Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans

Abstract

Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.

Trial registration: ClinicalTrials.gov NCT01152333.

Keywords: GLP-1; Insulin; Satiety; Visual analog scale.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. The effect of Ex-9 on appetite ratings and food intake

Ex-9 had no overall effect on hunger (A) or fullness (B) ratings throughout the experimental protocol. Hunger ratings tended to be lower after the standardized breakfast whereas fullness ratings were significantly lower after the buffet meal during Ex-9 treatment. Buffet intake did not differ between treatment days (C). All time points are 30 minutes apart except for between Post-Breakfast and Pre-Buffet (indicated by hash marks) where actual time elapsed was ~60–90 min. and was matched within subjects. Ex-9, Exendin-[9–39], VAS, visual analog scale, *P<0.05, #P=0.05.

Figure 2. Plasma glucose, insulin, GLP-1, and D-xylose concentrations during Ex-9 and placebo infusion

Inset bar graphs represent incremental area under the curve (AUC) for the corresponding hormone throughout the protocol period. There was a main effect of Ex-9 for plasma glucose (A; F1,7=8.84; P=0.02) and GLP-1 (B; F1,6=17.94; P<0.01), and a trend was present for insulin as well (C; F1,7=5.10; P=0.06). Compared to placebo, Ex-9 treatment increased AUC values in insulin and GLP-1. Time point specific analyses revealed that Ex-9 infusion as compared to placebo resulted in elevations in levels of: A) glucose after infusion initiation and after breakfast, C) insulin after the buffet meal and B) GLP-1 after the breakfast meal and prior to the buffet. D-xylose concentrations were not significantly different between treatments (D; F1,7=4.35; P=0.08). All time points are 30 minutes apart except for between Post-Breakfast and Pre-Buffet (indicated by hash marks) where actual time elapsed was ~60–90 min. and was matched within subjects. A, C &D: N=8 for all points except for Post-Infusion where N=6. B: N=7 for all time points except for Post-Infusion where N=5. Ex-9, Exendin-[9–39], GLP-1, glucagon-like peptide-1, #P=0.06, *P<0.05, **P<0.01.