GABA and GLP-1 receptor agonist combination therapy modifies diabetes and Langerhans islet cytoarchitecture in a rat model of Wolfram syndrome

GABA monotherapy had no significant effect on the diabetic phenotype in WS rats, while liraglutide monotherapy effectively delayed diabetes progression. However, the combination therapy of GABA and liraglutide demonstrated a markedly superior effect, not only reversing the diabetic phenotype but also significantly enhancing glucose homeostasis, insulin and C-peptide secretion, and β-cell mass. This combined treatment led to a restoration of Langerhans islet architecture, correction of the endocrine cell proportions, and a notable increase in GAD65/67-positive β-cells, indicating improved β-cell health and function. These findings provide strong evidence supporting the evaluation of GABA and GLP-1 RAs as a combination therapy in clinical trials. Their synergistic effects may offer enhanced β-cell protection, promote functional recovery, and uncover novel therapeutic pathways for treating patients with WS.