What is the role of incretin in glucose metabolism?

Role of Incretins in Glucose Metabolism

Incretins are gut hormones that play a crucial role in maintaining glucose homeostasis primarily by enhancing pancreatic beta-cell responsiveness to glucose, contributing to as much as 25% of the postprandial insulin response. 1

What Are Incretins?

Incretins are gut hormones secreted from enteroendocrine cells in the intestinal mucosa within minutes after eating. The two main incretin hormones are:

1. Glucagon-like peptide-1 (GLP-1):

   • Released by L-enteroendocrine cells in the terminal ileum and proximal colon
   • Secreted in response to glucose load and triglycerides 1
   • Has a short half-life of approximately 2 minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4)

2. Glucose-dependent insulinotropic polypeptide (GIP):

   • Released from K cells in the upper small intestine
   • Also rapidly degraded by DPP-4

Physiological Actions of Incretins

Primary Actions on Glucose Metabolism:

• Enhanced insulin secretion:

  • Incretins increase intracellular calcium in pancreatic beta cells, leading to exocytosis of insulin 1
  • This effect is glucose-dependent, meaning it occurs only when blood glucose is elevated
  • Together, GLP-1 and GIP are responsible for the "incretin effect" - a two to three-fold higher insulin response to oral versus intravenous glucose 2

• Suppression of glucagon secretion:

  • GLP-1 inhibits glucagon secretion from pancreatic alpha cells, particularly during hyperglycemia
  • This reduces hepatic glucose production 1

• Slowed gastric emptying:

  • GLP-1 delays gastric emptying, which moderates the rate of nutrient delivery to the small intestine and reduces postprandial glucose excursions 1

Additional Metabolic Effects:

• Beta-cell preservation:

  • GLP-1 may promote beta-cell proliferation/neogenesis and prevent apoptosis 3
  • This helps maintain long-term pancreatic function

• Appetite regulation:

  • GLP-1 reduces appetite and food intake, contributing to weight management 2

Incretin Dysfunction in Type 2 Diabetes

In type 2 diabetes, the incretin effect is severely reduced or absent due to:

• Near-normal GIP secretion but severely impaired effect on insulin secretion
• Impaired GLP-1 secretion, though its insulinotropic and glucagon-suppressive actions are preserved but with decreased potency 3

Clinical Applications

The understanding of incretin biology has led to two major classes of incretin-based therapies:

1. GLP-1 receptor agonists (incretin mimetics):

   • Resistant to DPP-4 degradation
   • Stimulate insulin secretion in a glucose-dependent manner
   • Suppress glucagon secretion
   • Slow gastric emptying
   • Reduce appetite and food intake 1

2. DPP-4 inhibitors (incretin enhancers):

   • Orally active agents that increase endogenous levels of active incretins
   • Prolong incretin action
   • Enhance glucose-dependent insulin secretion 1

Important Clinical Considerations

• Hypoglycemia risk: Due to their glucose-dependent mechanism of action, incretin-based therapies have a lower risk of hypoglycemia compared to other antidiabetic agents 1

• Gastric effects: The effect of GLP-1 on gastric emptying can increase the risk of gastric stasis and aspiration in perioperative settings 1

• Cardiovascular benefits: GLP-1 receptor agonists reduce rates of non-fatal myocardial infarction, stroke, and death in patients with type 2 diabetes and obesity 1

• Weight management: The anorectic effects of GLP-1 make it valuable for weight management in both diabetic and non-diabetic individuals 4

The incretin system represents a physiological pathway that has been successfully leveraged for therapeutic interventions in diabetes and obesity, with ongoing research continuing to expand our understanding of these hormones' diverse effects throughout the body.