miR-483 deficiency promotes loss of pancreatic beta-cell identity and aberrant glucagon production under metabolic stress.

Pancreatic β-cell dedifferentiation is a pathological mechanism that contributes to β-cell dysfunction and loss during type 2 diabetes (T2D), but the underlying mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of cellular identity and function. We previously identified miR-483 as a β-cell-enriched miRNA that promotes β-cell function by targeting Aldh1a3. Here, we investigated its role under high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced metabolic stress. β-cell-specific miR-483 deficiency exacerbated hyperglycemia and impaired glucose tolerance, accompanied by increased ALDH1A3 expression and reduced insulin expression in GFP-labeled cells. Under HFD/STZ-induced metabolic stress, miR-483 deficiency also increased glucagon production and the abundance of GFP+GCG+ and ALDH1A3+GCG+ cells, consistent with loss of β-cell identity and emergence of α-cell-like characteristics. Single-cell RNA sequencing revealed increased β-cells heterogeneity, including a subpopulation with glucagon expression and an altered endocrine phenotype. In addition, miR-483 deficiency was associated with mitochondrial fragmentation, impaired respiratory function, and increased oxidative stress. Together, these findings suggest that miR-483-ALDH1A3 axis contributes to the coordination of β-cell identity with mitochondrial and metabolic homeostasis during metabolic stress.