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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@utoronto.ca

Abbreviations: 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

The first 300 words of the full text of this article appear below.

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 ß-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 . . . [Full Text of this Article]

DPP-4 AND THE INACTIVATION OF INCRETIN HORMONES—

DPP-4 INHIBITORS LOWER BLOOD GLUCOSE—

DPP-4 INHIBITORS AND ß-CELL MASS AND SURVIVAL—

ROLE OF ENDOGENOUS DPP-4

Studies in rats and mice with inactivating DPP-4 mutations
IMPORTANCE OF DPP-4–SELECTIVE INHIBITION—

DPP-4 SUBSTRATES AND REDUCED DPP-4 ENZYME ACTIVITY

Physiology versus pharmacology
BIOLOGICAL ACTIVITIES OF DPP-4 NOT RELATED TO CONTROL OF GLUCOSE HOMEOSTASIS—

BIOLOGICAL IMPORTANCE OF GLP-1(9-36)AMIDE AND GIP(3-42)—

DPP-4 INHIBITION AND REDUCTION OF BLOOD GLUCOSE

Mechanisms of action
DPP-4 INHIBITORS

Current concepts and major unanswered questions

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