HX-1171 attenuates pancreatic β-cell apoptosis and hyperglycemia-mediated oxidative stress via Nrf2 activation in streptozotocin-induced diabetic model.

Jimin Kim,Jong-Koo Kang,Jae Wha Kim,Su-Hyun Shin

doi:10.18632/oncotarget.24916

Abstract

Streptozotocin (STZ) acts specifically on pancreatic beta cells, inducing cell destruction and cell dysfunction, resulting in diabetes. Many studies have reported that nuclear factor-erythroid 2-related factor 2 (Nrf2), a main regulator of antioxidant expression, prevents and improves diabetes-related diseases. In this study, we investigated the antidiabetic effect of the newly discovered Nrf2 activator, HX-1171, in the STZ-induced diabetic mouse model. HX-1171 enhanced insulin secretion by reducing STZ-induced cell apoptosis, and decreased intracellular reactive oxygen species (ROS) generation by upregulating the expression of antioxidant enzymes through Nrf2 activation in INS-1 pancreatic beta cells. In STZ-induced diabetic mice, HX-1171 administration significantly lowered blood glucose levels and restored blood insulin levels. In the STZ-only injected mice, the pancreatic islets showed morphological changes and loss of function, whereas the HX-1171-treated group was similar to that of the control group. These results suggest that HX-1171 may be developed as a promising therapeutic agent for diabetes-related diseases.

Highlights

Streptozotocin (STZ) has a glucose-like structure and enters the pancreatic beta cells through GLUT2, a glucose transporter, causing alkylation and fragmentation of DNA, generation of reactive oxygen species, activation of caspase-3-PKCδ-IL-1β apoptotic signal pathways, and fatal damage to the cells [1, 2]
In the STZinduced diabetic mouse model, the elevated blood glucose levels were reduced in the HX-1171-treated group, and HX-1171 protected pancreatic beta cells from acute tissue damage. These results suggested that HX-1171 attenuated apoptosis and hyperglycemia-mediated oxidative stress in pancreatic beta cells through nuclear factor-erythroid 2-related factor 2 (Nrf2) activation
The pancreas is more susceptible to STZ because it is sensitive to glucose and most highly expresses GLUT2, which acts as a channel for glucose and STZ [30, 31]

Summary

Introduction

Streptozotocin (STZ) has a glucose-like structure and enters the pancreatic beta cells through GLUT2, a glucose transporter, causing alkylation and fragmentation of DNA, generation of reactive oxygen species, activation of caspase-3-PKCδ-IL-1β apoptotic signal pathways, and fatal damage to the cells [1, 2]. The dysfunction of pancreatic beta cells induced by these actions of STZ results in a diabetic condition. That many diabetic patients suffer from these complications shows the risk of persistent hyperglycemia [5, 6]. Failure to regulate blood glucose levels causes hyperglycemia-mediated oxidative stress, which induces apoptosis in pancreatic beta cells [7]. Oxidative stress in the pancreas has been shown in the diabetic mouse model [10, 11] and diabetic patients [12, 13]. The action of antioxidant enzymes against oxidative stress in the pancreas has been closely associated with slowing the progression of diabetes and reducing the occurrence of diabetic complications [15]

Methods

Results

Conclusion