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  • Title: Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic β-cells.
    Author: Yuan H, He M, Yang Q, Niu F, Zou Y, Liu C, Yang Yang, Liu A, Chang X, Chen F, Wu T, Han X, Zhang Y.
    Journal: Diabetes Obes Metab; 2024 Oct; 26(10):4510-4521. PubMed ID: 39072950.
    Abstract:
    AIM: To assess the expression and function of miR-483-5p in diabetic β cells. METHODS: The expression of miR-483-5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual-luciferase activity, and western blotting assays, were utilized for miR-483-5p target gene verification. Mice with β cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine β-cell fate. RESULTS: miR-483-5p increased in the islets of obese mouse models. Expression levels of miR-483-5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR-483-5p in β cells results in impaired insulin secretion and β-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated β-cell identity genes (insulin, Pdx1 and MafA) and derepressed β-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in β cells of high-fat diet-fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR-483-5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β-cell maturation. CONCLUSIONS: These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies β-cell identity as a contributor to β-cell dysfunction via the loss of cellular differentiation.
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