Beyond Insulin: The Role of Amylin
Amylin hormone is secreted after eating and works to:
- Slow gastric emptying, helping nutrients enter the bloodstream more gradually
- Suppress glucagon, reducing unnecessary blood sugar spikes
- Promote satiety, signaling fullness and curbing overeating
While often overshadowed by insulin and GLP-1-based therapies, amylin has unique functions that make it a promising target for treating metabolic diseases like type 2 diabetes and obesity. Recent research is uncovering how restoring or enhancing amylin function could offer unique benefits that go beyond what insulin alone can achieve.
A Shared GPCR Family: Calcitonin, Amylin, and Beyond
Amylin receptors belong to the calcitonin family of G protein-coupled receptors, a group that also includes receptors for:
- Calcitonin (CT)
- Calcitonin Gene-Related Peptide (CGRP)
- Adrenomedullin (AM)
While these peptides are implicated in a wide range of distinct biological roles – from calcium regulation, blood vessel dilation, and metabolic balance – they all share a Class B (secretin-like) GPCR signaling framework, and typically activate cyclic AMP (cAMP) pathways, fine-tuned by receptor activity-modifying proteins (RAMPs), for nuanced physiological responses.
The Amylin Receptor: A Modular Signaling Hub
The amylin receptor is not a single structure—it’s a dynamic complex. It consists of the calcitonin receptor (CTR) combined with one of several receptor activity-modifying proteins (RAMPs).
Each RAMP pairing modifies the receptor’s behavior to recognize different calcitonin family peptides, altering ligand recognition and signaling properties:
Metabolic Dysfunction and Amylin Deficiency
Impaired amylin secretion is commonly seen in individuals with type 2 diabetes or obesity, often stemming from beta-cell dysfunction or reduced insulin sensitivity. This leads to lower insulin release, worsening insulin resistance, and ultimately poor glucose control. Without adequate amylin signaling, blood sugar swings become harder to manage, gastric emptying speeds up, and appetite increases — creating a positive feedback loop that drives further metabolic dysfunction over time.
Additionally, in patients with type 2 diabetes, the amylin peptide can form amyloids in the pancreatic islet, and this amyloid formation may exacerbate beta-cell loss, further impairing insulin and amylin secretion.
Synthetic amylin analogs are being developed to address this issue, the most promising of which is pramlintide, which has already been approved as an add-on treatment for diabetes. Pramlintide has been shown to improve glucose control and satiety.
This is only the beginning, as newer-generation, and perhaps more effective, amylin pharmaceuticals are being explored.
The Next Generation of Amylin-Based Metabolic Treatments
Amylin and calcitonin receptor agonists (DACRAs)
- Activates both amylin and calcitonin pathways
- Produces strong effects on weight loss, glucose regulation, and energy expenditure when compared to traditional amylin analogs
Preclinical and early clinical trials suggest that targeting the amylin system could lead to significant improvements in body weight, insulin sensitivity, and metabolic health — with fewer gastrointestinal side effects compared to traditional GLP-1 therapies. Researchers are also investigating whether combination therapies pairing amylin agonists with GLP-1 receptor agonists could produce additive or synergistic effects, potentially reshaping the future landscape of metabolic disease treatment.
| Drug | Amylin Receptor Target (CTR + RAMP) | GLP-1R Target | Development Status | Notes |
|---|---|---|---|---|
|
Pramlintide |
AMY1, AMY2, AMY3 |
No |
FDA-approved |
Synthetic amylin analog approved for type 1 and type 2 diabetes |
|
Cagrilintide |
AMY1, AMY2, AMY3 |
No |
Phase 3 |
Long-acting amylin analog under investigation for obesity treatment |
|
CagriSema |
AMY1, AMY2, AMY3 (via Cagrilintide) |
Yes (Semaglutide) |
Phase 3 |
Fixed-dose combination of cagrilintide and semaglutide; undergoing Phase 3 trials for obesity and type 2 diabetes |
|
Petrelintide |
AMY1, AMY2, AMY3 |
No |
Phase 2 |
Long-acting amylin analog being evaluated for weight management; currently in Phase 2 trials |
|
Amycretin |
AMY1, AMY2, AMY3 |
Yes |
Phase 2 |
Unimolecular dual agonist targeting both amylin and GLP-1 receptors; shown significant weight loss in early trials |
|
GUB014295 |
AMY1, AMY2, AMY3 |
No |
Phase 1 |
Long-acting amylin analog developed by Gubra and AbbVie; currently in Phase 1 clinical trials |
MULTISCREENTM Calcitonin Cell Assay Products
| Receptor Family | Receptor | Species | Parental | Stable Cell Lines | Division-Arrested Cells | Membranes |
|---|---|---|---|---|---|---|
| Calcitonin | CALCRL | human | HEK293T | C1232 | DC1232 | MC1232 |
| CALCRL | human | CHO-K1 | C1232-1 | DC1232-1 | MC1232-1 | |
| CGRP | human | CHO-K1 | C1515-1 | DC1515-1 | MC1515-1 | |
| AM1 | human | CHO-K1 | C1516-1 | DC1516-1 | MC1516-1 | |
| AM2 | human | CHO-K1 | C1517-1 | DC1517-1 | MC1517-1 | |
| CT | human | HEK293T | H1231 | DH1231 | MH1231 | |
| CT | human | CHO-K1 | C1231-1A | DC1231-1A | MC1231-1A | |
| CT | human | CHO-K1 | C1231-1B | DC1231-1B | MC1231-1B | |
| AMY1 | human | CHO-K1 | C1509-1a | DC1509-1a | MC1509-1a | |
| AMY2 | human | CHO-K1 | C1510-1a | DC1510-1a | MC1510-1a | |
| AMY2 | human | CHO-K1 | C1510-1b | DC1510-1b | MC1510-1b | |
| AMY3 | human | CHO-K1 | C1511-1a | DC1511-1a | MC1511-1a |
