GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice

Aim: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces glucose-dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP-1 receptors (GLP-1Rs) in peripheral nerve and to assess the impact of GLP-1R agonists on diabetes-induced nerve disorders. Methods: Tissues were collected from streptozotocin-diabetic rats. GLP-1R function was assessed by incubating tissues from normal and diabetic rats with GLP-1R agonists and antagonists and measuring induction of ERK1/2 phosphorylation by Western blot. Streptozotocin-diabetic mice were also treated with the GLP-1R agonist exenatide for 8 weeks to assess the impact of GLP-1R signalling on peripheral nerve function and structure. Results: GLP-1R protein was detected in rat dorsal root ganglia and the neurons and Schwann cells of the sciatic nerve. Protein levels were not affected by streptozotocin-induced diabetes. GLP-1R agonists did not signal via ERK1/2 in sciatic nerve of normal rats. However, GLP-1R agonists significantly increased pERK1/2 levels in sciatic nerves from diabetic rats, indicating that GLP-1Rs are functional in this tissue. Exenatide treatment did not affect blood sugar, insulin levels or paw thermal response latencies in either control or diabetic mice. However, the reductions of motor nerve conduction velocity and paw intraepidermal fibre density seen in diabetic mice were attenuated by exenatide treatment. Conclusions: These data show that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control.