title: Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence.
abstract: 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.
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. r.vangenugten@vumc.nl
authors.forename: R E
authors.initials: RE
authors.lastname: van Genugten
authors.forename: D H
authors.initials: DH
authors.lastname: van Raalte
authors.forename: M
authors.initials: M
authors.lastname: Diamant
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D018450:Disease Progression; D004285:Dogs; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects*; D051381:Rats
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4