IAPP gene

Islet amyloid polypeptide; amyloid; diabetes mellitus; appetite suppressant;

IAPP (islet amyloid polypeptide) is a protein-coding gene located on chromosome Chr 12: 21.42. Gene ontology (GO) annotations of this gene include identical protein binding and hormone activity. An important paralog of this gene is CALCB .

The IAPP gene encodes amylin, a member of the calcitonin family of peptide hormones. The primary structure of amylin consists of 37 amino acids with a disulfide bridge between the cysteines Cys-2 and Cys-7. Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino acid peptide hormone that is released co-secretorily with insulin from the β-cells of the pancreatic islets of Langerhans. It is functionally part of the enteropancreatic hormone axis, regulates blood glucose levels and mediates a satiety signal. Patients with type 1 diabetes and advanced type 2 diabetes have reduced levels of the encoded hormone in the blood and pancreas. This protein also has bactericidal and antimicrobial properties.

The peptide hormone amylin/IAPP, encoded by the IAPP gene, is a glucose-regulatory hormone that plays an important role in the regulation of energy homeostasis. Although the full functionality of amylin is not yet fully understood, it is believed that amylin stabilizes blood glucose levels by inhibiting the release of glucagon (Roberts AN et al. 1989). Amylin selectively inhibits insulin-induced glucose utilization and glycogen storage in muscle. In contrast, glucose metabolism in adipocytes is not affected. The synthesis pathway is via preproamylin, proamylin to mature amylin (37 AS, disulfide bridge between Cys2-Cys7, amidated C-terminus). Correct processing is crucial: misfolding promotes amyloid formation.

Central effects: Amylin acts in the CNS, especially in the brainstem via the area postrema (no blood-brain barrier) and the nucleus tractus solitarius. This explains an early feeling of satiety and nausea as a dose-limiting side effect of therapy.

The function of IAPP is mediated by CALCR-RAMPs (AMYRs) receptor complexes (Cao J et al. 2022; see also Calcitonin gene-related peptide receptor ). Amylin can also bind to the CALCR receptor in the absence of RAMPs, but reacts much more selectively with AMYRs. Amylin receptors are heterodimers of the calcitonin receptor (CTR) and one of three receptor activity modifying proteins (RAMPs), AMY1R, AMY2R and AMY3R. Selective AMYR agonists and dual AMYR/CTR agonists are currently being developed for the treatment of obesity; however, the molecular basis for peptide binding and selectivity is unknown (Eli Lilly has a selective amylin receptor agonist, eloralintide, in the pipeline for the treatment of obesity. Promising Phase II study data was published at the end of 2025 (su Briere DA et al. 2025)

Diseases associated with IAPP include insulinoma and amyloidosis.

1. Briere DA et al. (2025) Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept. Mol Metab 102:102271.
2. Cao J et al. (2022) A structural basis for amylin receptor phenotype. Science 375:eabm9609.
3. Cooper GJ et al. (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. In: Proc Natl Acad Sci U S A 84: 8628-8632.
4. Roberts AN et al. (1989) Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. Proc Natl Acad Sci U S A 86:9662-9666.
5. Westermark P et al. (1987) Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. In: Proc Natl Acad Sci U S A 84: 3881-3885.