Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia

Abstract

Acute administration of glucagon-like peptide 1 (GLP-1) and its agonists slows gastric emptying, which represents the major mechanism underlying their attenuation of postprandial glycemic excursions. However, this effect may diminish during prolonged use. We compared the effects of prolonged and intermittent stimulation of the GLP-1 receptor on gastric emptying and glycemia. Ten healthy men received intravenous saline (placebo) or GLP-1 (0.8 pmol/kg ⋅ min), as a continuous 24-h infusion ("prolonged"), two 4.5-h infusions separated by 20 h ("intermittent"), and a 4.5-h infusion ("acute") in a randomized, double-blind, crossover fashion. Gastric emptying of a radiolabeled mashed potato meal was measured using scintigraphy. Acute GLP-1 markedly slowed gastric emptying. The magnitude of the slowing was attenuated with prolonged but maintained with intermittent infusions. GLP-1 potently diminished postprandial glycemia during acute and intermittent regimens. These observations suggest that short-acting GLP-1 agonists may be superior to long-acting agonists when aiming specifically to reduce postprandial glycemic excursions in the treatment of type 2 diabetes.

Figure 1

Study protocol. Scintigraphic measurements of gastric emptying were performed over 4 h both from T = 0 h to T = 4 h and T = 24 h to T = 28 h. Infusion of study drug was commenced 30 min prior to ingestion of meal to allow for plasma concentrations to reach steady-state.

Figure 2

The effect of different GLP-1 regimens on gastric emptying. There was an effect between the various infusions (P < 0.001). Acute GLP-1 compared with placebo increased intragastric retention (P = 0.001), as did intermittent compared with prolonged infusion (P = 0.04). While prolonged infusion increased retention in comparison with placebo (P = 0.003), acute and intermittent infusions had similar effects (P = 1.0). Data are mean ± SEM. A mixed-effects maximum likelihood model was used to determine differences with post hoc testing adjusted for multiple comparisons.

Figure 3

The effect of different GLP-1 regimens on postprandial glycemia and insulinemia. A: There was an effect between infusions (P < 0.001). Acute GLP-1 reduced postprandial glycemia (AUC_0–60) compared with placebo (*P = 0.001), as did intermittent compared with prolonged (#P = 0.007), but there was no difference between prolonged and placebo (P = 0.21) or acute and intermittent (P = 1.0) regimens. B: There was an effect between the various infusions (P < 0.001). Postprandial insulin concentrations were reduced during intermittent compared with prolonged infusion (*P = 0.003); comparing acute infusion with placebo, the difference was not statistically significant (P = 0.07). Postprandial insulin concentrations were comparable between acute and intermittent infusions (P = 1.0) and between prolonged infusion and placebo (P = 0.21). Data are mean ± SEM. A mixed-effects maximum likelihood model was used to determine differences with post hoc testing adjusted for multiple comparisons. IV, intravenous.

Figure 4

Correlation between gastric emptying, glycemia, and insulinemia. The rate of gastric emptying (% gastric retention AUC₆₀) was closely associated with postprandial glycemia (AUC₆₀: r = −0.49; P = 0.005) (A) and postprandial insulinemia (AUC₁₈₀: r = −0.41; P = 0.02) (B). Data are correlated within subject (15).