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

• Published in: Diabetes, obesity & metabolism Vol. 12; no. s2; pp. 76 - 82
• Main Authors: Cnop, M, Ladrière, L, Igoillo-Esteve, M, Moura, R.F, Cunha, D.A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.10.2010; Blackwell Publishing Ltd; Wiley Subscription Services, Inc
• Subjects: Apoptosis; Beta cells; Calcium; Calcium - metabolism; Cell death; Cellular stress response; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - therapy; drug effects; Endoplasmic Reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum - physiology; endoplasmic reticulum stress; Fatty Acids, Nonesterified; Fatty Acids, Nonesterified - metabolism; free fatty acids; Glucagon; Humans; Insulin-Secreting Cells; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; islets; lipotoxicity; metabolism; Molecular Chaperones; Molecular Chaperones - metabolism; Molecular modelling; oleate; oleic acid; palmitate; Palmitic acid; pancreatic β-cells; pathology; physiology; Protein Unfolding; Signal Transduction; Stress, Physiological; Stress, Physiological - drug effects; Stress, Physiological - physiology; therapy; unfolded protein response
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/j.1463-1326.2010.01279.x

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 Ca²⁺ 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.