The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells

Although glucose uniquely stimulates proinsulin biosynthesis in beta cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1 alpha) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary beta cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1 alpha deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective beta cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1 alpha degrades insulin mRNAs, Ire1 alpha deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, beta cell failure upon Ire1 alpha deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1 alpha deletion in beta cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with beta cell-specific Ire1a deletion. The results demonstrate that glucose activates IRE1 alpha-mediated Xbp1 splicing to expand the secretory capacity of the beta cell for increased proinsulin synthesis and to limit oxidative stress that leads to beta cell failure.