Glucagon-Like Peptide (GLP) Overview
GLP-1 is a proglucagon cleavage product released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to glucose and triglycerides, functioning as an incretin hormone that stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, and promotes satiety. 1
Physiological Characteristics
- GLP-1 is secreted by L-enteroendocrine cells in the terminal ileum and proximal colon in response to nutrient ingestion, as well as by islet cells and neurons in the nucleus tractus solitarius in the brainstem 1
- It has a very short half-life of approximately 2 minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4) and elimination by the kidneys 1
- When GLP-1 activates its G-protein coupled receptor, it increases intracellular calcium in pancreatic β-cells, leading to insulin exocytosis 1
Pharmacological Actions
- GLP-1 receptor agonists have been molecularly modified to extend their duration of action while maintaining varying homology with endogenous GLP-1 1
- These medications are widely prescribed for type 2 diabetes management and weight loss 1
- They reduce rates of non-fatal myocardial infarction, stroke, and death in patients with type 2 diabetes and obesity 1
Mechanism of Action
- GLP-1 receptor activation stimulates glucose-dependent insulin secretion from pancreatic β-cells 1
- It inhibits glucagon secretion, which helps regulate blood glucose levels 1
- GLP-1 delays gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone, which contributes significantly to its glucose-lowering effects 1
- The peptide promotes satiety through receptors in the hypothalamus and brainstem nuclei that mediate appetite regulation 1
Clinical Applications
- GLP-1 receptor agonists are FDA-approved for treatment of type 2 diabetes mellitus (first approved in 2005 with exenatide) 1
- They are increasingly used for weight management in patients with obesity, with substantial weight loss benefits (6.1-17.4% reduction in body weight) 1
- Some GLP-1 receptor agonists like semaglutide have shown cardiovascular benefits in patients with established cardiovascular disease 1
- Emerging evidence suggests potential benefits in treating certain dermatological conditions through anti-inflammatory effects 2
Pharmacokinetic Properties
- Short-acting GLP-1 receptor agonists (like exenatide) require at least once-daily administration 1
- Long-acting formulations have been developed through various molecular modifications:
- Semaglutide has greater albumin affinity 1
- Albiglutide achieves prolonged action through non-covalent conjugation with albumin 1
- Dulaglutide's extended half-life comes from conjugation with immunoglobulin G fragments 1
- Long-acting exenatide uses microsphere encapsulation for gradual release from subcutaneous depots 1
Related Peptides: GLP-2
- GLP-2 is a 33-amino acid peptide encoded carboxyterminal to GLP-1 in the proglucagon gene 3
- Unlike GLP-1, GLP-2 primarily affects the gastrointestinal tract by:
- GLP-2 has therapeutic applications in short bowel syndrome, with teduglutide (a GLP-2 analog) approved for treatment of short bowel syndrome with intestinal failure 1
Common Side Effects and Considerations
- Gastrointestinal effects are most common: nausea, vomiting, dyspepsia, diarrhea 1
- Delayed gastric emptying may increase risk of aspiration during anesthesia 1
- Gallbladder disorders can occur but are rarely symptomatic 1
- Cardiac arrhythmias/tachycardia may require monitoring in susceptible patients 1
Clinical Significance
- GLP-1 receptor agonists represent an important therapeutic class that addresses multiple pathophysiological aspects of type 2 diabetes 5
- Their ability to promote weight loss while improving glycemic control makes them particularly valuable for patients with both diabetes and obesity 1
- The cardioprotective effects demonstrated in clinical trials have elevated their role in managing patients with diabetes and cardiovascular risk factors 1