A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion

Significance The role of STING in maintaining glucose homeostasis remains unknown. Herein, using global and β-cell–specific STING knockout mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through β-cells and peripheral tissues. Specially, while global STING knockout beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Further analyses revealed that STING deficiency down-regulated expression of β-cell key transcription factor Pax6, impairing Pax6 nuclear localization and binding activity to the promoters of its target genes, including Glut2 and Abcc8, causing impaired GSIS. These data highlight pathophysiological significance of fine-tuned STING signaling in β-cells and insulin target tissues for maintaining glucose homeostasis.