Mechanism of Action of GLP-1 (Glucagon-like peptide-1)
GLP-1 receptor agonists work primarily by activating the GLP-1 receptor, which stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, delays gastric emptying, and reduces appetite, collectively resulting in improved glycemic control and weight loss. 1, 2, 3
Primary Mechanisms of Action
Pancreatic Effects
- Insulin secretion: GLP-1 selectively binds to and activates the GLP-1 receptor, increasing intracellular cyclic AMP (cAMP) in pancreatic β-cells, which leads to insulin release in a glucose-dependent manner 2, 3
- Glucagon suppression: GLP-1 decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, helping reduce hepatic glucose production 1, 3
- β-cell protection: May promote β-cell proliferation and protect against apoptosis, potentially preserving β-cell function 1
Gastrointestinal Effects
- Delayed gastric emptying: GLP-1 inhibits gastric peristalsis, increases pyloric tone, and delays gastric emptying, which slows the rate at which postprandial glucose appears in circulation 1, 2, 3
- Reduced acid production: Decreases gastric acid production and increases gastric volumes 1
- Appetite suppression: Acts on the central nervous system to reduce food intake and promote satiety 1
Molecular Structure and Pharmacokinetics
- GLP-1 is a peptide hormone with 97% amino acid sequence homology to endogenous human GLP-1(7-37) 3
- Native GLP-1 has a short half-life (1-2 minutes) due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidases 2, 3
- GLP-1 receptor agonists are modified to resist enzymatic degradation by DPP-4, resulting in longer duration of action 1, 2
- The principal mechanism of protraction for some GLP-1 agonists (like semaglutide) is albumin binding, which decreases renal clearance and protects from metabolic degradation 2
Cardiovascular and Other Systemic Effects
- Cardiovascular protection: GLP-1 receptor agonists improve myocardial substrate utilization, provide anti-inflammatory and anti-atherosclerotic effects, reduce myocardial ischemia injury, and improve lipid profiles 1
- Renal effects: Provide kidney protection with reduced albuminuria and slower eGFR decline 1
- Hepatic effects: Decrease fatty degeneration of the liver, reduce liver fibrosis, and exert anti-inflammatory effects 1
Clinical Significance of Mechanism
- The glucose-dependent nature of insulin stimulation and glucagon suppression means GLP-1 receptor agonists have a low risk of hypoglycemia compared to other antidiabetic medications 1, 2, 3
- Multiple complementary mechanisms (insulin stimulation, glucagon suppression, delayed gastric emptying, appetite reduction) contribute to their efficacy in glycemic control and weight management 1
- The cardiovascular benefits of GLP-1 receptor agonists (12% reduction in cardiovascular death, 16% reduction in stroke, and 9% reduction in myocardial infarction) are likely related to their multiple effects beyond glucose control 1
Key Differences Between GLP-1 Receptor Agonists
- Short-acting GLP-1 receptor agonists have greater effects on postprandial glucose through more pronounced effects on gastric emptying 1
- Long-acting GLP-1 receptor agonists have greater effects on fasting glucose through their sustained action on insulin and glucagon secretion 1
- The molecular modifications of different GLP-1 receptor agonists affect their pharmacokinetic profiles, resulting in different dosing schedules and potentially different efficacy and side effect profiles 2, 3
Understanding the multifaceted mechanism of action of GLP-1 explains its broad therapeutic potential in type 2 diabetes, obesity, and potentially cardiovascular and neurodegenerative disorders.