How do Glucagon-like peptide-1 (GLP1) and Gastric inhibitory polypeptide (GIP) work?

How GLP-1 and GIP Work

GLP-1 and GIP are incretin hormones that regulate glucose homeostasis primarily by stimulating insulin secretion from pancreatic β cells in a glucose-dependent manner, with additional effects on glucagon secretion, gastric emptying, and appetite regulation. 1

Physiological Origin and Metabolism

• GLP-1 is released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to glucose load and triglycerides 1
• GLP-1 is also secreted by islet cells and neurons in the nucleus tractus solitarius in the brainstem 1
• GIP is released from the small intestine in response to meals 1, 2
• Natural GLP-1 has a very short half-life (approximately 2 minutes) due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4) enzyme 1

Mechanism of Action on Pancreatic Function

Effects on Insulin Secretion

• Both GLP-1 and GIP bind to specific G-protein coupled receptors (GLP-1R and GIPR) on pancreatic β cells 1, 3
• Receptor binding activates and increases intracellular cyclic adenosine monophosphate (cAMP) in β cells 3
• This stimulates insulin secretion only when blood glucose levels are elevated, explaining the low risk of hypoglycemia with GLP-1 receptor agonists 1
• GLP-1 receptor agonists may promote β cell proliferation and protect against apoptosis, potentially preserving pancreatic β cell mass 1, 3

Effects on Glucagon Secretion

• GLP-1 receptor activation inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 1, 4
• GIP receptor activation has a dual effect on glucagon:
  • Augments glucagon secretion during euglycemia or hypoglycemia 1
  • Inhibits glucagon secretion during hyperglycemia 1, 5
• Only a small proportion (10-15%) of pancreatic α cells express GLP-1 receptors, while GIP receptors are more widely expressed on these cells 1

Gastrointestinal Effects

• Gastric emptying is a primary determinant of postprandial glycemic response 1
• GLP-1 receptor activation delays gastric emptying by:
  • Inhibiting gastric peristalsis while increasing pyloric tone 1
  • This effect is mediated through the vagus nerve (vagotomy eliminates this effect) 1
  • GLP-1 receptors on the myenteric plexus activate nitrergic and cAMP pathways to inhibit vagal activity 1
• These actions result in reduced gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased gastric volumes 1
• Much of the glucose-lowering effect of GLP-1 receptor agonists comes from delayed gastric emptying rather than direct pancreatic effects 1

Tachyphylaxis with Continuous Exposure

• The effect of GLP-1 on gastric emptying shows tachyphylaxis (diminishing response) with continuous exposure 1
• Plasma concentrations of pancreatic polypeptide (a measure of vagal activity) are markedly suppressed by GLP-1 during the first meal but significantly less after subsequent meals 1
• This suggests adaptation of the autonomic nervous system to continuous GLP-1 administration 1
• Short-acting GLP-1 receptor agonists maintain their effect on gastric emptying longer than long-acting ones 1

Pharmacological Applications

• Dual GIP/GLP-1 receptor agonists like tirzepatide have shown greater reductions in HbA1c and body weight compared to GLP-1 receptor agonists alone 1, 6
• Tirzepatide binds to the GIP receptor with high affinity but has approximately five times less affinity for the GLP-1 receptor than endogenous GLP-1 1
• DPP-4 inhibitors like saxagliptin slow the inactivation of incretin hormones, increasing their blood concentrations and reducing glucose levels 4

Clinical Implications

• The glucose-dependent nature of insulin stimulation by both GLP-1 and GIP explains the low risk of hypoglycemia with incretin-based therapies 1, 4
• GLP-1's effect on slowing gastric emptying contributes to increased satiety and weight loss 1, 6
• GIP was initially thought to have limited therapeutic potential in type 2 diabetes due to reduced insulin response, but this resistance can be reversed by improving glycemic control 6
• Dual GLP-1/GIP receptor agonists represent a promising approach for managing type 2 diabetes with benefits on weight loss and glycemic control 6, 5

Key Differences Between GLP-1 and GIP

• GLP-1 inhibits glucagon secretion while GIP can stimulate it (during euglycemia/hypoglycemia) 1, 5
• GIP facilitates fat deposition in adipose tissue, while GLP-1 does not have this effect 2
• In bone metabolism, GIP promotes bone formation while GLP-1 inhibits bone absorption 2
• Both hormones are involved in brain functions related to memory formation and appetite control 2