Endocrinology, Vol 136, 3585-3596, Copyright © 1995 by Endocrine Society

ARTICLES

Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV

TJ Kieffer, CH McIntosh and RA Pederson
Department of Physiology, University of British Columbia, Vancouver, Canada.

The combined actions of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) may fully account for the incretin effect. These hormones are released from the small intestine in response to oral glucose and stimulate insulin release. Recently, evidence has been provided demonstrating the degradation of GIP-(1-42) and GLP-1-(7-36)NH2 by the serum enzyme dipeptidyl peptidase IV (DPP IV) into the biologically inactive products GIP-(3-42) and GLP- 1-(9-36)NH2. The objective of the current investigation was to develop a method to monitor the degradation of these hormones in vivo. Synthetic peptides were radiolabeled and purified by HPLC. Subsequent degradation of the peptides under various conditions was then monitored by further HPLC analysis. Incubation of [125I]GIP-(1-42) or [125I]GLP-1- (7-36)NH2 with Wistar rat serum or purified DPP IV resulted in the major N-terminal-truncated products [125I]GIP-(3-42) and [125I]GLP-1-(9- 36)NH2. These products were significantly reduced when the specific DPP IV inhibitor diprotin A was included in the incubation mixture and were absent when serum from DPP IV-deficient rats was used. When the labeled peptides were infused into rats at hormone levels within the physiological range, over 50% was metabolized to the truncated forms within 2 min. These products were absent when the tracers were infused into DPP IV-deficient animals. It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo. As the N- terminal-truncated products of the DPP IV cleavage may not be distinguished from the biologically active hormone by currently employed assays, reports of circulating hormone levels should be reconsidered. The method described in this manuscript may be useful for investigating the durations of action of GIP and tGLP-1 in normal and pathophysiological conditions.

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				B. Ahren, E. Simonsson, H. Larsson, M. Landin-Olsson, H. Torgeirsson, P.-A. Jansson, M. Sandqvist, P. Bavenholm, S. Efendic, J. W. Eriksson, et al. Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes Diabetes Care, May 1, 2002; 25(5): 869 - 875. [Abstract] [Full Text] [PDF]

				B. Sudre, P. Broqua, R. B. White, D. Ashworth, D. M. Evans, R. Haigh, J.-L. Junien, and M. L. Aubert Chronic Inhibition of Circulating Dipeptidyl Peptidase IV by FE 999011 Delays the Occurrence of Diabetes in Male Zucker Diabetic Fatty Rats Diabetes, May 1, 2002; 51(5): 1461 - 1469. [Abstract] [Full Text] [PDF]

				J.A. Pospisilik, S.G. Stafford, H-U. Demuth, R. Brownsey, W. Parkhouse, D.T. Finegood, C.H.S. McIntosh, and R.A. Pederson Long-Term Treatment With the Dipeptidyl Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and {beta}-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats Diabetes, April 1, 2002; 51(4): 943 - 950. [Abstract] [Full Text] [PDF]

				T. Perry, D. K. Lahiri, D. Chen, J. Zhou, K. T. Y. Shaw, J. M. Egan, and N. H. Greig A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 958 - 966. [Abstract] [Full Text] [PDF]

				S. A. Hinke, R. W. Gelling, R. A. Pederson, S. Manhart, C. Nian, H.-U. Demuth, and C. H.S. McIntosh Dipeptidyl Peptidase IV-Resistant [D-Ala2]Glucose-Dependent Insulinotropic Polypeptide (GIP) Improves Glucose Tolerance in Normal and Obese Diabetic Rats Diabetes, March 1, 2002; 51(3): 652 - 661. [Abstract] [Full Text] [PDF]

				G. S. Meneilly, C. H.S. McIntosh, R. A. Pederson, J. F. Habener, R. Gingerich, J. M. Egan, D. T. Finegood, and D. Elahi Effect of Glucagon-Like Peptide 1 on Non-Insulin-Mediated Glucose Uptake in the Elderly Patient With Diabetes Diabetes Care, November 1, 2001; 24(11): 1951 - 1956. [Abstract] [Full Text] [PDF]

				P. J. Larsen, C. Fledelius, L. B. Knudsen, and M. Tang-Christensen Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats Diabetes, November 1, 2001; 50(11): 2530 - 2539. [Abstract] [Full Text] [PDF]

				J. Korosi, C. H.S. McIntosh, R. A. Pederson, H.-U. Demuth, J. F. Habener, R. Gingerich, J. M. Egan, D. Elahi, and G. S. Meneilly Effect of Aging and Diabetes on the Enteroinsular Axis J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2001; 56(9): M575 - 579. [Abstract] [Full Text] [PDF]

				C. M. B. Edwards, S. A. Stanley, R. Davis, A. E. Brynes, G. S. Frost, L. J. Seal, M. A. Ghatei, and S. R. Bloom Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E155 - E161. [Abstract] [Full Text] [PDF]

				C. F. Deacon, P. Danielsen, L. Klarskov, M. Olesen, and J. J. Holst Dipeptidyl Peptidase IV Inhibition Reduces the Degradation and Clearance of GIP and Potentiates Its Insulinotropic and Antihyperglycemic Effects in Anesthetized Pigs Diabetes, July 1, 2001; 50(7): 1588 - 1597. [Abstract] [Full Text] [PDF]

				F. C. Lynn, N. Pamir, E. H.C. Ng, C. H.S. McIntosh, T. J. Kieffer, and R. A. Pederson Defective Glucose-Dependent Insulinotropic Polypeptide Receptor Expression in Diabetic Fatty Zucker Rats Diabetes, May 1, 2001; 50(5): 1004 - 1011. [Abstract] [Full Text]

				D. J. Drucker Glucagon-Like Peptide 2 J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1759 - 1764. [Abstract] [Full Text]

				D. J. Drucker Minireview: The Glucagon-Like Peptides Endocrinology, February 1, 2001; 142(2): 521 - 527. [Abstract] [Full Text] [PDF]

				C. F. Deacon, M. A. Nauck, J. Meier, K. Hücking, and J. J. Holst Degradation of Endogenous and Exogenous Gastric Inhibitory Polypeptide in Healthy and in Type 2 Diabetic Subjects as Revealed Using a New Assay for the Intact Peptide J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3575 - 3581. [Abstract] [Full Text]

				Q. Xiao, R. P. Boushey, M. Cino, D. J. Drucker, and P. L. Brubaker Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R1057 - R1063. [Abstract] [Full Text] [PDF]

				S. A. Hinke, J. A. Pospisilik, H.-U. Demuth, S. Mannhart, K. Kuhn-Wache, T. Hoffmann, E. Nishimura, R. A. Pederson, and C. H. S. McIntosh Dipeptidyl Peptidase IV (DPIV/CD26) Degradation of Glucagon. CHARACTERIZATION OF GLUCAGON DEGRADATION PRODUCTS AND DPIV-RESISTANT ANALOGS J. Biol. Chem., February 11, 2000; 275(6): 3827 - 3834. [Abstract] [Full Text] [PDF]

				W. Tavares, D. J. Drucker, and P. L. Brubaker Enzymatic- and renal-dependent catabolism of the intestinotropic hormone glucagon-like peptide-2 in rats Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E134 - E139. [Abstract] [Full Text] [PDF]

				T. J. Kieffer and J. Francis Habener The Glucagon-Like Peptides Endocr. Rev., December 1, 1999; 20(6): 876 - 913. [Abstract] [Full Text]

				L. Hansen, C. F. Deacon, C. Ørskov, and J. J. Holst Glucagon-Like Peptide-1-(7-36)Amide Is Transformed to Glucagon-Like Peptide-1-(9-36)Amide by Dipeptidyl Peptidase IV in the Capillaries Supplying the L Cells of the Porcine Intestine Endocrinology, November 1, 1999; 140(11): 5356 - 5363. [Abstract] [Full Text]

				D. J. Drucker, R. P. Boushey, Feng Wang, M. E. Hill, P. L. Brubaker, and B. Yusta Biologic Properties and Therapeutic Potential of Glucagon-like Peptide-2 JPEN J Parenter Enteral Nutr, September 1, 1999; 23(5_suppl): S98 - S100. [Abstract] [PDF]

				G. Grondin, N. M. Hooper, and D. LeBel Specific Localization of Membrane Dipeptidase and Dipeptidyl Peptidase IV in Secretion Granules of Two Different Pancreatic Islet Cells J. Histochem. Cytochem., April 1, 1999; 47(4): 489 - 498. [Abstract] [Full Text]

				A. S. Ryan, J. M. Egan, J. F. Habener, and D. Elahi Insulinotropic Hormone Glucagon-Like Peptide-1-(7-37) Appears Not to Augment Insulin-Mediated Glucose Uptake in Young Men during Euglycemia J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2399 - 2404. [Abstract] [Full Text]

				P. L. Brubaker, A. Crivici, A. Izzo, P. Ehrlich, C.-H. Tsai, and D. J. Drucker Circulating and Tissue Forms of the Intestinal Growth Factor, Glucagon-Like Peptide-2 Endocrinology, November 1, 1997; 138(11): 4837 - 4843. [Abstract] [Full Text] [PDF]