Endocrine Abstracts

Pancreatic beta cell dysfunction is central to the development and progression of type 2 diabetes (T2D). Lipotoxicity, i.e. chronic exposure to elevated levels of free fatty acids (FFAs), contributes to beta cell dysfunction and death in T2D.

The endoplasmic reticulum (ER) is the organelle where secreted proteins, such as insulin, are produced and folded. Demands placed on the beta cell ER vary greatly with glucose-stimulated insulin production. ER stress can be defined as the imbalance between protein folding demand and the folding capacity of the organelle. In response, the cell triggers the unfolded protein response (UPR) that transcriptionally upregulates the ER protein folding machinery and temporarily attenuates protein translation. The UPR is essential for the normal functioning and survival of beta cells, but chronic/severe ER stress and persistent UPR signaling triggers beta cell dysfunction and apoptosis.

FFAs induce ER stress in beta cells, but the UPR signaling differs for saturated and unsaturated FFAs. Saturated FFAs induce marked PERK signaling, and this contributes to beta cell apoptosis. Palmitate activates the IRE1 branch of the UPR to a greater extent than oleate, while ATF6 is activated regardless of FFA saturation. This differential signaling results in an unfavorable balance between beta cell protective and pro-apoptotic signals for saturated FFAs. FFAs induce ER stress by depleting ER calcium. In addition, saturated FFAs hamper ER-to-Golgi protein trafficking via ceramide production and lead to degradation of proinsulin maturation and processing enzymes in the ER. The increased demand for insulin secretion in insulin resistance in vivo further aggravates ER stress. Post-mortem studies have shown evidence for ER stress in beta cells from type 2 diabetic individuals. The possibility to intervene and modulate the UPR in pancreatic beta cells holds promise as a new approach to prevent progressive beta cell dysfunction in T2D.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.