Abstract
Although glucose uniquely stimulates proinsulin biosynthesis in β 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 (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary β 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 Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective β cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, β cell failure upon Ire1α 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, Ire1α deletion in β 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 β cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the β cell for increased proinsulin synthesis and to limit oxidative stress that leads to β cell failure.
Highlights
Type 2 diabetes (T2D) is a disease epidemic caused by failure of β cells to produce sufficient insulin to maintain glucose homeostasis [1]
One of the most remarkable features of the pancreatic beta cells—those that produce and secrete insulin to regulate glucose homeostasis—is their capacity to increase the synthesis of proinsulin up to 10-fold after glucose stimulation
This dramatic increase in the synthesis of proinsulin is a challenge to the proximal secretory pathway and triggers an adaptive stress response, the unfolded protein response, which is coordinated by the Inositol-requiring enzyme 1α (IRE1α) enzyme and the X-box-binding protein 1 (XBP1) transcription factor
Summary
Type 2 diabetes (T2D) is a disease epidemic caused by failure of β cells to produce sufficient insulin to maintain glucose homeostasis [1]. Insulin resistance and hyperglycemia pressure β cells to increase preproinsulin synthesis, processing, and secretion. Β cells can compensate by increasing insulin production, approximately one-third of individuals with insulin resistance eventually develop β cell failure and diabetes [2]. Upon glucose-stimulated release of insulin granules, preproinsulin mRNA translation increases up to 10-fold [4,5,6]. For the β cell to accommodate increased preproinsulin synthesis, it is necessary to expand the secretory pathway for preproinsulin cotranslational translocation, folding, processing, trafficking, and storage in secretory granules. Recent studies suggest that increased proinsulin synthesis overwhelms the capacity of the ER to properly fold, process, and secrete insulin in response to glucose and activates the unfolded protein response (UPR) [3,9,10,11,12]
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