Diabetes & Metabolism Journal

Original Article

Basic and Translational Research
Exosomal Circ_STAT1-AS Delivery Induced by Dexmedetomidine Modulates Microglial Polarization to Alleviate Diabetic Peripheral Neuropathy by Inhibiting JAK/STAT1 Pathway: Yu Wei, Xiaoling Zeng, Fujun Li, Shanshan Wei, Chunni Li, Zhaoyi Gan, Zhengzhuo Qin, Ying Lin, Maoying Ye, Xiongli Wei, Senlin Li, Yanzhuo Zhang; Received December 11, 2024 Accepted April 8, 2025 Published online November 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0809 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, characterized by neuroinflammation. Previous studies have shown that dorsal root ganglion (DRG) neurons can regulate microglial polarization. This study aims to investigate how exosomal circ_STAT1-AS from dexmedetomidine (DEX)-treated DRG neurons affects microglial polarization in DPN.
Methods
Exosomes were isolated from DRG neurons and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. DPN rat model was established by high sugar and fat diet combined with streptozotocin injection. The sciatic nerve conduction velocity, mechanical withdrawal threshold, and thermal withdrawal latency of rats were measured. Hematoxylin & eosin staining and immunohistochemical staining of S100B were used to detect spinal cord tissue injury. Chromatin immunoprecipitation quantitative polymerase chain reaction detected the interaction between histone deacetylase 5 (HDAC5) and unc-13 homolog D (UNC13D) promoter, as well as the H3 acetylation at lysine 27 (H3K27) acetylation level in UNC13D promoter region.
Results
Exosomal circ_STAT1-AS secretion from DRG neurons was enhanced by DEX treatment. These exosomes inhibited microglial M1 polarization and facilitated its M2 polarization by suppressing signal transducer and activator of transcription 1 (STAT1) translation. Mechanistically, the enhanced exosome secretion was attributed to the increased UNC13D expression, which resulted from HDAC5 inhibition and subsequent elevation of H3K27 acetylation modification at UNC13D promoter under DEX treatment. In DPN rat model, intrathecal administration of circ_STAT1-AS-enriched exosomes alleviated neuropathic symptoms and reduced neuroinflammation.
Conclusion
Exosomal circ_STAT1-AS delivery from DRG neurons was enhanced through DEX-mediated HDAC5/UNC13D axis. The increased exosomal circ_STAT1-AS absorbed by microglia suppressed STAT1 translation to inactivate JAK/STAT1 pathway, thereby modulating microglial M1/M2 polarization balance and alleviating DPN.

Review

Pathophysiology
Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance: Yajie Fan, Zhipeng Yan, Tingting Li, Aolin Li, Xinbiao Fan, Zhongwen Qi, Junping Zhang; Diabetes Metab J. 2024;48(1):19-36. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2023.0110

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Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.

Citations

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