GLP-1 Agonists: How Incretin Analogs Work
GLP-1, GIP, glucagon — the biology behind Tirzepatide, Retatrutide and Semaglutide.
Incretins
- GLP-1 — distal ileum L cells.
- GIP — duodenum K cells.
GLP-1 action
Native half-life < 2 min (DPP-4). Analogs resist it.
- Glucose-dependent insulin.
- Glucagon suppression.
- Slowed gastric emptying.
- Central appetite suppression.
What GIP adds
Co-activated with GLP-1: lipolysis + adipocyte insulin sensitivity. Tirzepatide > Semaglutide in SURPASS/SURMOUNT.
What glucagon adds
Sub-hyperglycemic glucagon: BAT thermogenesis. Retatrutide adds it → ~24% weight loss at 48 wk.
Comparison
| Molecule | Receptors | Status |
|---|---|---|
| Semaglutide | GLP-1 | FDA approved |
| Tirzepatide | GLP-1 + GIP | FDA approved |
| Retatrutide | GLP-1 + GIP + Glucagon | Phase III |
Adjuvants
- 5-Amino-1MQ
- SLU-PP-332
- AOD-9604
- MOTS-c
Related products
From the Huberman Lab × Dr. Abud Bakri episode
Bakri: GLP-1s have a well-identified receptor (predictable effects), were discovered in Gila monster saliva, and raise signaling thousands-fold over normal. ‘Training-wheels’ model: lowest effective dose + lifestyle, aiming to taper. Fertility caution (receptors in the ovary).
Educational context (RUO). Based on “Peptides: The Science, Uses & Safety” (Huberman Lab, Jun 2026). Not an endorsement by Dr. Bakri or Dr. Huberman. Watch the episode⚠ Research use only. Not medical advice.