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 beta-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 beta-cell proliferation and functions in transgenic mouse models. We generated 2 pancreatic beta-cell-specific-miR-221/222 transgenic mouse models on a C57BL/6J background. The glucose metabolic phenotypes, beta-cell mass, and beta-cell functions were analyzed in the mouse models. Adenovirus-mediated overexpression of miR-221/222 was performed on beta-cells and mouse insulinoma 6 (MIN6) cells to explore the effect and mechanisms of miR-221/222 on beta-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 beta-cells. The expression of miR-221/222 was significantly upregulated in beta-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 beta-cells and resulted in glucose intolerance in vivo. The beta-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 beta-cells. Our findings demonstrate that miR-221/222 are important regulators of beta-cell proliferation and insulin production. The expression of miR-221/222 in beta-cells could regulate glucose metabolism in physiological and pathological processes.