Network-based insights into miRNA regulation of β-cell insulin secretion in type 2 diabetes

Increasing evidence suggests that microRNAs (miRNAs) contribute to pancreatic β-cell compensation during type 2 diabetes (T2D) pathogenesis. To examine miRNA-mRNA interactions in human islets and their roles in β-cell insulin secretion and T2D, we performed small-RNA sequencing on pancreatic islets from nine individuals with T2D and 52 non-diabetic controls. We identified 70 differentially expressed miRNAs, with miRNAs upregulated in T2D enriched in a co-expression network associated with insulin secretion. Eight such upregulated miRNAs, including miR-101-3p and miR-9-5p associated with both first- and second-phase insulin secretion. Among them, miR-101-3p had the most mRNA targets, while highly abundant mRNA transcripts (e.g., <i>INS</i>) were regulated by few miRNAs. Overexpression of miR-101-3p in β-cells increased insulin release <i>in vitro</i> and reduced expression of CADM1, a target of miR-101-3p. In summary, we have comprehensively identified miRNA-mRNA alterations in human islets associated with T2D pathogenesis and propose that miR-101-3p plays an important role in β-cell insulin secretion.