A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion
Proceedings of the National Academy of Sciences of the United States of America(2022)
摘要
Insulin resistance and beta-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 beta-cells remains unknown. Herein, using global STING knockout (STING(-/-)) and beta-cell-specific STING knockout (STING-beta KO) mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through peripheral tissues and beta-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 beta-cell dysfunction. Indeed, STING-beta KO caused glucose intolerance due to impaired GSIS, indicating that STING is required for normal beta-cell function. Islet transcriptome analysis showed that STING deficiency decreased expression of beta-cell function-related genes, including Glut2, Kcnj11, and Abcc8, contributing to impaired GSIS. Mechanistically, the assay for transposase-accessible chromatin with highthroughput 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-beta KO mice. Indeed, Pax6 messenger RNA and protein levels were down-regulated and its nuclear localization was lost in STING-beta KO beta-cells. Together, these data revealed a function of STING in the regulation of insulin secretion and established pathophysiological significance of fine-tuned STING within beta-cells and insulin target tissues for maintaining glucose homeostasis.
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关键词
STING,beta-cells,insulin resistance,insulin secretion,T2D
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