In eukaryotes, increased protein folding demand at the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)[1], which plays a pivotal role in control of cellular functions and survival under ER stress [2]. Chronic ER stress is thought to contribute to the pathogenic progression of diabetes [3, 4]. Inositol-requiring enzyme 1 (IRE1), an ER-resident transmembrane Ser/Thr protein kinase and endoribonuclease, is the most conserved ER stress sensor that mediates a key branch of the UPR [1]. In mammals, activation of IRE1α results in non-conventional splicing of the mRNA encoding the transcription factor X-box binding protein 1 (XBP1), generating a spliced active form of XBP1 (XBP1s) to initiate a major UPR program [1]. The IRE1-XBP1 pathway has been implicated in the homeostatic regulation of pancreatic islet β-cells. Whereas glucose-stimulated IRE1α activation is coupled to insulin production [5-7], IRE1α also degrades insulin mRNAs under severe ER stress conditions [8]. Interestingly, genetic deletion of XBP1 in β-cells of mice was reported to result in a feedback hyperactivation of IRE1α, causing defective proinsulin processing and insulin secretion [9]. However, the precise role in vivo of IRE1α in integrating metabolic ER stress signals to regulate β-cell functions remains largely elusive.

To investigate the metabolic actions of IRE1α in β-cells, we generated mice (denoted Ire1αf/f: Cre) with specific Ire1α deletion in β-cells by intercrossing Ire1αf/f mice [10] with RIP-Cre transgenic mice (denoted Cre) that express Cre recombinase under the control of the rat insulin II promoter. Because no significant differences were observed in body weight and fed blood glucose levels between wild-type and Cre littermates (Supplementary information, Figure S1A), we used Cre and Ire1αf/f mice as the control. In Ire1αf/f: Cre mice, IRE1α protein levels were substantially decreased in primary islets (by~ 75%) and hypothalamus (by~ 50%) as compared to their Ire1αf/f: Cre or Cre counterparts, while no distinguishable changes were observed in their livers (Supplementary