What is the Incretin Effect

Incretins are gut-derived factors that enhance insulin release by pancreatic beta cells. These factors are produced by selective posttranslational modification of proglucagon, a 160-residue peptide expressed by the α-cells of the pancreas, K and L cells of the small intestine.

The incretin effect is described as enhanced insulin secretion in response to an oral glucose load (∼6–1.7-fold) compared with intravenous glucose administration. The incretin effect is mainly attributed to the action of two hormones gut hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1). K cells are responsible for the production of GIP and the L cells for GLP-1.

What do incretins do?

GLP-1• GLP-1 is released in the gut in proportion to ingested calories.
• Reduction in gastric emptying and suppression of gastric acid secretion
• Anorexegenic effects
Glucose-dependent insulinotropic polypeptide (GIP)• Along with GLP-1, GIP acts as an incretin to potentiate glucose-stimulated insulin release
• direct anabolic effects on adipose tissue, including
o stimulation of glucose import
o fatty acid synthesis
o Lipogenesis
o inhibition of lipolysis

What are incretin mimetics?

Incretin mimetics mimic the effect of the gut hormone GLP-1 or GIP or both, with favorable metabolic effects in type 2 diabetes mellitus. These agents promotes a myriad of effects…

  • Suppresses appetite
  • Inhibits glucose production in the liver
  • Slows gastric emptying
  • Stimulates insulin release
  • Glucagon-like peptide 1 is an incretin produced from the PROGLUCAGON gene in L cells of the small intestine and is secreted in response to exposure to gastrointestinal nutrients. It is worth noting that GLP-1 is usually deficient in patients with type 2 diabetes mellitus.
  • Dipeptidyl peptidase 4 (DPP-4) inhibitors inhibit DPP-4, which is a ubiquitous enzyme expressed on the surface of most cell types that deactivates GLP-1; therefore, its inhibition could potentially affect glucose regulation through multiple effects. DPP4 inhibitors have a very minimal effect on endogenous incretins (GLP-1, GIP)
  • Dual GLP-1/GIP agonists (Tirzepatide)  possess the properties of both incretins and are associated with more significant weight loss than GLP-1 agonist monotherapy.

Mechanism of action of incretins

Comparison of incretin drugs

DPP-4 inhibitorsGLP-1 agonist therapy
• Increases endogenous GLP-1
• Stimulate glucose-dependent insulin secretion from B cells
• Lower glucagon secretion
• Overall effect -- lowers hepatic glucose output
Exert all the effects of DPP-4 agents
• Slow gastric emptying
• Decrease food intake

Selected References

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