image: (A) The seven miRNAs, which were significantly up-regulated (fold-change > 2) and are known to be functional in cell survival, were further quantified by real-time quantitative PCR. Expression levels of these miRNAs were compared among three groups of subjects (n = 20 subjects/group). The values were presented as relative expression compared with healthy weight. Results are mean ± standard error of the mean (SEM). *P < 0.05, **P < 0.01, and ***P < 0.001 versus healthy weight. +P < 0.05 versus obesity. (B, C) Expression of miR-146b and miR-134 was quantified by real-time quantitative PCR in plasma exosomes, cultured tissue explants, and culture medium exosomes of db/db obese diabetic mice. The values were presented as relative expression compared with their wild-type littermates (LMs). Results are mean ± SEM for 8–10 mice/group. *P < 0.05, **P < 0.01, and ***P < 0.001 versus respective LMs. (D) Min6 cells, primary mouse islets, and primary human islets were cultured with or without high glucose, FFAs, or inflammatory cytokines for 24 h. Expression of miR-146b was quantified by real-time quantitative PCR. The values were presented as relative expression compared with the control (5 mM glucose). Results are mean ± SEM for three experiments. *P < 0.05 and **P < 0.01 versus control.
Credit: Genes & Diseases
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
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