Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition.
DPP-4 (dipeptidyl peptidase-4) degrades the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide), decreasing their stimulatory effects on beta-cell insulin secretion. In patients with Type 2 diabetes, meal-related GLP-1 secretion is reduced. DPP-4 inhibitors (alogliptin, saxagliptin, sitagliptin and vildagliptin) correct the GLP-1 deficiency by blocking this degradation, prolonging the incretin effect and enhancing glucose homoeostasis. DPP-4 is a member of a family of ubiquitous atypical serine proteases with many physiological functions beyond incretin degradation, including effects on the endocrine and immune systems. The role of DPP-4 on the immune system relates to its extra-enzymatic activities. The intracytosolic enzymes DPP-8 and DPP-9 are recently discovered DPP-4 family members. Although specific functions of DPP-8 and DPP-9 are unclear, a potential for adverse effects associated with DPP-8 and DPP-9 inhibition by non-selective DPP inhibitors has been posed based on a single adverse preclinical study. However, the preponderance of data suggests that such DPP-8 and DPP-9 enzyme inhibition is probably without clinical consequence. This review examines the structure and function of the DPP-4 family, associated DPP-4 inhibitor selectivity and the implications of DPP-4 inhibition in the treatment of Type 2 diabetes.
Bristol-Myers Squibb, Princeton, NJ 08540, USA.
Mark
M
Kirby
Denise M T
DM
Yu
Steven
S
O'Connor
Mark D
MD
Gorrell
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000633:toxicity; D013329:Structure-Activity Relationship
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4