miRNAs responsive to the diabetic microenvironment in the human beta cell line EndoC-βH1 may target genes in the FOXO, HIPPO and Lysine degradation pathways

Highlights: • The diabetic microenvironment causes changes in the MicroRNA milieu. • Some miRNAs demonstrate dysregulation across multiple diabetomimetic stimuli. • Affected miRNAs target genes in FOXO1, HIPPO and Lysine degradation pathways. • This has potential to result in attenuation of beta cell survival or beta cell fate. -- Abstract: Altered expression of miRNAs is evident in the islets of diabetic human donors, but the effects of specific aspects of the diabetic microenvironment and identity of gene ontology pathways demonstrating target gene enrichment in response to each is understudied. We assessed changes in the miRNA milieu in response to high/low glucose, hypoxia, dyslipidaemia and inflammatory factors in a humanised EndoC-βH1 beta cell culture system and performed miRPath analysis for each treatment individually. The 10 miRNAs demonstrating the greatest dysregulation across treatments were then independently validated and Gene Set Enrichment Analysis to confirm targeted pathways undertaken. 171 of 392 miRNAs displayed altered expression in response to one or more cellular stressors. miRNA changes were treatment specific, but their target genes were enriched in conserved pathways. 5 miRNAs (miR-136-5p, miR299-5p, miR-454-5p, miR-152 and miR-185) were dysregulated in response to multiple stressors and survived validation in independent samples (p = 0.008, 0.002, 0.012, 0.005 and 0.024 respectively). Target genes of dysregulated miRNAs were clustered into FOXO1, HIPPO and Lysine degradation pathways (p = 0.02, p = 5.84 × 10⁻⁵ and p = 3.00 × 10⁻³ respectively). We provide evidence that the diabetic microenvironment may induce changes to the expression of miRNAs targeting genes enriched in pathways involved in cell stress response and cell survival.