The gut hormone behind today's weight-loss drugs survives about two minutes
GLP-1, the natural hormone that modern diabetes and obesity drugs imitate, is released by your gut after a meal and then shredded almost at once. Enzymes cut it apart so quickly that only 10 to 15 percent reaches the wider bloodstream intact, and its half-life is roughly two minutes. That is still long enough to work.
GLP-1 is a short protein chain, 30 or 31 amino acids long, snipped from a larger precursor called proglucagon. The same gene is read in the pancreas, the gut and the brain, but each tissue cuts the precursor differently: pancreatic cells make glucagon, which raises blood sugar, while specialised L-cells in the lower small intestine and colon, plus some brainstem neurons, make GLP-1. Release comes in two waves after eating, one within 10 to 15 minutes and a longer one after 30 to 60 minutes.
Its best-known job is making the pancreas release more insulin, but only when blood sugar is high, which is why it is called glucose-dependent. It also restrains glucagon above fasting levels, encourages insulin-producing beta cells to replenish their stores and, at least in research settings, to multiply. Receptors in the brainstem and hypothalamus promote a feeling of fullness, and in the stomach it slows emptying and acid secretion. Slower emptying even throttles its own release, a neat negative feedback loop.
The main destroyer is an enzyme called DPP-4, which sits on blood vessel walls right beside the cells that secrete the hormone. Less than a quarter of GLP-1 leaves the gut intact, and the liver breaks down 40 to 50 percent of what remains. Fasting blood levels are tiny, 0 to 15 picomoles per litre, rising two- to threefold after food.
Drug designers attacked the problem from two sides: longer-lasting molecules that activate the GLP-1 receptor, such as semaglutide and liraglutide, and drugs that block DPP-4. Receptor agonists won approval for diabetes and obesity from the 2000s. Unlike insulin and sulphonylureas, GLP-1-based treatment is associated with weight loss and a lower risk of low blood sugar. Those same stomach effects explain the common side effects, including nausea, vomiting and diarrhoea, especially while doses are being raised; rarer risks include pancreatitis and gallbladder disease.
Source: Glucagon-like peptide-1
