MiR-221/222 Inhibit Insulin Production of Pancreatic β-Cells in Mice

Microribonucleic acids (miRNAs) are essential for the regulation of development, proliferation, and functions of pancreatic β-cells. The conserved miR-221/222 cluster is an important regulator in multiple cellular processes. Here we investigated the functional role of miR-221/222 in the regulation of β-cell proliferation and functions in transgenic mouse models. We generated 2 pancreatic β-cell-specific-miR-221/222 transgenic mouse models on a C57BL/6J background. The glucose metabolic phenotypes, β-cell mass, and β-cell functions were analyzed in the mouse models. Adenovirus-mediated overexpression of miR-221/222 was performed on β-cells and mouse insulinoma 6 (MIN6) cells to explore the effect and mechanisms of miR-221/222 on β-cell proliferation and functions. Luciferase reporter assay, histological analysis, and quantitative polymerase chain reaction (PCR) were carried out to study the direct target genes of miR-221/222 in β-cells. The expression of miR-221/222 was significantly upregulated in β-cells from the high-fat diet (HFD)-fed mice and db/db mice. Overexpression of miR-221/222 impaired the insulin production and secretion of β-cells and resulted in glucose intolerance in vivo. The β-cell mass and proliferation were increased by miR-221/222 expression via Cdkn1b and Cdkn1c. MiR-221/222 repressed insulin transcription activity through targeting Nfatc3 and lead to reduction of insulin in β-cells. Our findings demonstrate that miR-221/222 are important regulators of β-cell proliferation and insulin production. The expression of miR-221/222 in β-cells could regulate glucose metabolism in physiological and pathological processes.