X-Box Binding Protein 1 Is Essential for Insulin Regulation of Pancreatic α-Cell Function

摘要

Patients with type 2 diabetes (T2D) often exhibit hyperglucago-nemia despite hyperglycemia, implicating defective a-cell function. Although endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in a-cell biology remains unclear. X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), and its deficiency in β-cells has been reported to impair insulin secretion, leading to glucose intolerance. To evaluate the role of XBP1 in a-cells, we created complementary in vivo (a-cell-specific XBP1 knockout [aXBPKO] mice) and in vitro (stable XBP1 knockdown a-cell line [aXBPKD]) models. The aXBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. aXBPKD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun NH_2-terminal kinase. Interestingly, insulin treatment of aXBPKD cells reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) (pY~(896)) and phosphorylation of Akt while enhancing serine phosphorylation (pS~(307)) of IRS1. Consequently, the aXBPKD cells exhibited blunted suppression of glucagon secretion after insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic a-cells induces altered insulin signaling and dysfunctional glucagon secretion.