1620-P: Vagus Nerve Integrity Is Critical for GLP-1 (7-36) Safeness against Hypoglycemia

Introduction & Objective: GLP-1 optimizes glycemic control mostly by stimulating insulin and suppressing glucagon secretion. During hypoglycemia, the glucagon suppressing activity is abolished through unclear pathways. The parasympathetic nervous system, via the vagus nerve, modulates the pancreatic hormone secretion during hypoglycemia. The vagus nerve fibers run along the esophagus and stomach walls, and innervate the pancreas distally. We investigated the role of the vagus nerve anatomical integrity in modulating pancreatic endocrine response to cholinergic activity and GLP-1 under hypoglycemia.

Methods: In situ, isolated rat pancreas (A); and pancreas and stomach (B) were perfused at severe hypoglycemia (glucose 1.5mM). Ach 1 µM, Ach 1 µM + GLP-1 (7-36) 1nM and GLP-1 (7-36) 1nM were sequentially infused (A: n = 6; B: n = 6). L-Arginine 10 mM was infused at the end of all experiments (positive control). Glucagon and SST levels were measured. Total hormone output was calculated. Statistical significance was settled at p<0.05.

Results: During hypoglycemia, cholinergic stimulation suppresses SST and stimulates glucagon secretion. Active GLP-1 (7-36) overrides cholinergic activity by potentiating SST and suppressing glucagon secretion in the isolated pancreas (A), but GLP-1 (7-36) has no effect if the vagus nerve integrity is preserved (B). Once cholinergic stimulation is discontinued, GLP-1 (7-36) suppresses glucagon and stimulates SST secretion in both preparations.

Conclusion: Pancreatic cholinergic activity stimulates glucagon secretion during hypoglycemia through suppression of somatostatin secretion. Cholinergic signaling that is delivered through the gastric intramural autonomic ganglia and/or vagus nerve efferents to the pancreas is crucial for blunting GLP-1 (7-36) activity under hypoglycemia. These findings improve our understanding of GLP-1 physiology and shine light on the requirements to target vagal nerve function in optimizing pancreatic endocrine secretion.