A role for vagal activity in preventing the suppression of glucagon secretion by GLP-1 during hypoglycemia.

Glucagon-like peptide 1 (GLP-1) is generally safe against hypoglycemia, although it stimulates insulin and inhibits glucagon secretion. One explanation is that glucagon secretion is not inhibited by GLP-1 during hypoglycemia. We aimed at understanding the lack of suppression of glucagon secretion by GLP-1 by exploring the paracrine and neural regulation of pancreatic hormone secretion during hypoglycemia. Isolated rat pancreas (A) and an organ block comprising pancreas and stomach (B) were perfused. We performed 1 ) dose-response studies with GLP-1 (7-36) at hypoglycemia; 2 ) studies with GLP-1 (7-36) with and without blockage of somatostatin (SST) activity (with SST receptor antagonists); 3 ) and 4 ) dose-response experiments with acetylcholine at euglycemia and studies under hypoglycemia; and 5 ) finally, we studied the role of cholinergic signaling for modulation of GLP-1 activity under hypoglycemia. We measured glucagon, SST, and insulin levels. The secretion of SST was dependent on surgical preparation (A or B, P = 0.0006) and on cholinergic stimulation ( P < 0.0001), rather than on glucose levels ( P > 0.05). The infusion of SSTR antagonists in the isolated perfused rat pancreas blocked the paracrine effects of SST ( P = 0.0041) and stimulated glucagon secretion ( P = 0.0023). Cholinergic activity stimulated glucagon secretion during hypoglycemia through suppression of SST secretion. Cholinergic signaling delivered through the gastric intramural autonomic ganglia and/or vagus nerve efferents to the pancreas appears to be crucial for preventing GLP-1-induced inhibition of glucagon secretion during hypoglycemia. NEW & NOTEWORTHY Autonomic signaling suppresses somatostatin secretion, crucial for paracrine stimulation of glucagon secretion. SST mediates GLP-1-induced inhibition of glucagon secretion, but autonomic signaling may interfere with this mechanism. Activation of cholinergic pathways in a preparation with prepancreatic parasympathetic structures suppresses SST secretion in response to GLP-1 and potentiates glucagon secretion during hypoglycemia. These findings support the clinical importance of autonomic signaling in regulating pancreatic hormone secretion and hypoglycemia risk in some patients on GLP-1 receptor agonists.