GIP and GLP-1: Incretin Hormones
GIP (Gastric Inhibitory Polypeptide, also called Glucose-dependent Insulinotropic Polypeptide) and GLP-1 (Glucagon-Like Peptide-1) are incretin hormones secreted from the intestine that stimulate insulin secretion from pancreatic β cells in a glucose-dependent manner, with additional effects on glucagon secretion, gastric emptying, and appetite regulation. 1
Origin and Secretion
GIP:
- Secreted by enteroendocrine K-cells in the small intestine in response to nutrient ingestion, particularly glucose and lipids 2, 3
- A 42 amino acid hormone that is well conserved across mammalian species 4
GLP-1:
- Released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to glucose load and triglycerides 1
- Also secreted by islet cells and neurons in the nucleus tractus solitarius in the brainstem 1
- Has an extremely short half-life of approximately 1.5-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-IV) enzyme 5, 4
Mechanism of Action on Insulin Secretion
Both hormones bind to specific G-protein coupled receptors (GIP receptor [GIPR] and GLP-1 receptor [GLP-1R]) on pancreatic β cells 2, 3:
- Receptor activation increases intracellular cyclic AMP (cAMP) levels 5, 2
- This stimulates insulin secretion only when blood glucose levels are elevated, explaining the low risk of hypoglycemia with incretin-based therapies 1, 3
- Both hormones may promote β cell proliferation and inhibit apoptosis, potentially preserving pancreatic β cell mass 1, 2
Effects on Glucagon Secretion
GLP-1:
- Inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 1
- Consistently decreases glucagon levels 6
GIP:
- Has a bifunctional, glucose-dependent effect on glucagon 1, 6:
- At fasting or low glucose levels: increases glucagon secretion
- During hyperglycemia: inhibits glucagon secretion
- This dual action positions GIP as a blood glucose stabilizing hormone 6
Gastrointestinal Effects
GLP-1:
- Delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 1
- Results in reduced gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased gastric volumes 1
- Tachyphylaxis occurs with continuous exposure: short-acting GLP-1 receptor agonists maintain their effect on gastric emptying longer than long-acting formulations 1
- Gastric emptying is a primary determinant of postprandial glycemic response 1
GIP:
- Does not significantly affect gastric emptying 7
Additional Metabolic Effects
GLP-1:
- GLP-1 receptors located in the hypothalamus and brainstem nuclei mediate appetite, satiety, energy intake and expenditure 7
- Contributes to weight loss through increased satiety and delayed gastric emptying 1
GIP:
- Facilitates fat deposition in adipose tissue (unlike GLP-1) 3
- Promotes bone formation 3
- Interacts with insulin to increase lipoprotein lipase activity and lipogenesis 4
Clinical Relevance in Type 2 Diabetes
The incretin effect is severely impaired or abolished in patients with type 2 diabetes 8:
- GLP-1 secretion is impaired (likely a consequence of diabetic metabolic disturbances) 8
- GIP effect is impaired (the insulinotropic response to GIP is reduced, though GIP secretion remains near normal) 8
- The defective insulinotropic effect of GIP may be found in first-degree relatives of patients, suggesting a genetic background 8
Therapeutic Applications
GLP-1 receptor agonists (like liraglutide and semaglutide) are effective for both diabetes and weight management 7:
- Approved for weight loss in patients with BMI >30 or >27 with comorbidities 7
- Demonstrated cardiovascular benefits in high-risk patients 7
Dual GIP/GLP-1 receptor agonists (like tirzepatide) show greater reductions in HbA1c and body weight compared to GLP-1 receptor agonists alone 1
GIP antagonists may have potential in obesity management, as mice with GIP receptor deletion do not become obese on high-fat diets 8
Key Pathophysiological Role
Both hormones are involved in dumping syndrome after gastric surgery 7: