GLP-1 / GIP / Glucagon
Type Hormone receptor systems (incretin axis + counter-regulatory)
Related compounds Retatrutide, Tirzepatide, Ecnoglutide, Semaglutide, Orforglipron, CagriSema, Survodutide, Mazdutide
Three Axes
| Axis | Source | Primary Function |
|---|---|---|
| GLP-1 | L-cells (gut, post-prandial) | Satiety, gastric delay, insulin secretion |
| GIP | K-cells (duodenum, post-prandial) | Insulin synergy, adipose lipid buffering |
| Glucagon | α-cells (pancreas, fasting) | Hepatic glucose output, lipolysis, thermogenesis |
GLP-1 — Appetite Axis
- Released in response to food intake
- Binds hindbrain + hypothalamus → suppresses appetite independent of gastric stretch
- Delays gastric emptying → prolonged satiety
- Crosses BBB → hypothalamus + hindbrain → modifies food reward pathways
- Retatrutide: GLP-1R component is ~0.4× endogenous potency
vs. CB1 (Cannabis): GLP-1 and CB1 have reciprocal inhibitory cross-talk — CB1 activation can reduce circulating GLP-1; cannabis may partially blunt GLP-1 agonist weight-loss signaling. See GLP-1 vs CB1 cross-talk.
GIP — Lipid Buffering Axis
- Released from duodenal K-cells in response to fat + carbohydrate
- Potentiates glucose-stimulated insulin secretion (incretin effect)
- Improves subcutaneous adipocyte lipid buffering capacity
- Prevents ectopic fat deposition (visceral, hepatic, intramuscular)
- Retatrutide: GIPR component is ~8.9× MORE potent than endogenous GIP — the dominant receptor in its pharmacology
Glucagon — Energy Expenditure Axis
- Activated during fasting / hypoglycemia
- Stimulates hepatic glycogenolysis + gluconeogenesis → raises blood glucose
- Drives hepatic lipolysis + β-oxidation → ketone production
- Increases resting energy expenditure (REE) via thermogenesis
- The differentiator: Counteracts adaptive metabolic slowdown that kills GLP-1 mono-agonist weight loss
- Retatrutide: GCGR component (~0.3× endogenous) is deliberately moderated to drive thermogenesis without hepatic glucose dumping
Clinical Pharmacology Differences
| Drug | Mechanism | Weight loss | Key distinction |
|---|---|---|---|
| Semaglutide | GLP-1 mono | ~15% | First-gen injectable standard; CV-protection evidence exists for injectable semaglutide |
| Orforglipron | GLP-1 mono, non-peptide allosteric small molecule | ~9–11% | Oral once daily; no fasting requirement; lower weight-loss ceiling than injectable dual/triple agonists; GI tolerability is the main limitation |
| Tirzepatide | GLP-1 + GIP dual | ~21% | GIP adds lipid buffering |
| Ecnoglutide | cAMP-biased GLP-1 | ~15.4% | Bias toward lipolysis |
| Retatrutide | GLP-1 + GIP + Glucagon triple | ~28.7% | GCGR prevents plateau |
| Mazdutide | GLP-1 + Glucagon dual | ~14% | China-approved only; Chinese adults; GLORY-1 phase 3; no head-to-head vs semaglutide 2.4 mg, tirzepatide, or retatrutide |
| Survodutide | GLP-1 + Glucagon dual | ~15% (phase 2) | BI 456906; phase 3 SYNCHRONIZE; MASH signal |
Stack Implications
- GLP-1 agonists cause skin laxity → stack with GHK-Cu
- GLP-1 agonists cause lean mass loss → stack with SLU-PP-332 or XW4475/bimagrumab
- MC4R (Melanotan II PT-141) appetite suppression is separate axis — additive with GLP-1
- Retatrutide’s GCGR axis is unique — no plateau, unlike all prior GLP-1 agents
Links
- Retatrutide (anchor compound)
- Orforglipron — oral non-peptide GLP-1 mono-agonist contrast case
- Cannabis peptide interactions — goal conflict (CB1/GLP-1 cross-talk)
- Peptides MOC
- Substances MOC
Source: Gemini Deep Research · TRIUMPH-4 · PeptideDosages.com 2026-03-20