Incretin hormones

Incretin hormones are gut hormones released when food reaches the intestine, and they work by telling the pancreas to release insulin before blood glucose has finished rising — but only while glucose is actually elevated. The two human incretins are glucagon-like peptide-1 (GLP-1), from intestinal L-cells, and glucose-dependent insulinotropic polypeptide (GIP), from K-cells higher up the small intestine.

The incretin effect

An oral glucose load produces substantially more insulin than the same amount of glucose given intravenously, even at matched blood levels. That gap is the incretin effect, and it accounts for a large share of the insulin response to a normal meal. The effect is blunted in type 2 diabetes, which is what made these hormones a drug target.

What each one does

GLP-1

• Enhances glucose-dependent insulin secretion from pancreatic beta cells.
• Suppresses glucagon, so the liver releases less stored glucose.
• Slows gastric emptying, spreading the glucose load over more time.
• Acts on hypothalamic and brainstem receptors to increase fullness. See appetite regulation.

GIP

• Also enhances glucose-dependent insulin secretion.
• Acts on adipose tissue, where its role in fat storage and lipid handling is still being worked out.
• Its receptor is a target in its own right; dual GIP/GLP-1 agonism produces larger weight loss than GLP-1 agonism alone in head-to-head trials.

Because both act only when glucose is high, incretin-based drugs carry little intrinsic hypoglycaemia risk on their own — unlike insulin or sulfonylureas.

Why they need engineering

Native GLP-1 is destroyed by the enzyme dipeptidyl peptidase-4 within a couple of minutes, so it is useless as a medicine in unmodified form. Approved incretin analogs resist DPP-4 by design, and the once-weekly ones such as semaglutide also bind albumin, stretching the half-life from minutes to about a week.

Why peptides care

• Semaglutide — a GLP-1 receptor agonist with 94% homology to human GLP-1; FDA-approved for uses including type 2 diabetes, obesity, cardiovascular risk reduction, and MASH.
• Tirzepatide — a dual GIP/GLP-1 receptor agonist, FDA-approved for type 2 diabetes, obesity, and obstructive sleep apnoea.
• Retatrutide — investigational, adding glucagon-receptor agonism to the same pair.

The drug class built on these hormones is covered in GLP-1 receptor agonists.