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Beta-cell MiRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and β-Cell Decompensation

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posted on 2023-10-17, 20:55 authored by Yuncai Zhou, Kerong Liu, Wei Tang, Yan Zhang, Yi Sun, Yangyang Wu, Ying Shi, Zhengjian Yao, Yating Li, Rongjie Bai, Rui Liang, Peng Sun, Xiaoai Chang, Shusen Wang, Yunxia Zhu, Xiao Han

ABSTRACT

Chronic inflammation promotes pancreatic β-cell decompensation to insulin resistance due to local accumulation of supraphysiologic IL-1β levels. However, the underlying molecular mechanism(s) remains elusive. We show that miR-503-5p is exclusively upregulated in islets from type 2 diabetic humans and rodents due to its promoter hypomethylation and increased local IL-1β levels. Beta-cell-specific miR-503 transgenic (βTG) mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat-diet-induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses JNK interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinases (MAPKs) signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory β-cell proliferation. In addition, β-cell miR-503-5p is packaged in nano-vesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors (INSR). Notably, specifically blocking the miR-503 cluster in β cells effectively remits ageing-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our finding demonstrated that β-cell miR-503-5p is required for the development of insulin resistance and β-cell decompensation, providing a potential therapeutic target against diabetes.

Funding

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 81830024 81870531 82070843 82270844

Jiangsu Provincial Department of Science and Technology > Natural Science Foundation of Jiangsu Province BK20211375

Jiangsu Provincial Department of Human Resources and Social Security > Postdoctoral Science Foundation of Jiangsu Province 2022ZB718 to Y-C.Z.

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