Receptor binding & signalling cascades.

Cascade

1. 1.Gαs activation
2. 2.Adenylyl cyclase → ↑ cAMP
3. 3.PKA & Epac2 activation
4. 4.Closure of KATP channels in β-cells
5. 5.Ca²⁺ influx → insulin granule exocytosis

Downstream outcomes

• · Glucose-dependent insulin release
• · Slowed gastric emptying (vagal afferents)
• · POMC/CART activation in arcuate nucleus → satiety
• · β-cell preservation via PI3K/Akt

Cascade

1. 1.Gαs at both receptors → cAMP rise
2. 2.GIPR additionally engages adipocyte lipid buffering
3. 3.Central GIPR signalling modulates CNS reward & nausea pathways

Downstream outcomes

• · Enhanced insulinotropic response vs. GLP-1 alone
• · Improved adipose lipid handling
• · Reduced GI side-effects vs. mono-agonists at matched efficacy

Cascade

1. 1.Pancreatic insulinotropy via GLP-1R/GIPR
2. 2.Hepatic GCGR → ↑ cAMP → ↑ gluconeogenesis offset by insulin
3. 3.Brown adipose UCP1 induction → ↑ energy expenditure

Downstream outcomes

• · Greater preclinical weight loss than dual agonism
• · Hepatic fat reduction (NAFLD models)
• · Net thermogenic effect

Cascade

1. 1.PLCβ → IP₃ + DAG
2. 2.↑ intracellular Ca²⁺ in pituitary somatotrophs
3. 3.Pulsatile GH release
4. 4.Hepatic IGF-1 production

Downstream outcomes

• · Increased lean mass markers
• · Improved sleep-architecture markers (slow-wave)
• · Appetite signalling via NPY/AgRP neurons

Cascade

1. 1.Adenylyl cyclase → cAMP → PKA
2. 2.CREB phosphorylation
3. 3.GH gene transcription + secretion

Downstream outcomes

• · Restoration of physiological GH pulses
• · Synergy with GHRPs (additive, not redundant)
• · Longer half-life with DAC modification (~8 d)

Cascade

1. 1.cAMP rise in PVN neurons
2. 2.MAPK/ERK activation
3. 3.Modulation of POMC ↔ AgRP balance

Downstream outcomes

• · Appetite suppression
• · Penile-erection pathway (spinal MC4R)
• · Energy expenditure modulation

Cascade

1. 1.↑ VEGFR2 surface density
2. 2.eNOS activation → NO release
3. 3.FAK/paxillin → endothelial tubule formation

Downstream outcomes

• · Accelerated tendon/ligament repair (rat Achilles models)
• · Gut-mucosal cytoprotection
• · Modulation of dopaminergic & serotonergic systems

Cascade

1. 1.Binds G-actin monomers (1:1)
2. 2.Modulates actin polymerisation kinetics
3. 3.Promotes endothelial & keratinocyte migration

Downstream outcomes

• · Wound contraction & re-epithelialisation
• · Cardiac progenitor cell migration (preclinical MI models)

Cascade

1. 1.Stabilises ETC supercomplexes I+III+IV
2. 2.↓ electron leak → ↓ ROS
3. 3.Preserves ΔΨm under stress

Downstream outcomes

• · Improved ATP synthesis efficiency
• · Protection in ischaemia-reperfusion models
• · Restored mitochondrial cristae morphology