Visceral Adipocyte–Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion
Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte–derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db/db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p–containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte–mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. Article Highlights
Authors
- Yixue Shao (ORCID: https://orcid.org/0000-0003-1410-5455)
- Tijun Wu (ORCID: https://orcid.org/0000-0002-8788-5686)
- Yan Bi (ORCID: https://orcid.org/0000-0003-3914-7854)
- Fandi Niu
- Shulin Shao
- Peng Sun (ORCID: https://orcid.org/0000-0002-7820-712X)
- Yunxia Zhu (ORCID: https://orcid.org/0000-0002-4597-4445)
- Aiming Liu (ORCID: https://orcid.org/0000-0002-5937-6278)
- Xiao Han (ORCID: https://orcid.org/0000-0002-6467-1802)
- Yang� Yang (ORCID: https://orcid.org/0000-0003-1222-1209)
- Jianan Wang (ORCID: https://orcid.org/0009-0007-8301-780X)
- Bin Qian (ORCID: https://orcid.org/0000-0002-6207-1061)
- Yaqin Zhang (ORCID: https://orcid.org/0000-0003-3436-4569)
- Jingwen Wu (ORCID: https://orcid.org/0000-0003-0939-511X)
- Dongming Su (ORCID: https://orcid.org/0000-0003-0398-9013)
- Changsong Lin
- Wei Tang (ORCID: https://orcid.org/0000-0003-3091-0374)
- Honglei Yuan (ORCID: https://orcid.org/0009-0006-1711-1542)
- Xiaoai Chang
- Fang Chen (ORCID: https://orcid.org/0000-0001-7702-4244)
Institutions
- Jinan University (CN)
- China Pharmaceutical University (CN)
- Nanjing Traditional Chinese Medicine Hospital (CN)
- Nanjing Drum Tower Hospital (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Xijing Hospital (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Diabetes
- Published
- 2024-08-21
- DOI
- https://doi.org/10.2337/db24-0177
- Citations
- 18
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 10.31
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province