Amylin (revision 33)

Amylin, also called islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone stored in the same secretory granules as insulin and released with it in an approximately 1:20 molar ratio. Its physiological actions are complementary to those of insulin: it slows gastric emptying, suppresses postprandial glucagon secretion, and promotes satiety.^[1]

Amylin does not have a dedicated receptor. It acts at the calcitonin receptor in complex with one of three receptor-activity-modifying proteins, RAMP1, RAMP2 or RAMP3, which together constitute the AMY1, AMY2 and AMY3 receptors. The principal site of action for the satiety effect is the area postrema, outside the blood-brain barrier.^[1]

The human sequence is amyloidogenic: it aggregates into fibrils, and islet amyloid deposits derived from it are found in the pancreas in most people with long-standing type 2 diabetes. This property made native amylin undevelopable as a medicine and forced the design of non-aggregating analogues; see Amylin receptor agonist.^[2]

Amylin is co-packaged with insulin in the beta-cell secretory granule and released by the same stimuli, so its plasma profile mirrors that of insulin. Fasting concentrations are in the low picomolar range and rise several-fold after a meal.^[1]

Its three principal actions all restrain nutrient entry rather than promoting disposal. Gastric emptying slows, which flattens the postprandial glucose excursion. Glucagon secretion is suppressed in the postprandial state — but not during hypoglycaemia, where counter-regulation is preserved. Food intake falls through hindbrain signalling that is distinct from, and additive to, the GLP-1 satiety pathway.

Because insulin and amylin are co-secreted, amylin deficiency accompanies insulin deficiency: in type 1 diabetes both are essentially absent, and this contributes to the exaggerated postprandial glucose excursions seen when insulin is replaced alone.^[1][3]

The amylin receptors are heterodimers of the calcitonin receptor with a RAMP. The RAMP does not merely traffic the receptor; it alters the ligand-binding pocket, converting a calcitonin receptor into one with high affinity for amylin.

Because the receptor family overlaps with that for calcitonin and calcitonin gene-related peptide, selectivity is a real design constraint for analogues, and cross-activity at the calcitonin receptor is one route by which a long-acting analogue can produce effects beyond appetite.^[1]

Human amylin aggregates readily into cross-β fibrils; rodent amylin, which differs at several proline-containing positions, does not. This species difference is why rodent models do not spontaneously develop islet amyloid and why transgenic models were needed to study it.^[2]

Islet amyloid is present in the majority of pancreases examined post mortem from people with long-standing type 2 diabetes. Whether it is a cause of beta-cell loss or a consequence of prolonged secretory stress remains debated; oligomeric intermediates rather than mature fibrils are the species most often proposed as cytotoxic.

The practical consequence for peptide chemistry is that human amylin is a difficult peptide to handle: it aggregates in solution at ordinary concentrations, and any preparation of it requires attention to solvent, concentration and time. The engineered analogue pramlintide replaces three residues with prolines, which disrupts β-sheet formation and makes a stable formulation possible. Aggregation is accordingly a specification attribute for this chemistry rather than an incidental observation. See Peptide aggregation.^[2][4]

• Amylin receptor agonist
• Cagrilintide
• CagriSema
• Peptide aggregation
• Gastric emptying
• Satiety signalling

• Boyle CN, Lutz TA, Le Foll C. "Amylin — its role in the homeostatic and hedonic control of eating." Molecular Metabolism 8:203–210 (2018).