Amylin (IAPP)

Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino acid peptide hormone co-secreted with insulin from pancreatic beta cells in response to nutrient stimuli. Discovered independently by Per Westermark and Garth Cooper in 1987, amylin plays an important complementary role to insulin in glucose homeostasis. While insulin promotes glucose uptake, amylin acts primarily to regulate the rate at which glucose enters the bloodstream by slowing gastric emptying, suppressing postprandial glucagon secretion, and promoting satiety.

Amylin is secreted in a fixed ratio with insulin (approximately 1:100 amylin to insulin by molar ratio). In type 1 diabetes, amylin deficiency parallels insulin deficiency as beta cells are destroyed. In type 2 diabetes, amylin secretion becomes dysregulated, initially increasing with hyperinsulinemia and eventually declining as beta cell function deteriorates. This deficiency of amylin signaling contributes to postprandial glucose excursions that are incompletely controlled by insulin replacement alone.

Native amylin has a strong tendency to aggregate into amyloid fibrils, a property that has both pathological significance and pharmaceutical implications. Amyloid deposits composed of IAPP are found in the islets of approximately 90% of type 2 diabetes patients and are thought to contribute to beta cell dysfunction and death. This amyloidogenic property also makes native amylin unsuitable for therapeutic use, as it would aggregate in solution and at injection sites.

Pramlintide (Symlin) is a synthetic analog of amylin with three proline substitutions (A25P, S28P, S29P) that prevent amyloid formation while retaining biological activity. Approved by the FDA in 2005, pramlintide is used as an adjunct to mealtime insulin in both type 1 and type 2 diabetes. It reduces postprandial glucose excursions, decreases glucagon secretion, slows gastric emptying, and promotes satiety — often leading to modest weight loss, a benefit not seen with insulin alone. Cagrilintide, a long-acting amylin analog, is being developed in combination with semaglutide (CagriSema) for obesity, representing a next-generation approach to amylin-based therapy.