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, 8 normal weight participants (7 men, BMI 19–24.7 kg/m2, age 19–29 yr) 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 minutes 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.

Plasma Glucagon-Like Peptide-1 and Cholecystokinin Responses to Fast Food in Healthy-Weight and Obese Men

“…In both groups of respondents, levels of GLP-1 and CCK did not correlate significantly with the VAS Q1 (hunger) and VAS Q2 (fullness). This finding is supported by Melhorn et al, who reported that blocking GLP-1 receptors failed to decrease appetite and increased the food intake in humans and that it was not related to the personal response for satiety (VAS) (31). There are limitations in this research that need to be considered, such as the significant difference in CCK levels between the obese and healthy-weight respondents at baseline that might influence the final intervention result.…”

Ghrelin, CCK, GLP-1, and PYY(3–36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB

“…With respect to criterion 6 of TABLE 2, GLP-1R antagonism with exendin(9 -39) failed to increase test meal size in healthy humans tested under five distinct experimental conditions (492,721) and in two groups of RYGB patients tested 3-12 mo after surgery, when their mean BMI was ϳ34 kg/m 2 (737). In contrast, exendin(9 -39) did increase test meal size in one of the RYGB-patient groups in a preoperative test (737).…”

Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes

“…In addition, in rats, central endogenous GLP-1 affects food intake and body weight [ 11 , 18 ]. In humans, the effects of endogenous GLP-1 on prospective food consumption have been demonstrated [ 17 ], but changes in food intake could not be detected in a small pilot study [ 28 ]. Regarding the effects of endogenous GLP-1 on the CNS in humans, an association between postprandial increases in GLP-1 levels and the cerebral blood flow in areas involved in feeding behaviour has been observed [ 29 ], but our study is the first to investigate the effects of endogenous GLP-1 in an interventional setting.…”