On the contrary, the molecular bases of α cells higher resistance than β to the same cues are still largely uncharacterized. The pathways leading to mammalian β cell apoptosis, induced by proinflammatory cytokines, are complex but sufficiently known. Accordingly, efforts to increase our knowledge on the biomolecular mechanisms regulating proliferation, physiopathological functions, and apoptosis of α cells will likely result in improved medical approaches to the disease. It is associated to α cells dysfunctions and high glucagon secretion, which contribute to chronic hyperglycemia and ensuing clinical outcomes in DM. Post-insulitis decrease of pancreatic β cells is a major hallmark of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Insulitis is an inflammation of pancreatic Langerhans islets, which is known to precede the onset of diabetes mellitus (DM). Our computational analysis suggests that MAFB (a transcription factor exclusively expressed in pancreatic α cells within adult rodent islets of Langerhans) controls the expression of miR-296-3p and miR-298-5p. Both microRNAs control the expression of IGF1Rβ, its downstream targets phospho-IRS-1 and phospho-ERK, and TNFα. By exploiting specific microRNA mimics, we demonstrated that experimental upregulation of miR-296-3p and miR-298-5p raised the propensity to apoptosis of transfected and cytokine-treated αTC1-6 cells with respect to αTC1-6 cells, treated with cytokines after transfection with scramble molecules. The genes encoding them are physically clustered in the murine and human genome. These microRNAs share more targets than expected by chance and were co-expressed in αTC1-6 during a 6–48 h time course treatment with cytokines. We focused our study on two microRNAs, miR-296-3p and miR-298-5p, which were: (1) specifically expressed at steady state in αTC1-6, but not in βTC1 or INS-1 cells (2) significantly downregulated in αTC1-6 cells after treatment with cytokines in comparison to untreated controls. We also characterized the alterations of αTC1-6 cells microRNA transcriptome after treatment with proinflammatory cytokines. Through high-throughput real-time PCR, we analyzed the steady state microRNA transcriptome of murine pancreatic α (αTC1-6) and β (βTC1) cells: their comparison demonstrated significant differences.
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