Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans

Michael A Nauck, Guido Kemmeries, Jens J Holst, Juris J Meier, Michael A Nauck, Guido Kemmeries, Jens J Holst, Juris J Meier

Abstract

Objective: Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control.

Research design and methods: Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m(2)) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg(-1) · min(-1)) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently.

Results: GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1-induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05).

Conclusions: The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration.

Figures

FIG. 1.
FIG. 1.
Plasma concentrations of GLP-1 (A), glucose (C), insulin (D), glucagon (E), C-peptide (F), PP (G), and GIP (H), and gastric emptying (B) after instilling two liquid test meals (amino acids and sucrose) via a nasogastric tube into the stomach at 0 and 240 min in nine healthy young volunteers during the intravenous infusion of GLP-1 (0.8 pmol · kg−1 ⋅ min−1) or placebo. Mean ± SEM. P values were calculated by repeated-measures ANOVA. *Significant (P < 0.05) differences at specific time points between experiments with placebo and GLP-1. †Significant difference from the corresponding time point after the first meal during the exogenous administration of GLP-1.

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