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

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 euglycaemia and studies under hypoglycemia; 5) lastly, 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 0.05). 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 appear to be crucial for preventing GLP-1-induced inhibition of glucagon secretion during hypoglycemia.