The Incretin System: How GLP-1 & GIP Control Metabolism

What Is the Incretin System?

The incretin system is a hormonal feedback loop between the gut and the pancreas that plays a central role in glucose homeostasis. When you eat, specialised enteroendocrine cells lining the intestinal wall detect nutrients and release incretin hormones into the bloodstream. These hormones then travel to the pancreas, where they potentiate glucose-dependent insulin secretion — meaning they amplify insulin release, but only when blood glucose is elevated.

Two hormones comprise the incretin system: GLP-1 (glucagon-like peptide-1), secreted by intestinal L-cells, and GIP (glucose-dependent insulinotropic polypeptide), secreted by intestinal K-cells. Together, these hormones account for approximately 50–70% of postprandial insulin secretion — a phenomenon known as the "incretin effect."

Understanding this system is essential because its dysfunction underlies type 2 diabetes, and its therapeutic exploitation has produced the most impactful class of metabolic drugs in decades — including semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro).

The Incretin Effect

The incretin effect was first observed in the 1960s when researchers noticed that oral glucose produced a significantly greater insulin response than intravenous glucose at the same blood sugar concentration. This meant that something released from the gut during oral feeding was amplifying pancreatic insulin secretion beyond what glucose alone could achieve.

In type 2 diabetes, the incretin effect is severely diminished. While GLP-1 levels may be only slightly reduced, the pancreatic response to GIP is substantially impaired. This loss of incretin-mediated insulin amplification contributes significantly to the postprandial hyperglycaemia characteristic of type 2 diabetes.

GLP-1: The Satiety Hormone

GLP-1 is a 30-amino-acid peptide hormone produced by L-cells in the distal ileum and colon. It is derived from the proglucagon gene — the same gene that encodes glucagon — through tissue-specific post-translational processing. In the gut, proglucagon is cleaved by prohormone convertase 1/3 to yield GLP-1, while in the pancreatic alpha cells, prohormone convertase 2 cleaves the same precursor to produce glucagon.

Physiological Actions of GLP-1

Critically, endogenous GLP-1 has a half-life of only 2–3 minutes, as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). This ultra-short half-life means that native GLP-1 cannot be used therapeutically — which is why pharmaceutical development has focused on DPP-4-resistant analogues with dramatically extended half-lives.

GIP: The Forgotten Incretin

GIP is a 42-amino-acid peptide hormone secreted by K-cells in the duodenum and jejunum. It was actually the first incretin hormone discovered (originally named "gastric inhibitory polypeptide" for its ability to inhibit gastric acid secretion), but its insulinotropic properties were identified later.

For decades, GIP was considered a poor therapeutic target because its insulinotropic action is severely impaired in type 2 diabetes — unlike GLP-1, which retains much of its effect. This led to GIP being largely overlooked in drug development while GLP-1 received all the attention.

The re-evaluation of GIP came with the development of tirzepatide (Mounjaro), which combines GLP-1 and GIP receptor agonism in a single molecule. The SURMOUNT and SURPASS trial results — showing weight loss of 20–26% and superior glycaemic control compared to GLP-1 agonists alone — have demonstrated that GIP receptor agonism adds substantial therapeutic benefit when combined with GLP-1 activity.

DPP-4: The Incretin Destroyer

Dipeptidyl peptidase-4 (DPP-4) is a serine protease expressed on the surface of many cell types that rapidly cleaves and inactivates both GLP-1 and GIP. Within minutes of secretion, DPP-4 removes the two N-terminal amino acids from each hormone, rendering them biologically inactive. This is why only 10–15% of secreted GLP-1 reaches the systemic circulation in its active form.

This rapid degradation has been exploited therapeutically in two ways:

Therapeutic Exploitation of the Incretin System

The development of incretin-based therapies represents one of the most successful examples of translational pharmacology. From the discovery of GLP-1 in the 1980s to the approval of semaglutide for obesity in 2021, the journey from basic science to blockbuster drug has been remarkably productive.

Timeline of Incretin-Based Therapies

How Semaglutide Was Engineered

Semaglutide is a masterpiece of peptide engineering. Starting from native GLP-1 (half-life: 2–3 minutes), Novo Nordisk made three key modifications:

• 1. Position 8 substitution (Ala→Aib): Renders the molecule resistant to DPP-4 cleavage
• 2. Position 34 substitution (Lys→Arg): Prevents fatty acid attachment at an unwanted site
• 3. C-18 fatty diacid linker at Lys26: Enables strong, reversible albumin binding, extending the half-life to approximately 7 days and allowing once-weekly dosing

This approach — converting a short-lived endogenous peptide into a long-acting therapeutic through strategic chemical modification — exemplifies modern peptide drug design. The same principles have been applied to tirzepatide, which incorporates both GLP-1 and GIP receptor agonism in a single acylated peptide.

Beyond Diabetes & Obesity

The GLP-1 receptor is expressed throughout the body, not just in the pancreas and gut. This widespread expression has led to the discovery of effects far beyond glucose and weight regulation:

Further Reading

Continue exploring the science of peptides and the incretin system:

This article is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional regarding any medical conditions or treatments.