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

Patients with type 2 diabetes (T2D) often exhibit hyperglucagonemia despite hyperglycemia, implicating defective alpha-cell function. Although endoplasmic reticulum (ER) stress has been suggested to underlie beta-cell dysfunction in T2D, its role in alpha-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 beta-cells has been reported to impair insulin secretion, leading to glucose intolerance. To evaluate the role of XBP1 in alpha-cells, we created complementary in vivo (alpha-cell-specific XBP1 knockout [alpha XBPKO] mice) and in vitro (stable XBP1 knockdown alpha-cell line [alpha XBPKD]) models. The alpha XBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. alpha XBPICD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun NH2-terminal kinase. Interestingly, insulin treatment of alpha XBPICD 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 alpha XBPKD 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 alpha-cells induces altered insulin signaling and dysfunctional glucagon secretion.