Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

Abstract

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic b-cells against their cell death. In in vivo experiments, we used b-cell-specific calmodulinoverexpressing mice where massive apoptosis takes place in their b-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1 a, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in b-cellspecific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic b-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

Proteinuria and Hyperglycemia Induce Endoplasmic Reticulum Stress

“…10,14,20,21 The view that persistent ER stress favors the apoptotic pathway is based on cell culture studies in which severe pharmacologic ER stress induced apoptosis. 21,[31][32][33][34][35] Convincing experimental evidence was provided that moderate ER stress may favor an adaptive and protective rather than a proapoptotic UPR. 27 This view would conform to the slow and prolonged time course of diseases in which ER stress has been invoked as a pathophysiologic contributor (e.g., chronic hepatitis, diabetes, neurodegenerative diseases).…”

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

“…Drugs that drive more insulin secretion, like the sulphonylureas, are likely to place more pressure on the secretory pathway in individual b-cells, and, consistent with this argument, this class of drug, although initially effective, is now considered to hasten the loss of b-cell function. In contrast, although GLP1 receptor agonists also promote insulin secretion, they do this in a glucose-dependent manner and may also directly protect b-cells from ER stress and promote proliferation (Yusta et al 2006, Tsunekawa et al 2007, Tortosa & Dotta 2013. However, other data indicate that GLP1 receptor agonists also promote proinsulin secretion (Hasnain et al 2014) and this may have longer-term deleterious consequences.…”

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…The anti-apoptotic properties of GLP1 in β-cells are well known and they are at least partially mediated by reduced ER stress through actions on several targets including BiP, ASK1, SIRT1, and the transcription factors C/EBPs and JunB (Fig. 2) (Yusta et al 2006, Tsunekawa et al 2007, Cunha et al 2009, Kwon et al 2009, Widenmaier et al 2009, Oh et al 2013, Kim et al 2015.…”