Differential Protective Effects of Exenatide, an Agonist of GLP-1 Receptor and Piragliatin, a Glucokinase Activator in Beta Cell Response to Streptozotocin-Induced and Endoplasmic Reticulum Stresses

Abstract

BackgroundAgonists of glucagon-like peptide-1 receptor (GLP-1R) and glucokinase activators (GKA) act as antidiabetic agents by their ability protect beta cells, and stimulate insulin secretion. Oxidative and endoplasmic reticulum (ER) stresses aggravate type 2 diabetes by causing beta cell loss. It was shown that GLP-1R agonists protect beta cells from oxidative and ER stresses. On the other hand, little is known regarding how GKAs protect beta cells. We hypothesized that GKAs protect beta cells by mechanisms distinct from those underlying GLP-1R agonist and tested our hypothesis by comparing the molecular effects of exenatide, a GLP-1R agonist, and piragliatin, a GKA, on INS-1 cells under oxidative and ER-induced stresses.MethodsBeta cells were treated with streptozotocin (STZ) to induce oxidative stress and with palmitate or thapsigargin (Tg) to induce ER stress respectively, and the effects of exenatide and piragliatin on these cells were investigated by: a) characterizing the kinases involved employing specific kinase inhibitors, and b) by identifying the differentially regulated proteins in response to stresses with proteomic analysis.ResultsExenatide protected INS-1 cells from both ER and STZ-induced death. In contrast, piragliatin rescued the cells only from STZ-induced stress. Akt activation by exenatide appeared to contribute to its protective effects of beta cells while enhanced glucose utilization was the contributing factor in the case of piragliatin. Also, exenatide, not piragliatin, blocked changes in proteins 14-3-3β, ε and θ, and preserved the 14-3-3θ levels under the ER stress. Isoform-specific modifications of 14-3-3, and the reduction of 14-3-3θ, commonly associated with beta cell death were assessed.ConclusionsExenatide and piragliatin exert distinct effects on beta cell survival and thus on type 2 diabetes. This study which confirmed our hypothesis is also the first to observe specific modulation of 14-3-3 isoform in stress-induced beta cell death associated with progressive deterioration of type 2 diabetes.

Heterogeneous nuclear ribonucleoprotein K inhibits heat shock-induced transcriptional activity of heat shock factor 1

“…2D gel electrophoresis was performed as described previously (42). Briefly, 100 g of total protein was loaded onto the strip gels and rehydrated for 12 h (18 cm, pH 4 -7) with rehydration buffer (7 M urea, 2 M thiourea, 2% (v/v) CHAPS, 2% IPG buffer, pH 4 -7 (GE Healthcare)).…”

Coffee silverskin extract improves glucose-stimulated insulin secretion and protects against streptozotocin-induced damage in pancreatic INS-1E beta cells

“…Streptozotocin (STZ) is a potent DNA-methylating agent, which generates ROS that induce oxidative stress in pancreatic beta cells (Szkudelski, 2001). STZ has been used in beta cells to imitate the pathology of T2D and to evaluate the antidiabetic effect of novel compounds (Hong et al, 2013;Kim et al, 2013;Lee, Hang, Ko, Kang, & Jeon, 2013). The aim of the present study was to investigate the mechanism of action of CSE on the pathogenesis of diabetes using an in vitro model of beta cells, the INS-1E cells.…”

Coadministration of alloxan and nicotinamide in rats produces biochemical changes in blood and pathological alterations comparable to the changes in type II diabetes mellitus

“…1 Although various models of inducing type II DM have been reported and discussed in the literature, streptozotocin (STZ) and alloxan (Ax) are noted to be the most commonly used chemical induction models. [2][3][4][5][6][7] Among these two, STZ is more widely promoted for use in combination with nicotinamide (NA) to induce type II DM in experimental models. [8][9][10][11] Administration of NA has been proven to be advantageous in preventing -cell apoptosis.…”