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 regulate glucose homeostasis primarily by stimulating insulin secretion from pancreatic β cells in a glucose-dependent manner. 1
Origin and Secretion
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 2 minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4) enzyme 1
GIP:
- Released from enteroendocrine K-cells in the small intestine in response to meals 1
- Consists of 42 amino acids with well-conserved structure across mammals 2
- Also metabolized by DPP-IV following secretion 2
Mechanism of Action on Insulin Secretion
Both hormones work through similar pathways:
- Bind to specific G-protein coupled receptors (GLP-1R and GIPR) on pancreatic β cells 1
- Activate and increase intracellular cyclic adenosine monophosphate (cAMP) levels 3, 4
- Stimulate insulin secretion only when blood glucose levels are elevated, explaining the low risk of hypoglycemia 1, 5
- Insulin secretion subsides as blood glucose decreases and approaches euglycemia 5, 6
Effects on Glucagon Secretion
GLP-1:
- Inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 1
- Suppresses inappropriately elevated glucagon secretion 5
GIP:
- Has a dual, glucose-dependent effect on glucagon: augments glucagon secretion during euglycemia or hypoglycemia and inhibits glucagon secretion during hyperglycemia 1
- At fasting and lower glycemia levels, GIP increases glucagon with little effect on insulin release 7
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
- Shows tachyphylaxis (diminishing response) with continuous exposure, with short-acting GLP-1 receptor agonists maintaining their effect on gastric emptying longer than long-acting ones 1
- Slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation 5, 6
GIP:
- Does not significantly affect gastric emptying 1
Effects on Pancreatic β Cell Mass
Both hormones:
- Promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass 1, 3, 4
- Protect against β cell death through increased expression of anti-apoptotic Bcl-2 and decreased expression of pro-apoptotic Bax 2
Additional Metabolic Effects
GLP-1:
- Receptors located in the hypothalamus and brainstem nuclei mediate appetite, satiety, energy intake and expenditure 1
- Reduces food intake in both animals and humans 5
- Inhibits bone absorption 3
GIP:
- Facilitates fat deposition in adipose tissues 3
- Interacts with insulin to increase lipoprotein lipase activity and lipogenesis 2
- Promotes bone formation 3
- Plays an important role in lipid metabolism, promoting the disposal of ingested lipids 8
Both hormones:
- Involved in memory formation as well as control of appetite in the brain 3
Clinical Implications in Diabetes
Type 2 Diabetes:
- The incretin effect is severely impaired or abolished in patients with type 2 diabetes 8
- GLP-1 secretion is impaired (whereas GLP-1 effect remains near normal) 8
- GIP effect is impaired (whereas GIP secretion remains near normal) 8
- The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances 8
Therapeutic Applications
Dual GIP/GLP-1 receptor agonists:
- Tirzepatide has shown greater reductions in HbA1c and body weight compared to GLP-1 receptor agonists alone 1
- Produced improvements in insulin sensitivity and insulin secretory responses 1
GLP-1 receptor agonists: