HMD HISTORICAL RESEARCH GUIDELINE

Milestone 11 | GLP-1 Beyond Glucose

Gastric emptying, satiety and intake control as a physiological expansion of the incretin signal

Contents

• Executive summary

• Historical context

• From enterogastrone to metabolic satiety

• Key human evidence

• HMD chronological table

• HMD figure: gut-stomach-brain axis

• Independent HMD analysis

• Connection with later milestones

• References

Executive summary

Milestone 11 documents the point at which GLP-1 ceased to be interpreted only as an insulinotropic incretin and began to consolidate as an integrated physiological signal within the gut-stomach-pancreas-brain axis. From the 1990s onward, human studies showed that GLP-1 could inhibit gastric secretion, slow gastric emptying, enhance satiety and reduce energy intake [1-4].

This shift was decisive for modern metabolic medicine. GLP-1 actions on appetite and gastrointestinal motility clarified why GLP-1-based systems could modify not only postprandial glucose, but also ingestive behavior, meal size and the metabolic response following food intake [5,6].

From the HMD perspective, this milestone reframes GLP-1 as a systemic coordination signal. The peptide does not merely inform the pancreas that glucose has arrived; it also signals to the stomach, intestine and central nervous system that energetic entry must be modulated, distributed and limited.

Historical context

Previous milestones had established the incretin identity of GLP-1: intestinal secretion, glucose-dependent insulinotropic activity and glucagon suppression. Yet that interpretation could still remain restricted to glucose homeostasis. The turning point came when gastrointestinal-function and appetite studies demonstrated that GLP-1 also modulated gastric emptying and food intake [1-4].

In 1993, Wettergren and colleagues reported that truncated GLP-1 inhibited gastric and pancreatic functions in humans, including reduced postprandial acid secretion and delayed gastric emptying [1]. This observation expanded GLP-1 physiology from a pancreatic signal into an enterogastric signal.

By the late 1990s, Flint et al., Näslund et al. and Gutzwiller et al. provided human evidence that GLP-1 could increase satiety, prolong the postprandial period of fullness and reduce spontaneous food intake [2-4].

From enterogastrone to metabolic satiety

The classification of GLP-1 as an enterogastrone helped explain a central component of its postprandial effect. An enterogastrone is an intestinal signal capable of inhibiting gastric functions after nutrient entry; for GLP-1, this inhibition is expressed as reduced gastric secretion, delayed emptying and modulation of gastropancreatic function [1,6].

Schirra and Göke synthesized this interpretation by proposing that GLP-1 could be understood as an incretin, a candidate mediator of the ileal brake and a signal with broader effects on upper gastrointestinal function [5]. The ileal brake concept is important because it describes an intestinal braking response: when nutrients reach distal segments, transit is slowed and additional energy entry is limited.

GLP-1-induced satiety cannot be reduced to a single mechanism. Slower gastric emptying contributes to fullness, but central and vagal pathways also participate in hunger control, satiation and meal termination [5-8].

Figure 1. Timeline for Milestone 11. HMD figure based on references [1-6].

HMD chronological table

Key human evidence

The evidence from Flint et al. showed that GLP-1 enhanced satiety and reduced energy intake in humans, supporting a physiological role in appetite and intake control [2].

Näslund et al. added an important physiological bridge: in obese men, GLP-1 prolonged postprandial satiety and slowed gastric emptying, linking gastric mechanics with the subjective experience of fullness [3].

Gutzwiller et al. further supported the hypothesis by showing that intravenous GLP-1 infusions decreased spontaneous food intake even at physiological plasma concentrations, without overt side effects within that experimental design [4].

Figure 2. HMD model of the GLP-1 gut-stomach-brain axis. Transparent-background figure for documentary integration.

Independent HMD analysis

The HMD interpretation identifies three layers in this milestone. The first is mechanical: GLP-1 slows gastric emptying and changes the rate at which nutrients are delivered to the proximal intestine. The second is perceptual: that change is translated into fullness, satiety and reduced ingestive urgency. The third is systemic: by modulating glucose, glucagon, motility and appetite, GLP-1 operates as a postprandial coordination signal.

This milestone is essential for understanding why later GLP-1 therapies could not be assessed solely through HbA1c or postprandial glucose. Effects on intake, gastrointestinal tolerability, titration velocity, food volume, hydration and adherence become part of the technical framework.

From a metabolic-architecture perspective, GLP-1 turns a meal into a multi-node regulated event: intestinal signaling, gastric motility, pancreatic secretion, hepatic response, central perception and eating behavior. This model anticipates the later transition toward obesity, body composition and long-acting pharmacology.

HMD interpretive matrix

Connection with later milestones

Milestone 11 connects directly with the pharmacological translation of GLP-1. Once GLP-1 was recognized as a regulator of appetite and gastrointestinal motility, the technical problem was no longer only how to increase glucose-dependent insulin secretion; it also included duration of action, tolerability, satiety signaling and response maintenance [6-9].

This physiological expansion prepares the ground for long-acting GLP-1 receptor agonists, the obesity indication, semaglutide, GIP/GLP-1 coagonism and later multiagonist systems.

References

1. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38(4):665-673. doi:10.1007/BF01316798.

2. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-520. doi:10.1172/JCI990.

3. Näslund E, Gutniak M, Skogar S, Rössner S, Hellström PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998;68(3):525-530. doi:10.1093/ajcn/68.3.525.

4. Gutzwiller JP, Göke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, et al. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut. 1999;44(1):81-86. doi:10.1136/gut.44.1.81.

5. Schirra J, Göke B. The physiological role of GLP-1 in human: incretin, ileal brake or more? Regul Pept. 2005;128(2):109-115. doi:10.1016/j.regpep.2004.06.018.

6. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. doi:10.1152/physrev.00034.2006.

7. Maselli DB, Camilleri M. Effects of GLP-1 and its analogs on gastric physiology in diabetes mellitus and obesity. Adv Exp Med Biol. 2021;1307:171-192. doi:10.1007/5584_2020_496.

8. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010.

9. Holst JJ. Discovery of the GI effects of GLP-1: an historical perspective. Dig Dis Sci. 2022;67(7):2716-2720. doi:10.1007/s10620-022-07519-3.