Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes
Preclinical biology and mechanisms of action
- From the Department of Medicine, Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Ontario, Canada
- Address correspondence and reprint requests to Dr. Daniel J. Drucker, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario, Canada M5G 1X5. E-mail: d.drucker{at}utoronto.ca
- ADA, adenosine deaminase
- DFS, des-fluoro-sitagliptin
- DPP, dipeptidyl peptidase
- GHRH, growth hormone–releasing hormone
- GIP, glucose-dependent insulinotropic polypeptide
- GLP-1, glucagon-like peptide-1
- IGF, insulin-like growth factor
- M6P-IGFIIR, mannose-6-phosphate/insulin-like growth factor II receptor
- NK, natural killer
- NPY, neuropeptide Y
- PACAP, pituitary adenylate cyclase activating peptide
- PYY, peptide YY
- QPP, quiescent cell proline dipeptidase
- SDF, stromal cell–derived factor
- sDPP-4, soluble form of DPP-4
- VP, valine pyrrolidide
Dipeptidyl peptidase (DPP)-4 is a complex enzyme that exists as a membrane-anchored cell surface peptidase that transmits intracellular signals via a short intracellular tail and as a second smaller soluble form present in the circulation. DPP-4 cleaves a large number of chemokines and peptide hormones in vitro, but comparatively fewer peptides have been identified as endogenous physiological substrates for DPP-4 in vivo. Both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are endogenous physiological substrates for DPP-4, and chemical inhibition of DPP-4 activity, or genetic inactivation of DPP-4 in rodents, results in increased levels of intact bioactive GIP and GLP-1. Furthermore, mice and rats with genetic inactivation or inhibition of DPP-4 exhibit improved glucose tolerance, elevated levels of GLP-1 and GIP, and resistance to diet-induced obesity and hyperglycemia. Sustained DPP-4 inhibition lowers blood glucose via stimulation of insulin and inhibition of glucagon secretion and is associated with preservation of β-cell mass in preclinical studies. Although DPP-4 cleaves dozens of regulatory peptides and chemokines in vitro, studies of mice with genetic inactivation of incretin receptors demonstrate that GIP and GLP-1 receptor–dependent pathways represent the dominant mechanisms transducing the glucoregulatory actions of DPP-4 inhibitors in vivo. The available preclinical data suggests that highly selective DPP-4 inhibition represents an effective and safe strategy for the therapy of type 2 diabetes.
DPP-4 is a widely expressed cell surface peptidase that exhibits a complex biology encompassing cell membrane–associated activation of intracellular signal transduction pathways, cell-cell interaction, and enzymatic activity exhibited by both the membrane-anchored and soluble forms of the enzyme (1). DPP-4, also originally known as the lymphocyte cell surface marker CD26, or as the adenosine deaminase (ADA)-binding protein, is a 766–amino acid serine protease that preferentially cleaves peptide hormones containing a position two alanine or proline. The human gene encoding DPP has been localized …
