Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence

Diabetes Obes Metab. 2012 Feb;14(2):101-11. doi: 10.1111/j.1463-1326.2011.01473.x. Epub 2011 Nov 21.


Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / drug effects*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Disease Progression
  • Dogs
  • Gastric Inhibitory Polypeptide / antagonists & inhibitors*
  • Gastric Inhibitory Polypeptide / blood
  • Gastric Inhibitory Polypeptide / drug effects
  • Glucagon-Like Peptide 1 / antagonists & inhibitors*
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / drug effects
  • Humans
  • Islets of Langerhans / drug effects*
  • Rats


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4