HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mu, J. Articles by Zhang, B. B. Search for Related Content PubMed PubMed Citation Articles by Mu, J. Articles by Zhang, B. B. Social Bookmarking                What's this?

Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic ß-Cell Mass and Function in a Rodent Model of Type 2 Diabetes

¹ Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey
² Department of Immunology and Inflammation, Merck Research Laboratories, Rahway, New Jersey

Address correspondence and reprint requests to Dr. Bei B. Zhang, RY80W-180, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. E-mail: bei_zhang{at}merck.com

Abbreviations: DPP-4, dipeptidyl peptidase-4; FFA, free fatty acid; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; GRP, gastrin-releasing peptide; GSIS, glucose-stimulated insulin secretion; HFD, high-fat diet; PACAP, pituitary adenylate cyclase-activating polypeptide; STZ, streptozotocin

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ß-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic ß-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA_1c, and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2–3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive ß-cells in islets, leading to the normalization of ß-cell mass and ß-cell–to–-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. V. Wang, J. Mu, T. D. Schraw, L. Gautron, J. K. Elmquist, B. B. Zhang, M. Brownlee, and P. E. Scherer PANIC-ATTAC: A Mouse Model for Inducible and Reversible {beta}-Cell Ablation Diabetes, August 1, 2008; 57(8): 2137 - 2148. [Abstract] [Full Text] [PDF]

				S.-J. Kim, C. Nian, D. J. Doudet, and C. H.S. McIntosh Inhibition of Dipeptidyl Peptidase IV With Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin-Induced Diabetic Mice Diabetes, May 1, 2008; 57(5): 1331 - 1339. [Abstract] [Full Text] [PDF]

				B. J. Lamont and D. J. Drucker Differential Antidiabetic Efficacy of Incretin Agonists Versus DPP-4 Inhibition in High Fat Fed Mice Diabetes, January 1, 2008; 57(1): 190 - 198. [Abstract] [Full Text] [PDF]

				G. Flock, L. L. Baggio, C. Longuet, and D. J. Drucker Incretin Receptors for Glucagon-Like Peptide 1 and Glucose-Dependent Insulinotropic Polypeptide Are Essential for the Sustained Metabolic Actions of Vildagliptin in Mice Diabetes, December 1, 2007; 56(12): 3006 - 3013. [Abstract] [Full Text] [PDF]

				Z. T. Bloomgarden Exploring Treatment Strategies for Type 2 Diabetes Diabetes Care, October 1, 2007; 30(10): 2737 - 2745. [Full Text] [PDF]

				R. P. Robertson Estimation of {beta}-Cell Mass by Metabolic Tests: Necessary, but How Sufficient? Diabetes, October 1, 2007; 56(10): 2420 - 2424. [Abstract] [Full Text] [PDF]

				D. J. Drucker Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes: Preclinical biology and mechanisms of action Diabetes Care, June 1, 2007; 30(6): 1335 - 1343. [Full Text] [PDF]

				B. Ahren Dipeptidyl Peptidase-4 Inhibitors: Clinical data and clinical implications Diabetes Care, June 1, 2007; 30(6): 1344 - 1350. [Full Text] [PDF]

				R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells J. Biol. Chem., April 20, 2007; 282(16): 12030 - 12037. [Abstract] [Full Text] [PDF]

				M. G. Beconi, J. R. Reed, Y. Teffera, Y.-Q. Xia, C. J. Kochansky, D. Q. Liu, S. Xu, C. S. Elmore, S. Ciccotto, D. F. Hora, et al. Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs Drug Metab. Dispos., April 1, 2007; 35(4): 525 - 532. [Abstract] [Full Text] [PDF]

				B. L. Wajchenberg {beta}-Cell Failure in Diabetes and Preservation by Clinical Treatment Endocr. Rev., April 1, 2007; 28(2): 187 - 218. [Abstract] [Full Text] [PDF]