Abstract
Purpose
Pancreatic β-cell failure is a central hallmark of the pathogenesis of diabetes mellitus; however, the molecular basis underlying chronic inflammation-caused β-cell failure remains unclear. This study reported here specifically assessed the association between miR-25/miR-92b family and β-cell failure in diabetes.
Methods
IL-1β and two additional ER stress activators, palmitate and tunicamycin were applied to evaluate the expression level miR-25 by Taqman® RT-PCR. Glucose- and potassium-stimulated insulin secretion assays were performed to assess β-cell function. Dual-luciferase activity, and western blotting assays were utilized for miR-25 target gene verification. CCK-8 and TUNEL staining were used to evaluate β-cell viability and apoptosis.
Results
miRNA ChIP identified the increased level of miR-25 in INS-1 cells by IL-1β treatment. Expression levels of miR-25 were significantly upregulated with the treatment of IL-1β, palmitate or tunicamycin in both INS-1 cells and human islets. Ectopic elevation of miR-25 recapitulated most featured β-cell defects caused by IL-1β, including inhibition of insulin biosynthesis and increased β-cell apoptosis. These detrimental effects of miR-25 relied on its seed sequence recognition and repressed expression of its target genes Neurod1 and Mcl1. The miR-25/NEUROD1 axis reduced insulin biosynthesis via transcriptional regulation of β-cell specific genes. The miR-25/MCL1 axis caused β-cell apoptosis in a CASPASE-3/PARP1-dependent manner. Comparable impairments were generated by miR-92b and miR-25, emphasizing the redundant biological roles of miRNA family members with the same seed sequence.
Conclusion
MiR-25/miR-92b family plays a major role in β-cell failure occurring under inflammation and diabetes states.
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Funding
This study was supported by research grants from the National Natural Science Foundation of China (82070843 and 81870531 to Y.Z.; 81830024 to X.H.; 81770773 to W.T.). X.H. and Y.X. are fellows at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.
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All authors contributed to the study conception and design. Material preparation was performed by X.C. and W.T. Data collection and analysis were performed by Z.S., Y.Y., Y.Y., X.X., T.S., and Y.Z. The first draft of the manuscript was written by Z.S., and Y.Y., edited by Y.Z., and W.T., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Shen, Z., Yu, Y., Yang, Y. et al. miR-25 and miR-92b regulate insulin biosynthesis and pancreatic β-cell apoptosis. Endocrine 76, 526–535 (2022). https://doi.org/10.1007/s12020-022-03016-9
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DOI: https://doi.org/10.1007/s12020-022-03016-9