What is the incretin effect?

The Incretin Effect: Mechanism and Clinical Significance

The incretin effect is the physiological phenomenon where oral glucose intake stimulates a greater insulin response than intravenous glucose administration despite similar blood glucose levels, accounting for approximately 25% of postprandial insulin secretion in healthy individuals. 1

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) 1, 2
• These incretin hormones are released into the bloodstream from the small intestine after meals and enhance pancreatic beta-cell responsiveness to glucose, stimulating insulin secretion in a glucose-dependent manner 1, 2
• In healthy individuals, this effect results in a 2-3 fold higher insulin secretory response to oral glucose compared to intravenous glucose administration 3

Key Actions of Incretin Hormones

• GLP-1 has multiple physiological effects beyond insulin stimulation:

  • Suppression of pancreatic glucagon secretion from alpha cells, reducing hepatic glucose production 1, 2
  • Slowing of gastric emptying 1
  • Appetite reduction and increased satiety 1
  • Promotion of beta-cell function 2

• After an oral glucose load or meal, DPP-4 inhibition results in:

  • 2-3 fold increase in circulating levels of active GLP-1 and GIP 2
  • Decreased glucagon concentrations 2
  • Increased glucose-dependent insulin secretion from pancreatic beta cells 2

Pathophysiological Significance

• In type 2 diabetes, the incretin effect is diminished or absent due to:
  • Reduced effectiveness of GIP on the diabetic pancreas 4
  • Decreased GLP-1 concentrations, though insulin response to GLP-1 is preserved 2, 3
• This defect contributes to postprandial hyperglycemia in patients with type 2 diabetes 3

Clinical 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 1, 5
  • DPP-4 inhibitors (like saxagliptin) that slow the inactivation of incretin hormones, thereby increasing their bloodstream concentrations 1, 2

• These incretin-based therapies improve glycemic control through multiple mechanisms:

  • Stimulating insulin secretion in a glucose-dependent fashion 1, 2
  • Suppressing glucagon secretion 1, 2
  • Slowing gastric emptying 1
  • Reducing appetite and food intake 1, 6

Important Considerations

• GLP-1 receptor agonists have demonstrated significant weight loss effects (6.1-17.4% in non-diabetic individuals and 4-6.2% in diabetic patients) 6
• The dual GIP/GLP-1 receptor agonist tirzepatide has shown even greater reductions in body weight (up to 20.9% at higher doses) 6
• Common adverse effects of GLP-1 receptor agonists include nausea, vomiting, dyspepsia, diarrhea, and gastrointestinal reflux 6
• Enhanced GLP-1 response appears to be a key mediator in late dumping syndrome, contributing to hyperinsulinemia and reactive hypoglycemia after gastric surgery 1