Acute administration of glucagon-like peptide-1 (GLP-1) and its agonists slow gastric emptying markedly, which represents the major mechanism underlying their attenuation of postprandial glycaemic excursions. There is preliminary evidence that the slowing of gastric emptying with ‘long-acting’ agonists attenuates over time, potentially diminishing their postprandial glucose-lowering effect.
To determine the effects of prolonged and intermittent stimulation of the GLP-1 receptor on gastric emptying, glycaemia and insulinaemia.
Ten healthy men received intravenous saline (‘placebo’) or GLP-1 (0.8 pmol/kg.min), as a continuous 24h infusion (‘prolonged’), two 4.5h infusions separated by 20h (‘intermittent’), and a 4.5h infusion (‘acute’), in randomized, double-blind, crossover fashion. Gastric emptying of a radiolabeled, mashed potato, meal was measured using scintigraphy. Data are mean±SEM and were analysed with a mixed effects maximum likelihood model, with infusion as a fixed effect.
Gastric emptying was markedly affected by the different infusions (P<0.001). Acute GLP-1 potently slowed gastric emptying when compared to placebo (P=0.001), as did intermittent when compared to prolonged infusion (P=0.04). While prolonged infusion slowed gastric emptying in comparison to placebo (P=0.003), acute and intermittent infusions had comparable effects (P=1.0). Postprandial glycaemia was markedly affected by infusion type (P<0.001). Acute GLP-1 reduced postprandial glycaemia when compared to placebo (P=0.001), as did intermittent when compared to prolonged (P=0.007), but there was no difference between acute and intermittent regimens (P=1.0). Peak insulin concentrations were also affected (P=0.003), with levels being substantially less during acute than placebo (P=0.03), as were intermittent when compared to prolonged (P=0.03).
Stimulation of the GLP-1 receptor leads to tachyphylaxis to the slowing of gastric emptying within 20 hours. These observations suggest that ‘short-acting’ GLP-1 agonists may be superior to ‘long-acting’ agonists when aiming specifically to reduce postprandial glycaemic excursions in patients with type 2 diabetes.