Amylin

Amylin, also called islet amyloid polypeptide, is a thirty-seven residue peptide packaged in the same beta-cell granules as insulin and released alongside it, at roughly one amylin molecule per hundred of insulin. It has no dedicated receptor: it acts at the calcitonin receptor complexed with receptor activity-modifying proteins, giving the AMY1 to AMY3 subtypes. Its effects are those of a meal-termination signal rather than a glucose-lowering one: slowed gastric emptying, suppressed postprandial glucagon, and satiation signalling through the area postrema.

Human amylin aggregates, and the islet deposits found in most people with long-standing type 2 diabetes are amylin fibrils. Rodent amylin, which carries prolines in the aggregation-prone middle region, does not, and pramlintide was built on that observation. It was approved by the FDA in 2005 as an adjunct to mealtime insulin and carries a boxed warning for severe insulin-associated hypoglycaemia. Cagrilintide, a long-acting analogue combined with semaglutide as CagriSema, produced roughly a fifth of baseline body weight lost at sixty-eight weeks in the REDEFINE programme.

The reason amylin is interesting again is that it is a separate lever from incretin agonism, so the two combine rather than compete. It also sets the limits: strong effects on how a meal ends and on gastric handling, weaker independent effects on fasting glucose, and early nausea dominating tolerability.

Two misreadings recur. The first treats amylin analogues as insulin-sparing when the hypoglycaemia risk on the pramlintide label comes precisely from co-administration with insulin. The second reads aggregation as an inevitable property of any amylin-like peptide, when the analogues were designed around it; raw amylin sold on the grey market is the aggregating human sequence, not the therapeutic one.