Incretin physiology: where GLP-1 and GIP come from and what they hit

Every GLP-1 medicine is a copy of a hormone your gut already makes. To understand what the drugs do, start with what the hormones do on an ordinary Tuesday after lunch.

Two hormones, two sets of cells

Food arriving in the small intestine touches endocrine cells scattered through the gut lining. Two kinds matter here. K cells sit mostly in the duodenum and jejunum and release glucose-dependent insulinotropic polypeptide, GIP. L cells are densest further down, in the ileum and colon, and release glucagon-like peptide-1, GLP-1, cut from the same proglucagon gene the pancreas uses to make glucagon (PubMed 17498508). Both hormones appear in the blood within minutes of eating, GIP first because its cells are upstream.

The term incretin comes from an old observation: glucose you swallow produces more insulin than the same glucose infused into a vein. That gap is the incretin effect. Measured with matched glucose loads, it accounts for roughly 50 to 70% of the insulin response in healthy adults, and it grows with the size of the meal (PubMed 3514343). Kreymann and colleagues showed in 1987 that GLP-1 (7-36 amide) infused at physiological levels reproduced this effect in people (PubMed 2890903).

What happens at each target

Beta cells. Both hormones raise insulin secretion, but only while glucose is elevated. This glucose dependence is the whole reason incretin drugs rarely cause hypoglycaemia on their own; the page on glucose-dependent insulin secretion walks through the clamp experiments.

Alpha cells. GLP-1 suppresses glucagon at normal and high glucose. GIP does the opposite at low glucose, nudging glucagon up (PubMed 17498508). That difference is one reason a dual agonist behaves differently from a pure GLP-1 drug; see GIP and dual agonism.

Stomach. GLP-1 slows gastric emptying, which flattens the glucose rise after a meal. The effect is strongest at first exposure and fades with continuous stimulation, a pattern covered on the gastric emptying page.

Brain. GLP-1 reduces food intake. Whether native GLP-1 reaches the brain through the blood, signals through vagal nerves in the gut, or is made locally by brainstem neurons is still argued; the drug versions are large and long-lived enough to reach receptors at the blood-brain barrier's weak points (PubMed 17928588). The appetite circuits page covers the anatomy.

Why the natural hormone is not the drug

Native GLP-1 has a half-life of one to two minutes. DPP-4, an enzyme on the surface of blood vessels and in plasma, removes two amino acids from its N-terminus and the fragment no longer activates the receptor; the kidney clears what is left (PubMed 7657039). Semaglutide's designers replaced the alanine DPP-4 attacks with a synthetic amino acid and attached a C18 fatty diacid on a spacer so the molecule rides on albumin, which stretched the half-life to about a week (PubMed 26308095). The pharmacokinetics page has the numbers from the labels.

What this page does not say

It does not say the drug versions simply "boost" the natural hormone. A once-weekly injection holds receptor exposure at levels the body never produces on its own, continuously rather than in meal-timed bursts. Some downstream effects, like the fading of gastric slowing, exist precisely because of that difference.

Where to go next

• The trial numbers for each drug are digested at FormBlends Research.
• Every agent and its approvals are listed at GLP-1s Explained.
• FormBlends' own overview of the science is at formblends.com/science.