A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion
Jingting Qiao, Ziyin Zhang, Shuhui Ji, Tengli Liu, Xiaona Zhang, Yumeng Huang, Wenli Feng, Kunling Wang, Jianyu Wang, Shusen Wang, Zhuo‐Xian Meng, Ming Liu
Abstract
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.