This is a supplemental page to the GLP-1 Medication page. In this page, we cover some biology around GLP-1, and GLP-1’s history – discovery and development.

Also see:

• Diabetes, for more about the various types of diabetes,
• Weight Loss, Facts and Fiction to learn more about what really works for weight loss.

Why GPL-1

GLP-1 is a hormone that is used to regulate the blood glucose system and signals satiatiation. It activates the GLP-1 Receptor, which in biology we call Agonist – for activation (turned on). Antagonist means deactivated (turned off). We have GLP-1 Receptors around our gut system and in our brain.

From what we have discussed above, GLP-1 RA medication can address the BSL, cravings and feeling of satiation. This can have a secondary effect for many to help stabilise our mood and decrease brain fog a bit.

GLP-1 possesses several physiological properties making it (and its functional analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus (we will just say diabetes in this document), as these actions induce long-term improvements along with the immediate effects. The most noteworthy effect of GLP-1 is its ability to balance blood sugar. We discuss the mechanism of this below under Glucogen.

GLP-1 has multiple complementary metabolic effects, such as insulin stimulation, glucose-dependent glucagon suppression, inhibition of gastric emptying and promotion of satiety.

Discovering GPL-1

GLP-1 was first described in 1979 by a research group of Werner Creutzfeldt, a German chemist, in Göttingen, Germany. A number of scientists from various groups worked with this peptide from 1980 onwards until we created the modern medication. Richard Goodman harvested the DNA from the American anglerfish islet cells and spliced this DNA in o a bacteria to find the gene for somatostatin. Somatostatin is a hormone that regulates the endocrine system, which is important as insulin is a hormone, part of the endocrine system, that regulates sugar. Further investigation in Somatostatin led to the gene for GLP-1, GLP-2 and glucagon peptides.

Between 1985 and 1987, GLP-1 was identified as a potent incretin hormone, from the collaborative efforts of Svetlana Mojsov and Joel Habener, Massachusetts General Hospital, and Lotte Knudsen’s team at Novo Nordisk. These researchers discovered two related proglucagon-derived peptides, GLP-1 amide and GLP-1. Compared to the full length GLP-1 sequence, these possessed dramatically superior biological activity.

The discovery of GLP-1’s extremely short half-life meant that it was impossible to develop into a drug.

Monster Venom, useful spit

John Eng, 1992, was investigating Gila monster venom, as part of his work for the Veterans Affairs Medical Centre in New York. Gila monsters are a species of venomous lizard native to the Southwestern United States and the northwestern Mexican state of Sonora. Eng was investigating bioactive peptides in the Gila monster venom and identified a peptide with similar properties to GLP-1, called exendin-4, a 39-amino acid peptide, that had just a slight variation which led to it lasting much longer. Early work with this new peptide led Amylin Pharmaceuticals to create Exenatide, an early GLP-1 medication used to combat Diabetes Type 2. However, the peptides short life span (longer than regular human GLP-1) and other features meant it wasn’t ideal.

Anglerfish for a new Angle

The main problem with existing GLP-1 medication was how short lived it was. While the Gila monster GLP-1 analogue worked similarly to human GLP-1 and lasted much longer, it was still insufficient. The hunt was on for a GLP-1 analogue that would last longer, or a way to trick humans into making it directly.

The deep sea dwelling fish, the Atlantic Anglerfish, was the source for finding a way to encode GLP-1 analogues. To optimally maintain their own glucagon levels as they dwell on the ocean floor, while being mostly inactive, the anglerfish had evolved GLP-1 sites outside of the pancreas, making it much easier to understand how they make GLP-1 without all of the other complex functions of the pancreas. It was identified that anglerfish had a different GLP-1 production method to mammals in and in 1982, anglerfish glucagon gene was discovered. Once the fish’s method of production was isolated and understood, it facilitated understanding mammalian GLP-1 production, leading to the isolation of the mammalian glucagon gene. This gene was inserted into a bacteria to produce the human analogue GLP-1 peptide much like we use bacteria to mass produce insulin.

The problem was, the peptide would break down rapidly if stored in water. This led to two developments, a dry version that would reconstitute when sprayed in the nasal passages, and a liquid version where water was replaced with dimethyl sulfoxide (DMSO), which could then be safely injected – the current version of GLP-1 medication that most people recognise.

Understanding GLP-1 RA Biology

TLDR: The hormone GLP-1 is a Glucagon Like Peptide, type 1, that activates GLP-1 receptors.

In brief: When you eat a meal, if it contains the correct nutrients and is of sufficient quantity, your body releases the GLP-1 hormone from your intestinal epithelial endocrine L-cells. The GLP-1 enters your bloodstream and occupies GLP-1 receptors, activating them. On activation, the GLP-1 Receptors trigger the following changes:

• Metabolism:
  • How simple and complex sugars are managed (balanced and used),
  • Energy levels (cells and organs),
• Brain:
  • Cognition,
  • Mood,
• Satiation:
  • (no longer craving food and some other substances).

Peptides

Comprehending peptides starts with amino acids.

An amino acid is a basic building block for making protein, and a peptide is (generally) a small protein. The specific boundary between a peptide and protein is fuzzy, so some may refer to a molecule as a peptide while others may refer to it as a protein. While there are over 500 amino acids, 22 of them are referred to as ‘alpha’ or ‘essential’, using the greek letter ‘α’, as they are encoded in our DNA. We recombine these amino acids to create all of the various types of proteins that we are made of. [Source]

Glucagon

Glucagon is a catabolic peptide hormone, created by the pancreas. It raises the concentration of fatty acids and glucose in the bloodstream. Opposite glucagon is insulin, which decreases the presence of fatty acids and glucose in the bloodstream. By balancing the quantity of glucagon and insulin, the blood sugar level is homeostatic, hopefully within the Goldilocks Zone, not too much, not too little.

When the pancreas detects that the blood sugar is too low, it releases glucagon. This reaches the liver and engages a process called glycogenolysis, converting stored glycogen (complex sugar) into glucose (simple sugar). If the blood sugar becomes too high, insulin is released instead. Insulin allows skeletal muscle, adipose (fat) tissue and the liver to absorb simple sugar and either use them for energy, or convert them into glycogen (complex sugar).

Receptor Agonist

A receptor is a special molecule that can connect to another kind of molecule (hormone). Receptors are like switches – they can be toggled to be the opposite of their current mode. If the receptor is by default ‘on’, then the key molecule the receptor is expecting will turn it ‘off’, or vise versa. Sometimes a molecule fits in the receptor, but doesn’t toggle it, incapacitating its function as a switch – that is receptor blockade.

A receptor agonist is a molecule that fits in the receptor that activates the receptor to be ‘on’, sending a signal, which will activate a biological function.

More on receptors: Neurotransmitters.

Glucagon Like Peptide 1 Receptor Agonist Medication

Time to bring this all together. GLP-1 RA Medication is a chemical that is made in a lab. The chemical is similar enough to the natural human GLP-1 hormone that it can activate the GLP-1 receptors. These GLP-1 receptors are located around the body, mostly in the stomach and brain. Once activated, how your body manages the following is modified:

• The availability and use of blood sugar, acting as a glycogen, adjusting:
  • Glucose (simple sugar for use) to glycogen (complex sugar for storage), and
  • Glucagon to glucose,
• Improving how cells and organs can use sugar for energy production,
• Turning the ‘satiated feeling’ on:
  • Decreases cravings:
    • Mostly of food, and
    • Some other substances.
• Modifies some neurotransmitter levels:
  • Improved cognition,
  • Stabilised and improved mood.

If your body is managing any of these aspects affected by blood sugar well, the GLP-1 medication does not affect that aspect.

The natural human GLP-1 hormone is very short lived (1 to 5 minutes). Soon after the conditions for GLP-1 to be released into your bloodstream by your pancreas, which will activate the above list, ceases shortly after the condition have stopped. Unfortunately, for a number of people, the trigger point for when the conditions have stopped are in the wrong place, leading to insufficient GLP-1 being released. While we have been able to make human GLP-1 for quite a while, it was not useful as it would break down too quickly and not achieve anything. Your body gets around this limitation by continually making the GLP-1 messenger so long as the conditions are correct, if your body has those conditions markers in the optimal location.

The challenge was to make a chemical that triggers the GLP-1 receptors that doesn’t break down so rapidly. We covered that above in the section History.

Reference

Darwish, R., Abu-Sharia, G., & Butler, A. E. (2025). History of glucagon-like peptide-1 receptor agonists. Pharmacological Research, 108045. https://doi.org/10.1016/j.phrs.2025.108045

Wikipedia Contributors. (2019, August 3). Glucagon-like peptide-1. Wikipedia; Wikimedia Foundation. https://en.wikipedia.org/wiki/Glucagon-like_peptide-1

Wikipedia Contributors. (2019). Amino acid. In Wikipedia. Wikimedia Foundation. https://en.wikipedia.org/wiki/Amino_acid

Wikipedia Contributors. (2019). Glucagon. In Wikipedia. Wikimedia Foundation. https://en.wikipedia.org/wiki/Glucagon

Wikipedia Contributors. (2023) GLP-1 receptor agonist. Wikimedia Foundation. https://en.wikipedia.org/wiki/GLP-1_receptor_agonist

Collins, L., & Costello, R. A. (2024). Glucagon-like peptide-1 receptor agonists. In PubMed. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK551568/

Story of discovery: how different medications for diabetes and obesity emerged from basic research on one pancreatic hormone – NIDDK. (2021). In National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/news/archive/2021/story-discovery-medications-diabetes-obesity-emerged-research-pancreatic-hormone

Wilcox, G. (2005). Insulin and Insulin Resistance. Clinical Biochemist Reviews, 26(2), 19–39. https://pmc.ncbi.nlm.nih.gov/articles/PMC1204764/

Hui, H., Farilla, L., Merkel, P., & Perfetti, R. (2002). The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. European Journal of Endocrinology, 863–869. https://doi.org/10.1530/eje.0.1460863