|
 |
|
|||||||
|
|||||||||
© 2002 by the American Diabetes Association, Inc.
Long-Term Treatment With the Dipeptidyl Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and ß-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats
1 Department of Physiology, University of British Columbia, Vancouver, Canada
2 Probiodrug GmbH, Halle (Saale), Germany
3 Department of Biochemistry, University of British Columbia, Vancouver, Canada
4 School of Kinesiology, Simon Fraser University, Burnaby, Canada
The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are responsible for >50% of nutrient-stimulated insulin secretion. After being released into the circulation, GIP and GLP-1 are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV (DP IV). The use of DP IV inhibitors to enhance these insulinotropic hormonal axes has proven effective on an acute scale in both animals and humans; however, the long-term effects of these compounds have yet to be determined. Therefore, we carried out the following study: two groups of fa/fa Zucker rats (n = 6 each) were treated twice daily for 3 months with the DP IV inhibitor P32/98 (20 mg · kg-1 · day-1, p.o.). Monthly oral glucose tolerance tests (OGTTs), performed after drug washout, revealed a progressive and sustained improvement in glucose tolerance in the treated animals. After 12 weeks of treatment, peak OGTT blood glucose values in the treated animals averaged 8.5 mmol/l less than in the controls (12.0 ± 0.7 vs. 20.5 ± 1.3 mmol/l, respectively). Concomitant insulin determinations showed an increased early-phase insulin response in the treated group (43% increase). Furthermore, in response to an 8.8 mmol/l glucose perfusion, pancreata from controls showed no increase in insulin secretion, whereas pancreata from treated animals exhibited a 3.2-fold rise in insulin secretion, indicating enhanced ß-cell glucose responsiveness. Also, both basal and insulin-stimulated glucose uptake were increased in soleus muscle strips from the treated group (by 20 and 50%, respectively), providing direct evidence for an improvement in peripheral insulin sensitivity. In summary, long-term DP IV inhibitor treatment was shown to cause sustained improvements in glucose tolerance, insulinemia, ß-cell glucose responsiveness, and peripheral insulin sensitivity, novel effects that provide further support for the use of DP IV inhibitors in the treatment of diabetes.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  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. E. Dunning and J. E. Gerich The Role of {alpha}-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic Implications Endocr. Rev., May 1, 2007; 28(3): 253 - 283. [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]
|
|
|
|
 |
|
 S.-J. Kim, C. Nian, and C. H. S. McIntosh Activation of Lipoprotein Lipase by Glucose-dependent Insulinotropic Polypeptide in Adipocytes: A ROLE FOR A PROTEIN KINASE B, LKB1, AND AMP-ACTIVATED PROTEIN KINASE CASCADE J. Biol. Chem., March 23, 2007; 282(12): 8557 - 8567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Aschner, M. S. Kipnes, J. K. Lunceford, M. Sanchez, C. Mickel, D. E. Williams-Herman, and for the Sitagliptin Study 021 Group Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes Diabetes Care, December 1, 2006; 29(12): 2632 - 2637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Herman, A. Bergman, C. Stevens, P. Kotey, B. Yi, P. Zhao, B. Dietrich, G. Golor, A. Schrodter, B. Keymeulen, et al. Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4612 - 4619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Deacon, A. Plamboeck, M. M. Rosenkilde, J. de Heer, and J. J. Holst GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E468 - E475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A Miller and E. L St. Onge Sitagliptin: A Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes Ann. Pharmacother., July 1, 2006; 40(7): 1336 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mu, J. Woods, Y.-P. Zhou, R. S. Roy, Z. Li, E. Zycband, Y. Feng, L. Zhu, C. Li, A. D. Howard, et al. Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic {beta}-Cell Mass and Function in a Rodent Model of Type 2 Diabetes Diabetes, June 1, 2006; 55(6): 1695 - 1704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Riddle and D. J. Drucker Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1 Diabetes Care, February 1, 2006; 29(2): 435 - 449. [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. Burkey, X. Li, L. Bolognese, B. Balkan, M. Mone, M. Russell, T. E. Hughes, and P. R. Wang Acute and Chronic Effects of the Incretin Enhancer Vildagliptin in Insulin-Resistant Rats J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 688 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Lankas, B. Leiting, R. S. Roy, G. J. Eiermann, M. G. Beconi, T. Biftu, C.-C. Chan, S. Edmondson, W. P. Feeney, H. He, et al. Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes: Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9 Diabetes, October 1, 2005; 54(10): 2988 - 2994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Dungan and J. B. Buse Glucagon-Like Peptide 1-Based Therapies for Type 2 Diabetes: A Focus on Exenatide Clin. Diabetes, April 1, 2005; 23(2): 56 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Holst and C. Orskov The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism Diabetes, December 1, 2004; 53(suppl_3): S197 - S204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Deacon Therapeutic Strategies Based on Glucagon-Like Peptide 1 Diabetes, September 1, 2004; 53(9): 2181 - 2189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yasuda, T. Inoue, T. Nagakura, K. Yamazaki, K. Kira, T. Saeki, and I. Tanaka Metformin Causes Reduction of Food Intake and Body Weight Gain and Improvement of Glucose Intolerance in Combination with Dipeptidyl Peptidase IV Inhibitor in Zucker fa/fa Rats J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 614 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Foltz, A. Meyer, S. Theis, H.-U. Demuth, and H. Daniel A Rapid in Vitro Screening for Delivery of Peptide-Derived Peptidase Inhibitors as Potential Drug Candidates via Epithelial Peptide Transporters J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 695 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]
|
|
|
|
|
|
T. Hansotia, L. L. Baggio, D. Delmeire, S. A. Hinke, Y. Yamada, K. Tsukiyama, Y. Seino, J. J. Holst, F. Schuit, and D.J. Drucker Double Incretin Receptor Knockout (DIRKO) Mice Reveal an Essential Role for the Enteroinsular Axis in Transducing the Glucoregulatory Actions of DPP-IV Inhibitors Diabetes, May 1, 2004; 53(5): 1326 - 1335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Beconi, A. Mao, D. Q. Liu, C. Kochansky, T. Pereira, C. Raab, P. Pearson, and S.-H. Lee Chiu METABOLISM AND PHARMACOKINETICS OF A DIPEPTIDYL PEPTIDASE IV INHIBITOR IN RATS, DOGS, AND MONKEYS WITH SELECTIVE CARBAMOYL GLUCURONIDATION OF THE PRIMARY AMINE IN DOGS Drug Metab. Dispos., October 1, 2003; 31(10): 1269 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhu, C. Tamvakopoulos, D. Xie, J. Dragovic, X. Shen, J. E. Fenyk-Melody, K. Schmidt, A. Bagchi, P. R. Griffin, N. A. Thornberry, et al. The Role of Dipeptidyl Peptidase IV in the Cleavage of Glucagon Family Peptides: IN VIVO METABOLISM OF PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE-(1-38) J. Biol. Chem., June 13, 2003; 278(25): 22418 - 22423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Pamir, F. C. Lynn, A. M. J. Buchan, J. Ehses, S. A. Hinke, J. A. Pospisilik, K. Miyawaki, Y. Yamada, Y. Seino, C. H. S. McIntosh, et al. Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E931 - E939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Pospisilik, J. Martin, T. Doty, J. A. Ehses, N. Pamir, F. C. Lynn, S. Piteau, H.-U. Demuth, C. H.S. McIntosh, and R. A. Pederson Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates {beta}-Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats Diabetes, March 1, 2003; 52(3): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. MacDonald, W. El-kholy, M. J. Riedel, A. M. F. Salapatek, P. E. Light, and M. B. Wheeler The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion Diabetes, December 1, 2002; 51(90003): S434 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Pospisilik, S. G. Stafford, H.-U. Demuth, C. H.S. McIntosh, and R. A. Pederson Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat: A Euglycemic-Hyperinsulinemic Clamp Study Diabetes, September 1, 2002; 51(9): 2677 - 2683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Reimann and F. M. Gribble Glucose-Sensing in Glucagon-Like Peptide-1-Secreting Cells Diabetes, September 1, 2002; 51(9): 2757 - 2763. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |