Long-Term Treatment With the Dipeptidyl Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and β-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 4; pp. 943 - 950
• Main Authors: POSPISILIK, J. A, STAFFORD, S. G, DEMUTH, H.-U, BROWNSEY, R, PARKHOUSE, W, FINEGOOD, D. T, MCINTOSH, C. H. S, PEDERSON, R. A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2002
• Subjects: Acetyl-CoA Carboxylase - metabolism; Adipose Tissue - drug effects; Adipose Tissue - physiology; Animals; Biological and medical sciences; Biological transport; Blood Glucose - drug effects; Blood Glucose - metabolism; Body Weight - drug effects; Diabetes; Dipeptidyl Peptidase 4 - metabolism; Drinking Behavior - drug effects; Glucose - pharmacology; Glucose metabolism; Glucose Tolerance Test; Glycogen Synthase - metabolism; Hyperinsulinism - blood; Insulin; Insulin - pharmacology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Pentanoic Acids - pharmacology; Physiological aspects; Protease Inhibitors - pharmacology; Rats; Rats, Zucker; Reference Values; Thiazoles - pharmacology; Thiazolidines; Time Factors; Canada
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.4.943

Long-Term Treatment With the Dipeptidyl Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and β-Cell Glucose Responsiveness in VDF ( fa/fa ) Zucker Rats J.A. Pospisilik 1 , S.G. Stafford 1 , H-U. Demuth 2 , R. Brownsey 3 , W. Parkhouse 4 , D.T. Finegood 4 , C.H.S. McIntosh 1 and R.A. Pederson 1 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 Abstract 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 β-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, β-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. Footnotes Address correspondence and reprint requests to Dr. R.A. Pederson, Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. E-Mail: pederson{at}interchange.ubc.ca . Received for publication 28 August 2001 and accepted in revised form 9 January 2002. ACC, acetyl-CoA carboxylase; DP IV, dipeptidyl peptidase IV; GIP, glucose-dependent insulinotropic polypeptide-(1–42); GLP-1, glucagon-like peptide 1-(7-36)amide; GLP-1a, active GLP-1 7–36 ; GS, glycogen synthase; OGTT, oral glucose tolerance test. H.-U.D. is the Chief Executive Officer and Chief Scientific Officer of and a shareholder in Probiodrug GmbH, a pharmaceutical company in the process of developing a DP IV inhibitor treatment for diabetes and its complications. R.A.P. and C.H.S.M. are both members of a scientific advisory panel to Probiodrug and receive consulting fees for their participation. R.A.P. and C.H.S.M. also receive grant/research support from Probiodrug to support studies on the drug candidate P32/98 and its utility in treating diabetes and its complications. DIABETES