ER stress disrupts insulin release in murine models of type 2 diabetes by impairing retromer action and constitutive secretion.

Abstract

Using in vitro models of lipotoxicity and islets from the db/db mouse model of type 2 diabetes (T2D), we show that endoplasmic reticulum (ER) stress impairs β cell function. This is unrelated to apoptosis or alterations in insulin content or proinsulin processing, despite expansion of the Golgi compartment. Instead, the constitutive secretory pathway and endocytic recycling are disrupted, as revealed by depletion of glycosylated proteins and syntaxins from the plasma membrane (PM) and accumulation of E-cadherin in the retromer. This involves the PERK arm of the unfolded protein response. Proteomics identified multiple PM proteins mislocalized by ER stress, notably axon-guidance and cell-adhesion proteins, and many with glycosylphosphatidylinositol linkages. A retromer chaperone attenuated defective insulin secretion from islets of both db/db and high-fat-fed mice. By identifying different endpoints and mechanisms, our results redefine the relevance of ER stress to β cell failure. They also implicate retromer chaperones as potential T2D therapeutics.