What hormone do GLP-1 (Glucagon-Like Peptide-1) receptor agonists mimic?

GLP-1 Receptor Agonists Mimic the Endogenous Hormone GLP-1

GLP-1 receptor agonists mimic the action of the naturally occurring incretin hormone glucagon-like peptide-1 (GLP-1). 1, 2

Mechanism of Action

GLP-1 receptor agonists are synthetic peptides designed to activate the GLP-1 receptor, which is the same target for native GLP-1. Their key characteristics include:

• Structural similarity to endogenous GLP-1:

  • Liraglutide has 97% amino acid sequence homology to endogenous human GLP-1(7-37) 1
  • Semaglutide has 94% sequence homology to human GLP-1 2
  • Tirzepatide is unique as a dual-hormone agonist, acting on both GLP-1 receptors and GIP (glucose-dependent insulinotropic polypeptide) receptors 3

• Enhanced stability compared to native GLP-1:

  • Native GLP-1 has a very short half-life of only 1.5-2 minutes due to rapid degradation by DPP-IV and neutral endopeptidases 1
  • GLP-1 receptor agonists are modified to resist this enzymatic degradation, resulting in much longer half-lives (e.g., 13 hours for liraglutide) 1

Physiological Effects

GLP-1 receptor agonists mimic multiple actions of endogenous GLP-1, including:

• Glucose-dependent insulin secretion:

  • Increase intracellular cyclic AMP in pancreatic beta cells 1
  • Stimulate insulin release only when blood glucose is elevated 1, 2
  • Enhance both first- and second-phase insulin secretion 2

• Glucagon suppression:

  • Lower glucagon secretion in a glucose-dependent manner 1, 2
  • Do not impair counter-regulatory glucagon response during hypoglycemia 2

• Gastric emptying:

  • Delay gastric emptying, particularly in the early postprandial phase 1, 2
  • This effect contributes to reduced postprandial glucose excursions 4

• Central nervous system effects:

  • Some GLP-1 receptor agonists can cross the blood-brain barrier 5
  • Activate areas in the brain involved in appetite regulation 6
  • Inhibit food intake through central mechanisms 7

Clinical Applications

The mimicry of endogenous GLP-1 by these medications results in multiple therapeutic benefits:

• Glycemic control through multiple mechanisms:

  • Short-acting GLP-1 receptor agonists primarily reduce postprandial glucose 4
  • Long-acting GLP-1 receptor agonists predominantly reduce fasting glucose 4

• Weight management:

  • Reduce appetite and food intake 6
  • Promote significant weight loss (6.1-17.4% in non-diabetic patients) 6
  • Dual GIP/GLP-1 receptor agonists like tirzepatide produce even greater weight loss (up to 20.9%) 3

• Cardiovascular benefits:

  • Improve myocardial substrate utilization 6
  • Provide anti-inflammatory and anti-atherosclerotic effects 6
  • Reduce myocardial ischemia injury 6

Important Considerations

• Different GLP-1 receptor agonists have varying pharmacokinetic profiles, leading to differences in their clinical effects 4
• Dual GIP/GLP-1 receptor agonists like tirzepatide offer enhanced efficacy compared to GLP-1 receptor agonists alone 3
• Common side effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea 6

In summary, GLP-1 receptor agonists are synthetic peptides specifically designed to mimic the actions of the naturally occurring incretin hormone GLP-1, with modifications that enhance their stability and duration of action compared to the native hormone.