Deeper-than-usual pharmacology of GLP-1 RAs.
The GLP-1 receptor
GLP-1 receptors (GLP-1R) are GPCRs expressed across pancreatic alpha and beta cells, vagal afferent neurons, hypothalamus (arcuate nucleus), nucleus tractus solitarius, gastric smooth muscle, kidney, cardiac myocytes, vascular endothelium. Widespread distribution explains why effects extend beyond glycemia.
Glucose-dependent insulin secretion
In beta cells, GLP-1R activation enhances insulin secretion only when ambient glucose is elevated. Mechanism: GLP-1R activation raises cAMP, potentiating K-ATP channel closure (already closing in response to glucose). Why GLP-1 RAs don't produce hypoglycemia on their own.
Glucagon suppression
In alpha cells, GLP-1R suppresses glucagon secretion. Glucose-dependent — glucagon suppression preserved during eu- or hyperglycemia; doesn't fully suppress at low glucose.
Gastric emptying and satiety axis
Slowed gastric emptying contributes to both glycemic effect (slower glucose entry) and satiety (prolonged distension, vagal afferent signaling). Vagus carries satiety signal to NTS.
Central appetite — the food-noise story
Hypothalamic POMC neurons stimulated; AgRP/NPY neurons inhibited. Reward-system effects in VTA and nucleus accumbens reduce food reward responses. Direct CNS pharmacology, not behavioral.
Cardiovascular effects beyond weight
GLP-1R expressed in vascular endothelium and cardiomyocytes. Direct effects: improved endothelial function, reduced vascular inflammation, reduced atherosclerotic plaque progression, BP reduction ~3–5 mmHg. Contributes to SELECT findings.
Renal effects
Direct effects: reduced glomerular hyperfiltration, anti-inflammatory effects on renal interstitium, indirect benefits via BP and glycemia. Contributes to FLOW findings.
Dual-agonism (tirzepatide)
Tirzepatide activates both GLP-1R and GIP receptors. Added GIP component likely explains larger weight effect via adipose-tissue effects mediated through GIP receptors.
Why the side-effect profile is what it is
Nausea, slowed emptying, constipation: direct consequences of the same mechanisms producing beneficial effects. Not separable. Tolerance develops over weeks; titration built around this.
Pharmacokinetic engineering
Native GLP-1 half-life 1–2 min (DPP-4 cleavage). Semaglutide adds fatty acid side chain binding albumin — half-life ~7 days. Tirzepatide similar approach — ~5 days. Liraglutide ~13 hours (daily dosing).