Impact of glucagon-like peptide-1 receptor agonists on axonal function in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) affects approximately half of the 500 million people with type 2 diabetes worldwide. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) receptors in the peripheral nervous system may be a suitable target for DPN treatment. Fourteen participants were consecutively recruited after being prescribed either semaglutide or dulaglutide as part of standard clinical care for type 2 diabetes. Participants underwent clinical assessment, nerve conduction studies, and axonal excitability assessment at baseline and at 3 mo following commencement of GLP-1 receptor agonist (GLP-1RA) therapy. These data were combined with 10 participants who had previously received exenatide therapy, and mathematical modeling of excitability data was undertaken. Clinical neuropathy scores improved at 3 mo following commencement of GLP-1 (baseline TNS 3.7 ± 4.5, posttreatment TNS 2.3 ± 3.4, <i>P</i> = 0.005). Nerve conduction studies demonstrated an improvement in sural amplitude at 3 mo (baseline 11.9 ± 8.5 μV, posttreatment 14.2 ± 9.2 μV; <i>P</i> = 0.013). Axonal excitability studies revealed changes consistent with improvements in Na⁺/K⁺-ATPase pump function and Na⁺ permeability, and this was supported by mathematical modeling. GLP-1RA therapy improves clinical and neurophysiological outcomes in DPN. Treatment with GLP-1RA may reverse axonal dysfunction by improving Na⁺/K⁺-ATPase pump function.<b>NEW & NOTEWORTHY</b> Diabetic peripheral neuropathy is known to be relentlessly progressive and irreversible. Prospective studies in 24 participants with diabetic peripheral neuropathy (DPN) treated with glucagon-like peptide-1 receptor agonists (GLP-1RA) demonstrated improvements in clinical neuropathy scores, nerve conduction studies, and axonal excitability recordings. Analysis of axonal excitability recordings revealed the mechanism for GLP-1RA improvement in DPN were changed consistent with improvements in Na⁺/K⁺-ATPase pump function, and this was supported by mathematical modeling.