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

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

Authors :
Zhang, Yaqin
Qian, Bin
Yang, Yang
Niu, Fandi
Lin, Changsong
Yuan, Honglei
Wang, Jianan
Wu, Tijun
Shao, Yixue
Shao, Shulin
Liu, Aiming
Wu, Jingwen
Sun, Peng
Chang, Xiaoai
Bi, Yan
Tang, Wei
Zhu, Yunxia
Chen, Fang
Su, Dongming
Han, Xiao
Source :
Diabetes. Nov2024, Vol. 73 Issue 11, p1832-1847. 16p.
Publication Year :
2024

Abstract

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: miR-27a-5p expression in the islets is increased in obesity-associated diabetes mouse models. miR-27a-5p overexpression in β-cells impairs β-cell function in vitro and in vivo. Visceral adipocyte–derived extracellular vesicles and their cargo miR-27a-5p lead to β-cell insulin secretion injury and glucose intolerance by targeting L-type Ca2+ channel subtype CaV1.2. Blockage of visceral adipocyte extracellular vesicle miR-27a-5p expression improves β-cell insulin secretion and glucose tolerance in db / db mice. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00121797
Volume :
73
Issue :
11
Database :
Academic Search Index
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
180388661
Full Text :
https://doi.org/10.2337/db24-0177