The binary switch that controls the life and death decisions of ER stressed β cells

Abstract

Diabetes mellitus is a group of common metabolic disorders defined by hyperglycemia. One of the most important factors contributing to hyperglycemia is dysfunction and death of β cells. Increasing experimental, clinical, and genetic evidence indicates that endoplasmic reticulum (ER) stress plays an important role in β cell dysfunction and death during the progression of type 1 and type 2 diabetes as well as genetic forms of diabetes such as Wolfram syndrome. The mechanisms of ER stress-mediated β cell dysfunction and death are complex and not homogenous. Here we review the recent key findings on the role of ER stress and the unfolded protein response (UPR) in β cells and the mechanisms of ER stress mediated β cell dysfunction and death. Complete understanding of these mechanisms will lead to novel therapeutic modalities for diabetes.

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

“…Both the UPR and inflammation are important protective cellular/tissue responses that when deregulated can lead to cellular damage. In line with this, UPR dysfunction is involved in many autoimmune and inflammatory disorders, such as diabetes (Hotamisligil 2010, Kaser & Blumberg 2010, Oslowski & Urano 2011a, Chaudhari et al 2014.…”

“…An increase in insulin production, up to 20-fold induced by glucose, is a common physiological response of β-cells that results in an intense trafficking of proteins through the ER (Eizirik et al 2008). Therefore, β-cells express high levels of the UPR transducers IRE1α and PERK, which are necessary for strict quality control of pro-insulin synthesis and to limit oxidative stress induced during the insulin folding, a process that could lead to β-cell failure (Lipson et al 2006, Eizirik et al 2008, Back et al 2009, Oslowski & Urano 2011a, Hassler et al 2015. Thus, β-cell exposure to intermittent physiological levels of high glucose increases pro-insulin production with a controlled and regulated UPR activation, which contributes to proper β-cell function and survival (Oslowski & Urano 2011a).…”

“…Therefore, β-cells express high levels of the UPR transducers IRE1α and PERK, which are necessary for strict quality control of pro-insulin synthesis and to limit oxidative stress induced during the insulin folding, a process that could lead to β-cell failure (Lipson et al 2006, Eizirik et al 2008, Back et al 2009, Oslowski & Urano 2011a, Hassler et al 2015. Thus, β-cell exposure to intermittent physiological levels of high glucose increases pro-insulin production with a controlled and regulated UPR activation, which contributes to proper β-cell function and survival (Oslowski & Urano 2011a). However, chronic exposure to hyperglycemia induces prolonged activation of the IRE1α pathway leading to β-cell apoptosis (Lipson et al 2006, Elouil et al 2007, Pirot et al 2007a, Hou et al 2008, Han et al 2009, Jonas et al 2009).…”

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders

“…It is the accumulation of these proteins within the ER that is responsible for the ER stress and the initiation of the unfolded protein response (UPR). [12] Terpenoids linked to endoplasmic reticulum stress…”

Azoramide: a new drug for the treatment of type 2 diabetes?

“…The UPR facilitates ER function by different mechanisms, maintaining cell function and cell survival. However, if the situation becomes chronic, UPR initiates cell disruption and apoptosis (4). At steady-state the three sensors are associated with glucose-related protein 78 (GRP78/Bip), a resident ER chaperone.…”