What is Glucagon-Like Peptide-1 (GLP-1)?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which means it’s released from the gut (intestine) in response to food and helps regulate blood glucose levels. It’s a critical player in glucose and lipid metabolism, and in energy regulation generally (Campbell & Drucker, 2013; Chia & Egan, 2019). It is also the basis for several modern treatments for type 2 diabetes, hormone disorders and obesity (Rajeev & Wilding, 2016).

GLP-1 was the second incretin hormone to be identified. The first was gastric inhibitory polypeptide (GIP), which is now called glucose-dependent insulinotropic polypeptide (GIP). It has been effectively reviewed by Müller et al., (2019).

Key Facts About GLP-1

1. Origin:

• GLP-1 is produced by L-cells (L-enteroendocrine cells) in the small intestine, especially the ileum and colon.

• It’s released after eating, particularly in response to macronutrients like carbohydrates and fats.

• It is also synthesized in response to α and β adrenergic receptor agonists and by insulin itself (Lim et al., 2009).

• It is synthesized as a precursor peptide [preproglucagon (Gcg)], which is subsequently cleaved by the proteolytic enzyme proprotein convertase 1/3 to generate GLP-1, glucagon-like protein 2 (GLP-2), intervening peptide 2, glicentin, and oxyntomodulin.

• GLP-2 is referenced elsewhere but the other peptides are poorly understood.

  Intervening peptide 2 (IP-2), glicentin, and oxyntomodulin are all proglucagon-derived peptides, meaning they are produced through the post-translational processing of a larger precursor protein called proglucagon. These peptides are primarily involved in gastrointestinal and metabolic regulation, and they are secreted from enteroendocrine L-cells in the gut and pancreatic alpha cells, depending on the tissue. 

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  1. Intervening Peptide 2 (IP-2)

  • What it is: A small peptide fragment released during the cleavage of proglucagon. It is sometimes referred to as a “spacer” peptide.

  • Function: Not well understood. IP-2 itself does not appear to have a significant known biological function, and is often considered an inactive byproduct of proglucagon processing.

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  2. Glicentin

  • What it is: A large peptide (69–amino acid) also derived from proglucagon.

  • Structure: Contains sequences of glucagon, IP-1, and part of oxyntomodulin.

  • Function:

    • May help regulate gut motility and growth.

    • Involved in insulin secretion and intestinal mucosal growth.

    • Potential role in satiety (feeling full), although less prominent than oxyntomodulin.

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  3. Oxyntomodulin

  • What it is: A 37-amino acid peptide, also derived from proglucagon.

  • Structure: Includes the full glucagon sequence with an 8-amino acid C-terminal extension.

  • Function:

    • Reduces appetite and body weight.

    • Stimulates energy expenditure.

    • Weak agonist of GLP-1 receptor and glucagon receptor.

    • Interest in obesity and diabetes treatment due to these metabolic effects.

2. Functions

GLP-1 has multiple important physiological roles which are directly related to glucose homeostasis. It modulates satiety, food intake and gastric emptying as well as fluid homeostasis (Müller et al., 2019).

• Stimulates insulin secretion (glucose-dependent).

• Suppresses glucagon secretion, which prevents excess glucose production by the liver.

• Slows gastric emptying by slowing gastrointestinal tract motility, prolonging digestion and enhancing satiety. 

• Reduces appetite through central nervous system effects.

It is also a major signaling molecule in the gut-brain axis. It has pleiotropic effects which refers to the phenomenon that a single gene or genetic variant affects two or more seemingly unrelated phenotypic traits. These include blood pressure control,  thermogenesis, neuroprotection and neuorogenesis (Grieco et al., 2019)

GLP-1 binds to the G-protein GLP-1 receptor of various organs .

3. Medical Significance:

Because of its powerful effects on insulin and appetite, GLP-1 is a target for:

• Type 2 Diabetes treatments (e.g., GLP-1 receptor agonists like liraglutide, semaglutide, dulaglutide).

• Obesity medications, since it reduces food intake and promotes weight loss.

4. GLP-1 Receptor Agonists:

These are synthetic drugs that mimic natural GLP-1 but resist breakdown, making them longer-acting. Examples include:

• Liraglutide (Victoza, Saxenda)

• Semaglutide (Ozempic, Wegovy)

• Dulaglutide (Trulicity)

5. Degradation:

• Natural GLP-1 has a very short half-life (1–2 minutes) due to rapid breakdown by the enzyme DPP-4 (dipeptidyl peptidase-4). This is either before the hormone leaves the GI tract or on entering blood circulation.

• This is why DPP-4 inhibitors (e.g., sitagliptin, linagliptin) are also used to treat diabetes—they extend the activity of natural GLP-1.

How GLP-1 Agonists Compare In Terms of Weight Loss And Glucose Control

GLP-1 Agonists Comparison Chart

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Key Takeaways

• Semaglutide (Wegovy/Ozempic) is currently the most potent GLP-1 agonist for both weight loss and glucose control, especially at higher doses.

• Tirzepatide (Mounjaro), although not a pure GLP-1 agonist (it targets both GLP-1 and GIP receptors), is even more effective in clinical trials and may become the standard for obesity and diabetes in the future.

• Liraglutide also shows strong weight loss benefits, but daily injection can be a drawback compared to weekly agents.

• Dulaglutide and exenatide ER are good options for glucose control but tend to cause less weight loss.

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Real-World Effectiveness

• Weight loss with semaglutide (Wegovy) can exceed 15% of body weight in many individuals over ~68 weeks.

• A1c reduction is generally best with agents like semaglutide and tirzepatide, particularly in patients with high baseline A1c.

The Effect Of Polyphenols

Particular polyphenols based on the flavonoids and those containing them in extracts also affect GLP-1 synthesis. These polyphenols have both antiobesity and antidiabetic effects (Gonzalez-Abuin et al., 2014). They showed grape seed extract raised GLP-1 levels after ingestion in a rat model.

Other polyphenols reported to raise GLP-1 levels:

• Resveratrol (red grapes, red wine) – has anti-hyperglycemic effect, which could be attributed to an increase in GLP-1 levels.
• coffee, especially chlorogenic acid. Improves glycaemia in mice when they receive an oral glucose load.
• mate (Ilex paraguariensis) leaf extract. It is rich in the phenolic compound 3,5-O-dicaffeoyl-D-quinic acid. Said to improve glycemia and insulinemia in mice fed a high-fat diet (HFD), which may be related to higher active plasma GLP-1 levels.
• Berberine (Rhizoma coptidis), improves glycemia, insulinemia and GLP-1 levels after oral glucose challenge.
• berries – improve insulin levels following sucrose ingestion.
• grape seed extracts improve glycaemia by possible inhibition of DPP-4
• blackcurrant extracts (FoodWrite, 2020 Internal report – confidential)
• olive oil extracts (FoodWrite, 2020 Internal report – confidential)
• anthocyanins (FoodWrite, 2020 Internal report – confidential) (Oteiza et al., 2023)

The mechanisms of their action have yet to be established.

References

Campbell, J. E., & Drucker, D. J. (2013). Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metabolism, 17(6), pp. 819-837 (Article)

Chia, C. W., & Egan, J. M. (2020). Incretins in obesity and diabetes. Annals of the New York Academy of Sciences, 1461(1), pp. 104-126.

González-Abuín, N., Martínez-Micaelo, N., Margalef, M., Blay, M., Arola-Arnal, A., Muguerza, B., … & Pinent, M. (2014). A grape seed extract increases active glucagon-like peptide-1 levels after an oral glucose load in rats. Food & Function, 5(9), pp. 2357-2364.  

Grieco, M., Giorgi, A., Gentile, M. C., d’Erme, M., Morano, S., Maras, B., & Filardi, T. (2019). Glucagon-like peptide-1: a focus on neurodegenerative diseases. Frontiers in Neuroscience, 13, 1112 (Article)

Lim, G. E., Huang, G. J., Flora, N., LeRoith, D., Rhodes, C. J., & Brubaker, P. L. (2009). Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology, 150(2), pp. 580-591.

Müller, T. D., Finan, B., Bloom, S. R., D’Alessio, D., Drucker, D. J., Flatt, P. R., … & Tschöp, M. H. (2019). Glucagon-like peptide 1 (GLP-1). Molecular Metabolism, 30, pp. 72-130 (Article).

Oteiza, P. I., Cremonini, E., & Fraga, C. G. (2023). Anthocyanin actions at the gastrointestinal tract: Relevance to their health benefits. Molecular Aspects of Medicine, 89, 101156.  

Rajeev, S. P., & Wilding, J. (2016). GLP-1 as a target for therapeutic intervention. Current Opinion in Pharmacology, 31, pp. 44-49