miR-146b/Btg2 axis as a potential inducer of islet beta-cell decline during the progression of obesity to T2DM

IF 6.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Weixuan Wang , Dan Ma , Yong Chen , Rui Cheng , Ting Zhang , Qian Ge , Xi Li
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Abstract

We evaluated the potential mechanisms responsible for inducing beta-cell decline during the progression of obesity to type 2 diabetes mellitus (T2DM). Between February 2021 and February 2022, 25 subjects with non-diabetic obesity, 20 subjects with obesity and new-onset T2DM, and 25 healthy volunteers were recruited. Circulating exosome-contained miRNA expression profiling was performed by miRNA sequencing. The role of specific miRNA was analyzed by a gain-of-function approach in Min6 beta-cells, mouse islets, and human islets. Expression of 83 exosomal miRNAs was differently regulated in the circulation of subjects with non-diabetic obesity. We focused on miR-146b, which was mildly up-regulated in non-diabetic obesity and dramatically up-regulated in obese new-onset T2DM. Using an obese diabetic db/db mouse model, we found the expression of miR-146b to be mainly increased in islets. Overexpression of miR-146b in mouse beta-cells, mouse islets, and human islets in vitro facilitated beta-cell apoptosis yet inhibited its proliferation and insulin synthesis, leading to impaired insulin secretion. Eventually, miR-146b directly targeted the B cell translocation gene 2 (Btg2), an antiapoptotic transcriptional factor. Overexpression of Btg2 reversed miR-146b-induced apoptosis and -suppressed proliferation in beta-cells. miR-146b that targets Btg2 might be a predictive biomarker and an inducer of beta-cell decline.
miR-146b/Btg2轴作为肥胖发展为T2DM过程中胰岛β细胞衰退的潜在诱导剂
我们评估了肥胖症发展为2型糖尿病(T2DM)过程中诱导β细胞衰退的潜在机制。在2021年2月至2022年2月期间,招募了25名非糖尿病性肥胖受试者、20名肥胖合并新发T2DM受试者和25名健康志愿者。循环外泌体含miRNA表达谱通过miRNA测序进行。通过功能获得法分析了特异性miRNA在Min6 β细胞、小鼠胰岛和人胰岛中的作用。83种外泌体mirna的表达在非糖尿病性肥胖受试者的循环中受到不同的调节。我们关注的是miR-146b,它在非糖尿病性肥胖中轻度上调,在肥胖新发T2DM中显著上调。通过肥胖糖尿病小鼠db/db模型,我们发现miR-146b的表达主要在胰岛中增加。miR-146b在小鼠β细胞、小鼠胰岛和体外人胰岛中过表达,促进β细胞凋亡,抑制其增殖和胰岛素合成,导致胰岛素分泌受损。最终,miR-146b直接靶向B细胞易位基因2 (Btg2),这是一种抗凋亡转录因子。Btg2的过表达逆转了mir -146b诱导的β细胞凋亡和增殖抑制。靶向Btg2的miR-146b可能是一种预测性生物标志物和β细胞衰退的诱导剂。
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来源期刊
Genes & Diseases
Genes & Diseases Multiple-
CiteScore
7.30
自引率
0.00%
发文量
347
审稿时长
49 days
期刊介绍: Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. Aims and Scopes Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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