Causes and cures for endoplasmic reticulum stress in lipotoxic β‐cell dysfunction

Abstract

Pancreatic β-cell dysfunction is central to the pathogenesis of type 2 diabetes, and the loss of functional β-cell mass in type 2 diabetes is at least in part secondary to increased β-cell apoptosis. Accumulating evidence suggests that endoplasmic reticulum (ER) stress is present in β-cells in type 2 diabetes. Free fatty acids (FFAs) cause ER stress and are putative mediators of β-cell dysfunction and death. In this review, we discuss the molecular mechanisms underlying ER stress induced by saturated and unsaturated FFAs. Oleate and palmitate trigger ER stress through ER Ca 2+ depletion and build-up of unfolded proteins in the secretory pathway. Saturated and unsaturated FFAs elicit a differential signal transduction in the three branches of the ER stress response, resulting in different survival/apoptosis outcomes. The protection of β-cells against FFAs through the interference with ER stress signalling has opened novel therapeutic perspectives for type 2 diabetes. Chemical chaperones, salubrinal and glucagon-like peptide-1 (GLP-1) analogues have been used to protect β-cells from lipotoxic ER stress. Importantly, the pro-and antiapoptotic effects of these compounds are cell and context dependent.

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

“…The involvement of other NEFA-dependent signals in the promotion of beta cell dysfunction and death has also been proposed. These include activation of Erk-1/2 [32], NF-κB [33], protein-kinase C (PKC)-δ [34], endoplasmic reticulum (ER) stress [35], calpain-10 [36] and ceramide formation [37], and induction of sterol regulatory element-binding protein [38], macrophage migration inhibitory factor [39], cell death-inducing DNA fragmentation factor a-like effector A [40] and cell death-inducing DFF45-like effector b [41]. NEFA-mediated inhibition of Akt activity [42] has also been implicated.…”

“…Wollheim, University of Geneva, Geneva, Switzerland) were grown as previously described [15]. Murine glucagon-secreting alpha-TC1-6 cells (passage [35][36][37][38][39][40]; a gift from Professor F. Purrello, University of Catania, Catania, Italy) were grown in monolayer at 37°C in a humidified incubator gassed with 5% CO 2 , in DMEM containing 4 mmol/l L-glutamine supplemented with 0.02% BSA, 3 g/l glucose, 10% heat-inactivated FBS, 100 IU/ml penicillin, 100 μg/ml streptomycin, 0.1 mmol/l non-essential amino acids (all from Gibco Invitrogen, Paisley, UK) and 15 mmol/ l HEPES (pH 7.4).…”

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

“…In the LEAD-2 trial, the liver-to-spleen attenuation ratio increased after treatment with 1.8 mg sition by the inhibition of cell apoptosis. The possible mechanism of its effect may be due to its ability to reduce hepatic ER stress, because hepatocytes are known to have a high content of ER and are particularly susceptible to ER stress [48] . The C/EBP homolog (CHOP) was decreased, which leads to ER stress-related cell necrosis after Ex-4 treatment; reduced CHOP protein expression can significantly decrease the fatty degeneration of liver cells [41] .…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Despite an increase in unfolded protein response (UPR) signalling, which allows proinsulin synthesis by increasing the ER folding capacity after acute exposure to hyperglycaemia [137], chronic ER stress leads to a decrease in insulin synthesis and activation of the apoptotic cell death programme [138]. NEFA have been recognised as key contributors that can trigger the apoptotic programme, in part mediated by the ER stress response, and this highlights the significance of obesity and nutrients in the context of lipotoxic effects on beta cells [139].…”