Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity

Abstract To respond to protein misfolding in the endoplasmic reticulum (ER), cells trigger the unfolded protein response (UPR) to re-establish proteostasis. However, unresolved UPR results in chronic ER stress, which is critical to the development and advancement of type 2 diabetes mellitus (T2DM), a multifactorial disease whose prevalence has continued to rise. The UPR consists of three transmembrane signaling branches - protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1α), which collectively attempts to restore proteostasis, or trigger apoptosis if ER stress persists. Among the three, the IRE1α pathway is the most evolutionarily conserved and serves as a central regulator of UPR signaling through the splicing of X-box binding protein 1 mRNA (XBP1s). In the adaptive mode, XBP1s drives the expression of genes that expand ER capacity and alleviate cellular stress. Conversely, chronic activation of the IRE1α pathway activates the regulated IRE1-dependent decay (RIDD) process, recruits tumour necrosis factor receptor-associated factor 2/c-Jun N-terminal kinase (JNK), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), with their attendant deleterious effects. Thus, the therapeutic utility of the IRE1α/XBP pathway depends on the duration and extent of UPR as well as tissue and cellular metabolic state. The extensive crosstalk of the pathway with metabolic and inflammatory pathways makes it an attractive therapeutic target. This review examines the role of the IRE1α/XBP1 pathway in T2DM and highlights the potential of modulating the pathway as a novel disease-modifying strategy in the context of the increasing burden of the disease.