miR-101a and miR-30b contribute to inflammatory cytokine-mediated β-cell dysfunction

• DOI: 10.1038/labinvest.2015.112
• Publication Date: 2015-09-14T12:41:42Z
• Authors: Ying Zheng; Zhen Wang; Yiting Tu; Hongwei Shen; Zhijie Dai; Jian Lin; Zhiguang Zhou
• Keywords: Homeodomain Proteins; 0301 basic medicine; Apoptosis; MicroRNAs; 03 medical and health sciences; Diabetes Mellitus, Type 1; HEK293 Cells; Proto-Oncogene Proteins c-bcl-2; Insulin-Secreting Cells; Basic Helix-Loop-Helix Transcription Factors; Animals; Cytokines; Humans; Insulin; Transcription Factors

Inflammatory cytokines have a critical role in the progressive deterioration of pancreatic β-cell function and development of type 1 diabetes. Prolonged exposure of β-cells to inflammatory cytokines results in gene expression modifications, leading to loss of β-cell function. MicroRNAs (miRNAs) are small non-coding RNAs acting as key regulators of gene expression. Here, we demonstrate that miR-101a and miR-30b are key players in cytokine-mediated β-cell dysfunction. We found that IL-1β induces an increase in miR-101a and miR-30b in MIN6 cells, and that the two miRNAs participate in β-cell dysfunction, including decreased insulin content, gene expression, and increased β-cell death. miR-101a and miR-30b reduce proinsulin expression and insulin content by directly targeting the transcriptional factor Neurod1. In addition, β-cell apoptosis mediated by miR-101a and miR-30b is associated with diminished expression level of the antiapoptotic protein Bcl2. Moreover, we show that miR-101a causes an impairment in glucose-induced insulin secretion by decreasing the expression of the transcription factor Onecut2. Taken together, our findings suggest that changes in the levels of miR-101a and miR-30b contribute to cytokine-mediated β-cell dysfunction occurring during the development and progression of type 1 diabetes.