Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 7, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101848119
Keywords
STING; beta-cells; insulin resistance; insulin secretion; T2D
Categories
Funding
- National Natural Science Foundation of China [81830025, 81620108004, 81700699, 81700720, 91857110, 81722012]
- National Key R&D Program of China [2019YFA0802502, 2018YFA0800403]
- Tianjin Municipal Education Commission [2021KJ209]
- Tianjin Municipal Science and Technology Commission [17ZXMFSY00150]
- Tianjin Research Innovation Project for Postgraduate Students [2019YJSB107]
- Tianjin Medical University Postgraduate Innovation Fund of 13th Five-Year Comprehensive Investment [YJSCX201904]
- Zhejiang Provincial Natural Science Foundation of China [LZ21H070001]
- Fundamental Research Funds for the Central Universities
- Training Program of Hangzhou Key Discipline of Geriatrics
- Innovative Institute of Basic Medical Sciences of Zhejiang University
- Construction Fund of Medical Key Disciplines of Hangzhou
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This study revealed the importance of STING in regulating insulin secretion, especially in beta-cell function. STING deficiency leads to a decrease in islet glucose-stimulated insulin secretion, affecting glucose homeostasis.
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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