Incretin

Incretins are peptide hormones secreted by enteroendocrine cells of the intestine in response to nutrient intake that potentiate glucose-dependent insulin secretion from pancreatic beta-cells. The two established human incretins are glucose-dependent insulinotropic polypeptide (GIP), released mainly from K cells of the upper small intestine, and glucagon-like peptide-1 (GLP-1), released mainly from L cells of the lower gut. Each acts through its own G protein-coupled receptor (GIPR and GLP-1R). Together they account for the incretin effect: the two- to three-fold greater insulin response to oral glucose compared with an intravenous glucose infusion that produces the same blood glucose levels. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

In type 2 diabetes the incretin effect is reduced or lost, largely because GIP becomes less effective, while the insulin-stimulating and glucagon-lowering actions of GLP-1 are preserved. This finding made GLP-1 the parent compound of two drug classes: DPP-4-resistant GLP-1 receptor agonists and DPP-4 inhibitors. Tirzepatide, which activates both GIP and GLP-1 receptors, extended the approach to dual incretin receptor agonism.

The incretin concept explains why the same amount of glucose causes a much larger insulin response when it is swallowed than when it is infused into a vein. Human studies in the 1980s measured this difference and found it was substantially reduced in people with type 2 diabetes. That observation pointed researchers toward the gut hormones themselves as possible treatment targets, rather than treating the pancreas in isolation, and it shaped decades of later research.

Incretins are the biological basis of some of the most widely used peptide medicines. Native GLP-1 and GIP are broken down by DPP-4 within minutes, so they cannot be used directly as drugs. Developers responded in two ways: by engineering GLP-1 receptor agonists that resist DPP-4 and last much longer, and by creating DPP-4 inhibitors that protect the body's own incretins. Both classes are now established treatments for type 2 diabetes.

Incretin hormones do more than release insulin. GLP-1 also slows stomach emptying, lowers glucagon when glucose is high and reduces appetite, while GIP acts on fat tissue and bone. These wider effects help explain why incretin-based drugs affect body weight and are studied in obesity and cardiovascular disease. They also mean that unapproved products claiming to act like incretins can have effects well beyond blood sugar, which approved drugs characterize in trials.

“Incretin means GLP-1”

GLP-1 is one of two established human incretins. GIP is the other, and in healthy people it is thought to contribute more to the incretin effect than GLP-1. GLP-1 became the main drug target because its insulin-releasing action is preserved in type 2 diabetes, whereas the response to GIP is markedly reduced.

“Incretins push insulin up whatever the blood sugar”

Incretin action on beta-cells is glucose-dependent: the insulin-releasing effect is strong when glucose is raised and weak when it is normal or low. This glucose dependence is why incretin-based treatments used on their own carry a low intrinsic risk of hypoglycemia, although that risk can change when they are combined with other glucose-lowering drugs.

“Incretin drugs simply replace a missing hormone”

In type 2 diabetes GLP-1 secretion is not simply absent, and native GLP-1 lasts only minutes in the blood. GLP-1 receptor agonists produce sustained receptor activation that the natural hormone does not achieve, so their effects reflect pharmacology at the receptor rather than a straightforward hormone replacement.

What is the incretin effect?

The incretin effect is the larger insulin response seen when glucose is taken by mouth compared with an intravenous glucose infusion that produces the same blood glucose levels. In healthy people the oral route produces roughly two to three times more insulin. The difference is mainly due to GIP and GLP-1 released from the gut, and it is reduced in type 2 diabetes.

Where are incretin hormones made?

GIP is secreted mainly by K cells in the upper small intestine, and GLP-1 mainly by L cells in the lower small intestine and colon. Both are released within minutes of eating. GLP-1 is also produced by a small group of neurons in the brainstem, where it is involved in appetite regulation.

How do DPP-4 inhibitors relate to incretins?

DPP-4 is the enzyme that rapidly inactivates GLP-1 and GIP by cutting two amino acids from the start of each peptide. DPP-4 inhibitors block this enzyme, so the body's own incretins remain active for longer after a meal. GLP-1 receptor agonists take a different route, using molecules engineered to resist DPP-4 and activate the receptor directly.