What is the mechanism of action (MOA) of Glucagon-Like Peptide-1 (GLP-1)?

GLP-1 Mechanism of Action

GLP-1 receptor agonists work by binding to and activating GLP-1 receptors throughout the body, triggering glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite through central nervous system pathways. 1, 2

Core Pancreatic Mechanisms

Glucose-Dependent Insulin Secretion:

• GLP-1 receptors are G-protein coupled receptors that, when activated, increase intracellular cyclic AMP (cAMP) in pancreatic beta cells, leading to insulin release only when blood glucose is elevated 1, 2
• This glucose-dependent mechanism explains the remarkably low hypoglycemia risk with GLP-1 receptor agonists 3, 4
• Both first- and second-phase insulin secretion are enhanced, with insulin secretion rates in diabetic patients approaching those of healthy subjects 1

Glucagon Suppression:

• GLP-1 receptor activation inhibits glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, reducing hepatic glucose production 3
• Fasting glucagon is reduced by 8%, postprandial glucagon by 14-15%, and mean 24-hour glucagon by 12% 1
• Critically, during hypoglycemia, GLP-1 does not impair the counter-regulatory glucagon response, preserving this essential safety mechanism 1

Beta Cell Preservation:

• GLP-1 receptor activation may promote beta cell proliferation and differentiation while protecting against apoptosis, potentially preserving pancreatic beta cell mass 3, 4

Gastrointestinal Effects

Gastric Emptying Delay:

• GLP-1 delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, mediated through vagal nerve pathways 3, 5
• This results in reduced phasic gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased fasting and postprandial gastric volumes 3, 5
• The delay in gastric emptying is a primary determinant of postprandial glycemic response and contributes significantly to glucose-lowering effects 4, 1

Tachyphylaxis Phenomenon:

• Short-acting GLP-1 receptor agonists maintain more pronounced effects on gastric emptying than long-acting formulations due to tachyphylaxis (diminishing response) with continuous exposure 6, 4, 5
• Acute and intermittent infusions have more pronounced effects than continuous infusions 6
• The motility effects are more pronounced in individuals with normal or rapid baseline gastric emptying 3, 5

Central Nervous System Mechanisms

Appetite and Satiety Regulation:

• GLP-1 receptors in the hypothalamus (arcuate nucleus) and brainstem nuclei (area postrema and nucleus tractus solitarius) mediate appetite, satiety, energy intake, and expenditure 6, 3
• Systemic GLP-1 receptor agonists suppress the arcuate nucleus and induce meal termination in parabrachial neurons, either directly or indirectly via the nucleus tractus solitarius 6
• Receptors in the hepatoportal region and on afferent vagal nerve endings in the intestinal mucosa generate central nervous system signals that influence metabolism 6

Additional CNS Distribution:

• GLP-1 receptors are also found in the hippocampus, neocortex, spinal cord, and cerebellum, though their full functional significance remains under investigation 6, 3

Cardiovascular Mechanisms

Cardioprotective Effects:

• GLP-1 receptors are localized primarily to the sinoatrial node of the heart 6, 3
• Cardioprotective mechanisms include improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance 6, 3
• GLP-1 receptors in arterial walls are important for endothelial function and autonomic nervous system regulation 6

Pharmacokinetic Considerations

Protraction Mechanisms:

• Native GLP-1 has an extremely short half-life of approximately 1.5-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) enzyme 4, 2
• Semaglutide achieves a half-life of approximately 1 week through albumin binding (facilitated by C18 fatty di-acid modification) and stabilization against DPP-4 degradation 1
• Liraglutide achieves a 13-hour half-life through self-association that delays absorption, plasma protein binding, and stability against metabolic degradation 2

Clinical Implications

Weight Loss Mechanisms:

• GLP-1 receptor agonists result in substantially greater weight loss in non-diabetic patients (6.1-17.4%) compared to diabetic patients (4-6.2%) 6
• Weekly semaglutide 2.4 mg reduced mean body weight by 14.9% in non-diabetic, overweight/obese patients, approaching weight loss previously only seen with bariatric surgery 6

Important Cautions:

• Avoid GLP-1 receptor agonists in patients with pre-existing gastroparesis or delayed gastric emptying, as they may exacerbate symptoms 3, 5
• The vagal-dependent mechanism means effects on gastric emptying are not present in patients who have had a vagotomy 5
• Start at low doses and titrate slowly to minimize gastrointestinal side effects 6, 5