro and in vivo. Results. Isonitramine exerted significant inhibitory effect on alpha-glucosidases but not alpha-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (SIZ)-induced postprandial hyperglycemia and protected the pancreatic damages against alloxan-induced oxidative stress in vivo. Also, isonitramine induced insulin without any toxicities and downregulated phosphoenolpyruvate caxboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis. Conclusion. Taken together, isonitramine inhibited a-glucosidase activity and PEPCK expression, while increased insulin expression, resulting in attenuating the postprandial hyperglycemia. Also, isonitramine protected the pancreas from ROS-mediated toxicities. Therefore, isonitramine may be a new drug candidate for the treatment of diabetes mellitus. (C) 2017 Elsevier Inc. All rights reserved.