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Introduction & Objective: Apoptosis plays important roles in the pathophysiology of Type 2 diabetes mellitus (T2DM). Loss of functional β-cell mass is one mechanism by which diabetes can develop. ER stress plays an important role in the progressive reductions in insulin secretion that are associated with β-cell failure and apoptotic β-cell death.We aimed to elucidate the specific molecular mechanisms of β-cell apoptosis by exploring the relationship between miRNA and endoplasmic reticulum homeostasis. Methods: RNA sequencing was performed to analyse the islets of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). The function in β-cells of the selected miR-106b-5p was assessed after its overexpression or knockdown in MIN6 cells and primary islet cells, as well as in siRNA-treated mice. Then, RNA pull-down, RNA immunoprecipitation and coimmunoprecipitation were performed to investigate the mechanism of miR-106b-5p regulation of islet function. Results: MiR-106b-5p was dramatically downregulated in the islets of the obese mice, as well as in the sera of obese donors with type 2 diabetes. Treatment with miR-106b-5p showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in HFD mice.Furthermore, we demonstrated that miR-106b-5p reshapes endoplasmic reticulum homeostasis and improves β-cells’function by downregulating the expression of GRP78. Conclusion: Taken together, we clarified that the modulation of the ER homeostasis pathways by miR-106b-5p shifts the translational status from repression to the recovery phase and improves the survival of β-cells by protecting them from apoptosis. Disclosure W. Xu: None. J. Yu: None. X. Zhou: None. Funding National Natural Science Foundation of China(82174293, 82205025, 82104751)
XU et al. (Fri,) studied this question.