What are GIP (Gastric Inhibitory Polypeptide) and GLP (Glucagon-Like Peptide)?

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 rapidly 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 adenylyl cyclase and increase intracellular cAMP levels 3, 4
• Stimulate insulin secretion only when blood glucose levels are elevated, explaining the low risk of hypoglycemia with incretin-based therapies 1, 3
• This glucose-dependent insulin secretion subsides as blood glucose decreases and approaches euglycemia 3, 4

Effects on Glucagon Secretion

GLP-1:

• Inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 1
• Does not impair the normal glucagon response to hypoglycemia 3

GIP:

• Has a bifunctional, glucose-dependent effect on glucagon 1, 5:
  • Augments glucagon secretion during euglycemia or hypoglycemia 1
  • Inhibits glucagon secretion during hyperglycemia 1

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

GIP:

• Does not significantly affect gastric emptying 1

Effects on Pancreatic β Cell Preservation

Both hormones:

• Promote β cell proliferation and inhibit apoptosis, potentially preserving pancreatic β cell mass 1, 6
• May 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 3

GIP:

• Facilitates fat deposition in adipose tissue (unlike GLP-1) 7
• Interacts with insulin to increase lipoprotein lipase activity and lipogenesis 2
• Promotes bone formation 7

Clinical Relevance in Type 2 Diabetes

Key differences in diabetes:

• GLP-1 secretion is impaired in patients with type 2 diabetes 8
• The insulinotropic effect of GIP is impaired in type 2 diabetes, while GLP-1's effect remains near normal 8
• This explains why GLP-1 receptor agonists are effective therapeutic agents, while GIP analogues alone are unlikely to be effective 8

Therapeutic Applications

Dual GIP/GLP-1 receptor agonists:

• Tirzepatide (dual agonist) has shown greater reductions in HbA1c and body weight compared to GLP-1 receptor agonists alone 1
• The glucose-dependent nature of both hormones explains the low risk of hypoglycemia with incretin-based therapies 1