What is the incretin effect?

The Incretin Effect: Mechanism and Clinical Significance

The incretin effect is the phenomenon whereby oral glucose administration stimulates a 2-3 fold higher insulin secretory response compared to intravenous glucose administration at equivalent blood glucose levels, accounting for up to 70% of postprandial insulin secretion. 1, 2

Physiological Mechanism

• The incretin effect is mediated by two primary gut hormones released in response to nutrient intake: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) 3
• GIP is secreted by K cells in the upper small intestine, while GLP-1 is produced by L cells in the distal intestine 4
• These incretin hormones enhance pancreatic beta-cell responsiveness to glucose, stimulating insulin secretion in a glucose-dependent manner 3
• The incretin effect accounts for approximately 25% of the postprandial insulin response in healthy individuals 3

Physiological Actions

• GLP-1 has multiple physiological effects beyond insulin stimulation:
  • Suppression of pancreatic glucagon output 3
  • Slowing of gastric emptying 3
  • Appetite reduction and increased satiety 3
  • Potential trophic effects on pancreatic beta-cells 5
• GIP primarily acts on the pancreas to stimulate insulin secretion but also has effects on adipose tissue and bone 1
• Both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), limiting their biological half-life 4

Clinical Significance in Diabetes

• The incretin effect is severely reduced or absent in patients with type 2 diabetes 6
• In type 2 diabetes:
  • GIP secretion remains relatively normal, but its insulinotropic effect is impaired 6
  • GLP-1 secretion is reduced, but its effects on insulin stimulation and glucagon suppression are partially preserved 6
  • This dysfunction contributes to impaired glucose homeostasis 6
• Exaggerated GLP-1 response appears to be a key mediator in late dumping syndrome, contributing to hyperinsulinemia and reactive hypoglycemia after gastric surgery 3

Therapeutic Applications

• The preserved action of GLP-1 in type 2 diabetes has led to two major therapeutic approaches:
  • GLP-1 receptor agonists that mimic endogenous GLP-1 effects 3
  • DPP-4 inhibitors that enhance circulating concentrations of active GLP-1 and GIP 3
• These incretin-based therapies improve glycemic control through multiple mechanisms:
  • Stimulating insulin secretion in a glucose-dependent fashion 3
  • Suppressing glucagon secretion 3
  • Slowing gastric emptying 3
  • Reducing appetite and food intake (particularly GLP-1 receptor agonists) 3
• Bariatric surgical procedures can enhance GLP-1 responses and restore the incretin effect in obese individuals with type 2 diabetes 2

Important Clinical Considerations

• While incretin-based therapies are effective for treating type 2 diabetes, they do not actually restore the defective incretin effect, as they stimulate GLP-1 receptors in response to both oral and intravenous glucose 2
• GLP-1 receptor agonists produce substantial weight loss (6.1-17.4% in non-diabetic individuals and 4-6.2% in diabetic patients) 7
• Dual GIP/GLP-1 receptor agonists like tirzepatide show enhanced weight loss effects (up to 20.9% at higher doses) 7
• Common adverse effects of GLP-1 receptor agonists include nausea, vomiting, dyspepsia, diarrhea, and gastrointestinal reflux 7