X-box binding protein 1 is essential for insulin regulation of pancreatic alpha cell function.
Type 2 diabetes mellitus (T2D) patients often exhibit hyperglucagonemia despite hyperglycemia suggesting defective α-cell function. While endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in α-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 α-cells, we created complementary in vivo (α-cell specific XBP1 knockout (αXBPKO) mice) and in vitro (stable XBP1 knock down α-cell line, αXBPKD) models. αXBPKO mice exhibited glucose intolerance, mild insulin resistance and an inability to suppress glucagon secretion following glucose stimulation. αXBPKD cells exhibited activation of IRE1, an upstream activator of XBP1, leading to phosphorylation of JNK. Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of IRS-1 (pY(896)), and phosphorylation of Akt, while enhancing serine phosphorylation (pS(307)) of IRS-1. Consequently the αXBPKD cells exhibited blunted suppression of glucagon secretion following insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion.
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XBP glucagon insulin XBP1 insulin glucagon X-box binding protein 1 XBP1 insulin XBP1 tyrosine XBP1 XBP XBP1 XBP XBP insulin glucagon XBP IRE1 XBP1 serine JNK insulin XBP X-box binding protein 1 insulin glucose glucose glucose glucose IRS-1 Akt IRS-1