Endocrine Abstracts

The mature 37 amino acid peptide amylin is derived from the IAPP (islet amyloid polypeptide) gene and is produced in pancreatic beta-cells and – in much lower amounts – in other tissues, like the stomach, spinal ganglia and in the brain. Amylin is characterized by an interesting dichotomy because amylin has to propensity to aggregate into fibrils in some species, but on the other hand also to the physiological control of metabolism (probably in all species). These dichotomous roles seem to be “functionally independent” in that some amylin forms (e.g., human, feline) aggregate into oligomers and eventually mature amyloid fibrils; this process is probably independent of the cell membrane bound amylin receptor (AMY) because aggregation is initiated intracellularly. On the other hand, the soluble monomeric form of mature amylin activates the AMY in the brain to produce hormonal effects on glucose metabolism (inhibition of glucagon secretion, control of gastric emptying) and nutrient intake (induction of satiation), hence beneficial weight-lowering and anti-diabetic effects. The AMY is a specific heterodimer receptor that consists of the calcitonin receptor core protein (CTR) and one of several receptor activity modifying proteins (RAMP). The mechanisms underlying amylin’s metabolic effects and the responsible AMY subtypes have been amply investigated in recent years and are the basis for the development of amylin agonists that are already in clinical use for the treatment of diabetes mellitus or that are in clinical development as weight lowering drugs, respectively. Similarities and differences between amylin and its receptor agonists will be discussed.2