Amylin

Amylin (Islet Amyloid Polypeptide, IAPP) is a 37-amino-acid peptide hormone (3.9 kDa) co-secreted with insulin by pancreatic β-cells in ~1:100 molar ratio (amylin:insulin). Identified by Westermark and Cooper in 1987, it belongs to the CGRP/calcitonin/adrenomedullin/intermedin peptide family, sharing ~20-50% sequence identity and a characteristic C2-C7 disulfide bridge.

Physiological roles. Amylin acts as a metabolic co-regulator of insulin: it (1) slows gastric emptying via vagal centre activation, (2) suppresses postprandial glucagon secretion (via area postrema and arcuate nucleus), (3) induces satiety via the nucleus of the solitary tract (NTS) and area postrema, (4) reduces homeostatic and hedonic food intake. It is degraded by the IDE enzyme (Insulin-Degrading Enzyme) and exhibits 10-20 minute plasma half-life.

AMY-R receptors. Amylin activates amylin receptors formed by heteromeric complexes between the calcitonin receptor (CTR) and modifying proteins RAMP1, RAMP2 or RAMP3 (Receptor Activity-Modifying Proteins), producing AMY1R, AMY2R and AMY3R respectively. Gαs coupling → cAMP → PKA predominates. Amylin can also activate the CGRP receptor and adrenomedullin receptor at pharmacological doses.

Pathology and therapeutics. Human amylin exhibits tendency to form amyloid fibrils (pancreatic amylin deposits in 90% of type 2 diabetics, contribution to β-cell dysfunction). Therapeutic analogues stabilised against aggregation include pramlintide (Symlin®, triple Pro25/28/29 substitution copied from rat amylin, FDA-approved 2005 for type 1 and 2 diabetes) and cagrilintide (long-acting analogue acylated by C20 fatty acid, combined with semaglutide in CagriSema, phase III REDEFINE/REIMAGINE ongoing).