Incretins: their physiology and application in the treatment of diabetes mellitus

Diabetes Metab Res Rev. 2014 Jul;30(5):354-71. doi: 10.1002/dmrr.2501.

Abstract

Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.

Keywords: DPP-4 inhibitors; GLP-1; GLP-1 analogues; diabetes; incretins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Exenatide
  • Gastric Inhibitory Polypeptide / biosynthesis
  • Gastric Inhibitory Polypeptide / physiology
  • Glucagon-Like Peptide 1 / biosynthesis
  • Glucagon-Like Peptide 1 / physiology
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / adverse effects
  • Incretins / physiology*
  • Incretins / therapeutic use*
  • Insulin / metabolism
  • Insulin Glargine
  • Insulin Secretion
  • Insulin, Long-Acting / therapeutic use
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology
  • Peptides / therapeutic use
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / drug effects
  • Venoms / therapeutic use

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Insulin, Long-Acting
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • hemoglobin A1c protein, human
  • Insulin Glargine
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Exenatide
  • Dipeptidyl Peptidase 4