What is the mechanism of action of GLP-1 (Glucagon-Like Peptide-1) agonists, including the specific receptors they bind to?

Mechanism of Action of GLP-1 Receptor Agonists

GLP-1 receptor agonists work by selectively binding to and activating the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein (Gs) in pancreatic beta cells, which increases intracellular cyclic AMP (cAMP) leading to glucose-dependent insulin release. 1, 2

Primary Molecular Mechanisms

GLP-1 receptor agonists are structurally similar 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

The receptor binding activates multiple downstream pathways:

1. Pancreatic effects:

   • Enhances insulin secretion in a glucose-dependent manner (occurs only when blood glucose is elevated)
   • Suppresses glucagon secretion in a glucose-dependent manner
   • Does not impair glucagon response during hypoglycemia 2

2. Gastrointestinal effects:

   • Delays gastric emptying, reducing the rate of postprandial glucose appearance
   • Short-acting GLP-1 receptor agonists have more pronounced effects on gastric emptying 3

3. Central nervous system effects:

   • Activates receptors in the hypothalamus and brainstem nuclei
   • Mediates appetite, satiety, and energy intake 3

Pharmacokinetic Adaptations

GLP-1 receptor agonists overcome the rapid degradation of native GLP-1 (half-life of 1-2 minutes) through various mechanisms:

• Liraglutide: Achieves a 13-hour half-life through:

  • Self-association that delays absorption
  • Plasma protein binding (primarily albumin)
  • Stability against metabolic degradation by DPP-IV and NEP 1

• Semaglutide: Achieves a longer half-life through:

  • Albumin binding, resulting in decreased renal clearance
  • Protection from metabolic degradation
  • Stabilization against degradation by DPP-4 enzyme 2

Differences Between Short-Acting vs. Long-Acting GLP-1 Receptor Agonists

The pharmacokinetic differences lead to important distinctions in their effects:

• Short-acting agents (exenatide b.i.d., lixisenatide):

  • Primarily target postprandial glucose excursions
  • Have more pronounced effects on delaying gastric emptying
  • Maintain their effect on gastric emptying during long-term treatment 3, 4

• Long-acting agents (liraglutide, semaglutide, dulaglutide, exenatide once-weekly):

  • Provide more consistent 24-hour glucose control
  • Have stronger effects on fasting and overnight plasma glucose
  • Experience some tachyphylaxis (decreased effect over time) on gastric emptying 3, 4

Novel GLP-1 Receptor Agonist Developments

Recent developments include:

• Oral semaglutide: First oral GLP-1 receptor agonist with effectiveness close to injectable formulations 4
• Retatrutide: A triple-hormone receptor agonist that simultaneously activates GLP-1, GIP, and glucagon receptors 3

Clinical Implications of Receptor Activation

The GLP-1 receptor activation produces several beneficial effects:

• Metabolic effects:

  • Glucose-dependent insulin secretion minimizes hypoglycemia risk
  • Reduction in postprandial glucose AUC (35-38% lower with liraglutide) 1
  • Weight reduction of 6.1-17.4% in non-diabetic individuals and 4-6.2% in diabetic patients 3

• Cardiovascular effects:

  • Improved myocardial substrate utilization
  • Anti-inflammatory and anti-atherosclerotic effects
  • Reduced myocardial ischemia injury
  • Lowered systemic and pulmonary vascular resistance
  • Improved lipid profiles 3

• Renal effects:

  • Reduced albuminuria
  • Slower eGFR decline 3

Common Pitfalls in Understanding GLP-1 Receptor Mechanisms

• Misconception about hypoglycemia risk: Unlike insulin, GLP-1 receptor agonists stimulate insulin secretion only when blood glucose is elevated, making hypoglycemia unlikely when used as monotherapy 3, 2

• Confusion about receptor specificity: Different GLP-1 receptor agonists have varying receptor binding profiles. While most target only the GLP-1 receptor, newer agents like retatrutide target multiple receptors 3

• Gastric emptying effects over time: The effect on gastric emptying diminishes over time with long-acting GLP-1 receptor agonists but persists with short-acting agents, which has implications for postprandial glucose control 4, 5

The molecular understanding of GLP-1 receptor agonists continues to evolve, leading to development of more effective agents with expanded therapeutic applications beyond diabetes management.