Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.

Autor:	Zhang Y; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Qian B; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.; School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China., Yang Y; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong, China., Niu F; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Cardiology, Xijing Hospital, Air Force Military Medical University, Xi'an, Shanxi, China., Lin C; Department of Bioinformatics, Nanjing Medical University, Nanjing, Jiangsu, China., Yuan H; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Wang J; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Wu T; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Shao Y; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Shao S; Department of Laboratory, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China., Liu A; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China., Wu J; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China., Sun P; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Chang X; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Bi Y; Department of Endocrinology, Drum Tower Hospital affiliated to Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China., Tang W; Department of Endocrinology, Islet Cell Senescence and Function Research Laboratory, Jiangsu Province Geriatric Institute, Nanjing, Jiangsu, China., Zhu Y; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China., Chen F; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China., Su D; Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China., Han X; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2024 Nov 01; Vol. 73 (11), pp. 1832-1847.
DOI:	10.2337/db24-0177
Abstrakt:	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. (© 2024 by the American Diabetes Association.)
Databáze:	MEDLINE
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