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

Insulin resistance and β-cell dysfunction are two main molecular bases yet to be further elucidated for type 2 diabetes (T2D). Accumulating evidence indicates that stimulator of interferon genes (STING) plays an important role in regulating insulin sensitivity. However, its function in β-cells remains unknown. Herein, using global STING knockout (STING^-/-) and β-cell-specific STING knockout (STING-βKO) mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through peripheral tissues and β-cells. Specially, although STING^-/- beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Importantly, STING is decreased in islets of db/db mice and patients with T2D, suggesting a possible role of STING in β-cell dysfunction. Indeed, STING-βKO caused glucose intolerance due to impaired GSIS, indicating that STING is required for normal β-cell function. Islet transcriptome analysis showed that STING deficiency decreased expression of β-cell function-related genes, including Glut2, Kcnj11, and Abcc8, contributing to impaired GSIS. Mechanistically, the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation (CUT&Tag) analyses suggested that Pax6 was the transcription factor that might be associated with defective GSIS in STING-βKO mice. Indeed, Pax6 messenger RNA and protein levels were down-regulated and its nuclear localization was lost in STING-βKO β-cells. Together, these data revealed a function of STING in the regulation of insulin secretion and established pathophysiological significance of fine-tuned STING within β-cells and insulin target tissues for maintaining glucose homeostasis.