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

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.

4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity

“…4C). Our results support the idea that IRE1α RNase activity is required for insulin secretion (Hassler et al, 2015). Next, we treated MIN6 (Ire1α ΔR/ΔR ) cells with 4μ8C (Fig.…”

“…2), whereas the overexpression of the K907A mutant of IRE1α has been reported to inhibit insulin biosynthesis (Hassler et al, 2015). In the latter case, the K907A mutant was overexpressed for 72 hr.…”

“…They proposed that proinsulin biosynthesis is dependent on the phosphorylation of IRE1α, rather than XBP1s production, as XBP1s mRNA expression was not increased by "physiological" levels of ER stress induced by high glucose (Lipson et al, 2006). On the other hand, Hassler et al reported that the overexpression of the K907A IRE1α mutant that lacks RNase activity, decreases proinsulin protein synthesis (Hassler et al, 2015), indicating that the RNase domain of IRE1α also plays an important role in proinsulin biosynthesis. However, the precise role of the RNase domain of IRE1α in insulin secretion remains unknown.…”

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…An increase in insulin production, up to 20-fold induced by glucose, is a common physiological response of β-cells that results in an intense trafficking of proteins through the ER (Eizirik et al 2008). Therefore, β-cells express high levels of the UPR transducers IRE1α and PERK, which are necessary for strict quality control of pro-insulin synthesis and to limit oxidative stress induced during the insulin folding, a process that could lead to β-cell failure (Lipson et al 2006, Eizirik et al 2008, Back et al 2009, Oslowski & Urano 2011a, Hassler et al 2015. Thus, β-cell exposure to intermittent physiological levels of high glucose increases pro-insulin production with a controlled and regulated UPR activation, which contributes to proper β-cell function and survival (Oslowski & Urano 2011a).…”

“…The everchanging demand for insulin production and secretion in response to nutrient stimulation relies greatly on the ER, to ensure synthesis and proper folding of pro-insulin (Back et al 2009, Hassler et al 2015. As a result, β-cells are exquisitely sensitive to additional ER pressure and accumulating evidence indicate a major role of the UPR in the context of β-cell demise leading to diabetes (Brozzi & Eizirik 2016, Hasnain et al 2016.…”