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

So Jung Kwon a, 1, Su Jung Hwang a, b, 1, Yeonghun Jung a, b, 1, Hyeung-geun Park c, Mi-hyun Kim d, Yohan Park a, b, *, Hyo-Jong Lee a, b, *

a College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 607 Obang-dong, Gimhae, Gyungnam, 621-749, South Korea
b u-Healthcare & Anti-aging Research Center (u-HARC), Inje University, Gyeongnam, South Korea
c Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea
d College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon, 406-799, South Korea

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 anti-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 α-glucosidases but not α-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (STZ)-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 carboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis.
Conclusion. Taken together, isonitramine inhibited α-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.

Metabolism, 2017, 70, 107.