Obesity is one of the major contributors to the development of type 2 diabetes mellitus (T2DM). A progressive decline in the islet β-cell population is associated with the progression of obesity to T2DM; however, the mechanisms regulating β-cell survival remain poorly understood.

In a recent study published in the Genes & Diseases journal, researchers at Chongqing Medical University explored the potential mechanisms regulating β-cell decline during the progression of obesity to T2DM i) by evaluating the circulating exosomal miRNA profile in non-diabetic obese, obese, and new-onset T2DM patients and ii) by characterizing the functions of miR-146b in obesity and T2DM.

Plasma exosomes-derived miRNA expression profiling of the study cohort revealed differential expression of 83 miRNAs, of which 38 were up-regulated and 45 down-regulated. Further analysis identified that two miRNAs, miR-146b and miR-134, were up-regulated in obesity and further up-regulated in new-onset T2DM. The expression of these miRNAs correlated positively with fasting glucose and HbA1C levels. In vivo studies with the db/db mouse model further substantiated that miR-146b was expressed in the islets and other insulin-responsive tissues (including epididymal adipose tissue, skeletal muscle, and liver).

The authors showed that the expression of miR-146b remained unchanged upon supplementing with either high free fatty acids (FFA) or inflammatory cytokines; while a marked up-regulation was noticed upon exposure to both factors. Overexpression of miR-146b was associated with increased apoptosis, decreased proliferation, and reduced insulin synthesis and secretion by the islet β-cells.
Subsequent bioinformatics analysis identified that miR-146b suppressed the expression of three genes (Btg2, Med1, and Taf9b) involved in the negative regulation of the apoptotic process and one gene (Syt1) associated with cell differentiation. Luciferase reporter assays showed that only Btg2 exhibited decreased activity in the presence of a miR-146b mimic, which was validated in vivo. Btg2 overexpression abolished miR-146b mimics-induced apoptosis and restored the proliferation of islet β-cells.

In conclusion, the findings of this study i) highlight the potential of miR146b as a diagnostic marker for T2DM risk in adults with obesity, ii) show how miR146b impacts beta cell decline by regulating the expression of Btg2, and iii) suggest that targeting the miR-146b/Btg2 axis might facilitate the development of new T2DM prevention and management therapeutic strategies.

Reference

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

Journal: Genes & Diseases

Genes & Diseases is a 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.

DOI: https://doi.org/10.1016/j.gendis.2025.101621

Funding Information:

Natural Science Foundation of Chongqing, China (No. CSTC2020jcyj-msxmX0093)
National Key R&D Program of China (No. 2018YFA0800401)
National Natural Science Foundation of China (No. 81770861, 82070899)
Natural Sciences Foundation of Chongqing, China (No. CSTB2022NSCQ-MSX0827)
CQMU Program for Youth Innovation in Future Medicine (Chongqing, China) (No. W0046).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is 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.

Scopus CiteScore: 7.3 | Impact Factor: 6.9

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