MiR-30d-5p modulation induces expression changes related to β-cell function, survival and regeneration

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells, leading to hyperglycemia. A temporary partial remission (PR) phase often follows diagnosis, marked by improved glycemic control and reduced autoimmunity. This study investigates the role of miR-30d-5p, a microRNA highly expressed during PR, on beta-cell recovery and regeneration. Remarkably, human pancreatic slices were successfully transfected with oligonucleotides (miR-30d-5p inhibitor or mimic), enabling exploration of post-transcriptional regulation in a human context. Bulk RNA sequencing on human pancreatic slices from 3 non-diabetic donors confirmed the regulation of gene networks linked to both β-cell function and regeneration. PCA revealed clustering by donor, indicating strong inter-donor variability; this was corrected using ComBat, allowing clearer separation of treatment groups. Differential expression analysis identified 273 DEGs for miR-30d-5p inhibition, 518 for overexpression, and 480 between the two treatments. Key gene changes reflected biological roles aligned with the miRNA’s proposed regulatory function: inhibition of miR-30d-5p upregulated genes linked to stress, immune activation, and metabolism (e.g., GLUT6, TGFB3, CYP4F8), while overexpression enhanced β-cell function and insulin secretion genes (e.g., HOOK1, ISL1, TTR, CACNB3). GO analysis showed that miR-30d-5p inhibition enriched pathways related to protein stress and impaired differentiation, whereas overexpression activated processes involved in ion homeostasis, morphogenesis, and β-cell maintenance. Transcription factor analysis highlighted FOXO3, NOTCH3, JUND, and NR1H2 as potential regulators. Overall, miR-30d-5p promotes β-cell survival, insulin synthesis, and immunoregulation.