Mechanism of Action of GLP-1
GLP-1 activates G-protein coupled receptors on pancreatic beta cells, stimulating glucose-dependent insulin secretion while simultaneously suppressing glucagon release, delaying gastric emptying, and reducing appetite through central nervous system pathways. 1, 2
Pancreatic Effects
Insulin Secretion
- GLP-1 binds to GLP-1 receptors (GLP-1R), which are membrane-bound cell-surface receptors coupled to adenylyl cyclase by the stimulatory G-protein Gs in pancreatic beta cells 3
- This activation increases intracellular cyclic AMP (cAMP), leading to elevated intracellular calcium concentrations and subsequent insulin exocytosis 2, 3
- The insulin secretion is strictly glucose-dependent—it occurs only when blood glucose levels are elevated and subsides as glucose approaches euglycemia, explaining the exceptionally low hypoglycemia risk 1, 2
- GLP-1 stimulates both first- and second-phase insulin secretion, approaching levels seen in healthy subjects 1
Glucagon Suppression
- GLP-1 inhibits glucagon secretion from pancreatic alpha cells only when glucose is elevated, reducing hepatic glucose production 1, 4
- During euglycemia or hypoglycemia, glucagon response remains intact and is not impaired by GLP-1 3
- This glucose-dependent mechanism prevents hypoglycemia during fasting states 2
Beta Cell Preservation
- GLP-1 receptor agonists may promote beta cell proliferation and protect against apoptosis, potentially preserving pancreatic beta cell mass over time 2
Gastrointestinal Effects
Gastric Emptying
- GLP-1 delays gastric emptying by inhibiting gastric peristalsis while simultaneously increasing pyloric tone 2
- This results in reduced gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased gastric volumes 2
- Gastric emptying is a primary determinant of postprandial glycemic response, and this delay reduces the rate at which postprandial glucose appears in the circulation 2, 3
Tachyphylaxis Phenomenon
- The effect of GLP-1 on gastric emptying shows tachyphylaxis (diminishing response) with continuous exposure 2
- Short-acting GLP-1 receptor agonists maintain their effect on gastric emptying longer than long-acting formulations 2, 5
Central Nervous System Effects
Appetite and Satiety Regulation
- GLP-1 receptors located in the hypothalamus and brainstem nuclei (nucleus tractus solitarius) mediate appetite suppression and induce meal termination 1, 2
- These central pathways regulate satiety, energy intake, and energy expenditure, contributing to weight loss effects 2
- GLP-1 is secreted not only by intestinal L-cells but also by neurons in the brainstem, suggesting both peripheral and central mechanisms 2
Cardiovascular Mechanisms
- GLP-1 receptors are localized primarily to the sinoatrial node in cardiac tissue 1
- Activation of these receptors mediates improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance 1
Physiological Origin and Metabolism
Secretion
- GLP-1 is released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to glucose load and triglycerides 2
- Natural 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 and neutral endopeptidases 2, 3
Pharmacological Modifications
- Therapeutic GLP-1 receptor agonists like liraglutide are modified to resist metabolic degradation by DPP-IV, achieving a plasma half-life of 13 hours after subcutaneous administration 3
- This extended half-life results from self-association that delays absorption, plasma protein binding, and stability against enzymatic degradation 3
Clinical Implications
Safety Profile
- The glucose-dependent nature of both insulin stimulation and glucagon suppression explains why GLP-1-based therapies have an exceptionally low intrinsic risk of hypoglycemia 1, 2
- Insulin secretion is significantly attenuated when plasma glucose is not elevated 2