PMID-21742788 – IAPP Islet Amyloid and Diabetes Mellitus
Westermark P, Andersson A, Westermark GT. "Islet amyloid polypeptide, islet amyloid, and diabetes mellitus," Physiol Rev, 2011;91(3):795-826.
Quick Reference
| Property | Value |
|---|---|
| PMID | 21742788 |
| DOI | 10.1152/physrev.00042.2009 |
| Year | 2011 |
| Journal | Physiological Reviews |
| Study Type | Narrative Review |
| Evidence Level | V |
| Sample | N/A (review) |
| Peptide(s) Studied | Amylin |
Key Findings
- IAPP (amylin) is a 37-amino acid peptide co-secreted with insulin from pancreatic beta cells at a molar ratio of approximately 1:100 (IAPP:insulin)
- Normal physiological functions: slows gastric emptying, suppresses postprandial glucagon secretion, promotes satiety via area postrema signaling, complements insulin's glucose-lowering action
- IAPP has a native tendency to form amyloid fibrils — aggregated IAPP is a hallmark pathological feature of type 2 diabetes (found in >90% of T2D pancreata at autopsy)
- Amyloid fibril formation is cytotoxic to beta cells via membrane disruption, oxidative stress, and inflammation — contributing to progressive beta cell loss in T2D
- Human IAPP is amyloidogenic but rodent IAPP is not (3 proline substitutions in residues 25-29 prevent aggregation in rodents)
- IAPP signaling occurs through the amylin receptor complex: calcitonin receptor (CTR) paired with receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3)
- IAPP aggregation is promoted by high IAPP concentrations (insulin resistance), hyperglycemia, and certain lipids
Study Design
Comprehensive Physiological Reviews article covering IAPP discovery, molecular biology, processing, normal physiology, amyloid fibril formation mechanisms, cytotoxicity pathways, animal models, and therapeutic implications.
Limitations
- Review article; no new primary data
- Published 2011; predates some recent work on therapeutic targeting of IAPP aggregation
- Limited coverage of pramlintide and cagrilintide therapeutic development
Clinical Relevance
This definitive review provides the physiological and pathological context for understanding amylin-based therapeutics. Pramlintide (Symlin) is a synthetic amylin analog with 3 proline substitutions that prevent aggregation while preserving receptor activity — directly informed by the structure-aggregation relationship described here. Cagrilintide (sold by Ageless Peps) is a long-acting amylin analog designed using similar principles. Understanding native IAPP physiology explains why amylin analogs promote satiety, slow gastric emptying, and reduce postprandial glucagon — the exact mechanisms that make cagrilintide effective for weight management.
Related
#research #narrative-review #evidence-level-V #metabolic #amylin #endogenous