Hyaluronan induces ERK activation with minimal transcriptomic changes in pancreatic α-cells

Type 1 diabetes (T1D) is driven by the immune-mediated destruction of pancreatic β-cells. While β-cells are selectively targeted and depleted in T1D, α-cells that secrete glucagon are relatively spared from this autoimmune attack. Hyaluronan (HA), a glycosaminoglycan component of the extracellular matrix, accumulates within pancreatic islets in patients with T1D and in animal models, and has been implicated in promoting chronic inflammation. Given that surviving α-cells reside within this HA-rich microenvironment, we investigated whether HA contributes to molecular alterations in α-cells associated with the T1D phenotype. A murine α-cell line, αTC1-6, was stimulated with low-molecular-weight HA, which induced sustained extracellular signal-regulated kinase (ERK) phosphorylation upon HA stimulation, indicating activation of intracellular signaling. To assess whether this signaling response was accompanied by transcriptional changes, RNA sequencing was performed, and the resulting profile was compared with publicly available RNA-seq datasets from α-cells isolated from T1D donors. Despite robust ERK activation, HA stimulation elicited only minimal transcriptional changes relative to the T1D α-cell transcriptome. Gene set enrichment analysis further revealed a modest shift toward reduced peroxisome proliferator-activated receptor (PPAR) signaling in both HA-stimulated and T1D α-cells, suggesting a shared pathway-level signature. These findings indicate that HA alone does not fully recapitulate the extensive transcriptional remodeling observed in T1D α-cells, and that additional inflammatory or microenvironmental cues are required. • Low-molecular-weight hyaluronan activates ERK signaling in α cells. • Hyaluronan alone elicits modest transcriptional changes in αTC1-6 cells. • Low-molecular-weight hyaluronan induces minimal transcriptional changes in α-cells. • Hyaluronan-stimulated and T1D α-cells share reduced PPAR signaling signatures. • Hyaluronan alone is insufficient to drive T1D-like α-cell transcriptomic remodeling.