Best Practice & Research Clinical Endocrinology & Metabolism
Volume 23, Issue 4 , Pages 443-452 , August 2009

Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP

  • Rolf Mentlein, PhD (Professor)

      Affiliations

    • Corresponding Author InformationTel.: +49 431 2460; Fax: +49 431 1557.

References 

  1. Elrick H, Stimmler L, Hlad CJ, et al. Plasma insulin response to oral and intravenous glucose administration. The Journal of Clinical Endocrinology and Metabolism. 1964;24:1076–1082
  2. Creutzfeldt M. Candidate hormones of the gut. XV. Insulin-releasing factors of the gastrointestinal mucosa (Incretin). Gastroenterology. 1974;67:748–750
  3. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157
  4. Green BD, Flatt PR. Incretin hormone mimetics and analogues in diabetes therapeutics. Best practice & Research. Clinical Endocrinology & Metabolism. 2007;21:497–516
  5. Filipsson K, Holst JJ, Ahrén B. PACAP contributes to insulin secretion after gastric glucose gavage in mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2000;279:R424–R432
  6. Mest HJ, Mentlein R. Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes. Diabetologia. 2005;48:616–620
  7. Ørskov C, Rabenhøj L, Wettergren A, et al. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes. 1994;43:535–539
  8. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. The Journal of Clinical Investigation. 1987;79:616–619
  9. Gallwitz B, Schmidt WE, Conlon JM, et al. Glucagon-like peptide-1(7–36)amide: characterization of the domain responsible for binding to its receptor on rat insulinoma RINm5F cells. Journal of Molecular Endocrinology. 1990;5:33–39
  10. Dupre J, Ross SA, Watson D, et al. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. The Journal of Clinical Endocrinology and Metabolism. 1973;37:826–828
  11. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocrine Reviews. 1999;20:876–913
  12. Sherwood NM, Krueckl SL, McRory JE. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocrine Reviews. 2000;21:619–670
  13. Gault VA, Parker JC, Harriott P, et al. Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3–42), is a GIP receptor antagonist in vivo. The Journal of Endocrinology. 2002;175:525–533
  14. Knudsen LB, Pridal L. Glucagon-like peptide-1-(9–36) amide is a major metabolite of glucagon-like peptide-1-(7–36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. European Journal of Pharmacology. 1996;318:429–435
  15. Wettergren A, Wøjdemann M, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (7–36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9–36)amide. Peptides. 1998;19:877–882
  16. Deacon CF, Plamboeck A, Rosenkilde MM, et al. GIP-(3–42) does not antagonize insulinotropic effects of GIP at physiological concentrations. American Journal of Physiology. Endocrinology and Metabolism. 2006;291:E468–E475
  17. Vahl TP, Paty BW, Fuller BD, et al. Effects of GLP-1-(7–36)NH2, GLP-1-(7–37), and GLP-1- (9–36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. The Journal of Clinical Endocrinology and Metabolism. 2003;88:1772–1779
  18. Nagell CF, Pedersen JF, Holst JJ. The antagonistic metabolite of GLP-1, GLP-1 (9–36)amide, does not influence gastric emptying and hunger sensations in man. Scandinavian Journal of Gastroenterology. 2007;42:28–33
  19. Mentlein R. Cell surface peptidases. International Review of Cytology. 2004;235:165–213
  20. Mentlein R, Lucius R. Methods for the investigation of neuropeptide catabolism and stability in vitro. Brain Research. Brain Research Protocols. 1997;1:237–246
  21. Hassan M, Eskilsson A, Nilsson C, et al. In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7–36) amide in the rat studied by gamma camera. Nuclear Medicine and Biology. 1999;26:413–420
  22. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. European Journal of Biochemistry/FEBS. 1993;214:829–835
  23. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. The Journal of Clinical Endocrinology and Metabolism. 1995;80:952–957
  24. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136:3585–3596
  25. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131
  26. Hansen L, Deacon CF, Orskov C, et al. 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. 1999;140:5356–5363
  27. Vilsbøll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–613
  28. Jörnvall H, Carlquist M, Kwauk S, et al. Amino acid sequence and heterogeneity of gastric inhibitory polypeptide (GIP). FEBS Letters. 1981;123:205–210
  29. Schmidt WE, Siegel EG, Kümmel H, et al. Commercially available preparations of porcine glucose-dependent insulinotropic polypeptide (GIP) contain a biologically inactive GIP-fragment and cholecystokinin-33/-39. Endocrinology. 1987;120:835–837
  30. Frohman LA, Downs TR, Heimer EP, et al. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. The Journal of Clinical Investigation. 1989;83:1533–1540
  31. Zhu L, Tamvakopoulos C, Xie D, 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). The Journal of Biological Chemistry. 2003;278:22418–22423
  32. Hansen L, Hare KJ, Hartmann B, et al. Metabolism of glucagon-like peptide-2 in pigs: role of dipeptidyl peptidase IV. Regulatory Peptides. 2007;138:126–132
  33. Hinke SA, Pospisilik JA, Demuth HU, et al. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. The Journal of Biological Chemistry. 2000;275:3827–3834
  34. Hopsu-Havu VK, Glenner GG. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemistry. 1966;7:197–201
  35. Koivisto V. Discovery of dipeptidyl-peptidase IV-a 40 year journey from bench to patient. Diabetologia. 2008;51:1088–1089
  36. Mentlein R. Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regulatory Peptides. 1999;85:9–24
  37. Lambeir AM, Durinx C, Scharpé S, et al. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Critical Reviews in Clinical Laboratory Sciences. 2003;40:209–294
  38. Busek P, Malík R, Sedo A. Dipeptidyl peptidase IV activity and/or structure homologues (DASH) and their substrates in cancer. The International Journal of Biochemistry & Cell Biology. 2004;36:408–421
  39. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clinical Science (London, England: 1979). 2005;108:277–292
  40. Flatt PR, Bailey CJ, Green BD. Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes. Frontiers in Bioscience. 2008;13:3648–3660
  41. Ohkubo I, Huang K, Ochiai Y, et al. Dipeptidyl peptidase IV from porcine seminal plasma: purification, characterization, and N-terminal amino acid sequence. Journal of Biochemistry. 1994;116:1182–1186
  42. Iwaki-Egawa S, Watanabe Y, Kikuya Y, et al. Dipeptidyl peptidase IV from human serum: purification, characterization, and N-terminal amino acid sequence. Journal of Biochemistry. 1998;124:428–433
  43. Durinx C, Lambeir AM, Bosmans E, et al. Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. European Journal of Biochemistry/FEBS. 2000;267:5608–5613
  44. Mentlein R, Dahms P, Grandt D, et al. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regulatory Peptides. 1993;49:133–144
  45. Lambeir AM, Proost P, Durinx C, et al. Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. The Journal of Biological Chemistry. 2001;276:29839–29845
  46. Lambeir AM, Durinx C, Proost P, et al. Kinetic study of the processing by dipeptidyl-peptidase IV/CD26 of neuropeptides involved in pancreatic insulin secretion. FEBS Letters. 2001;507:327–330
  47. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opinion on Investigational Drugs. 2003;12:87–100
  48. Faidley TD, Leiting B, Pryor KD, et al. Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs. Experimental Biology and Medicine (Maywood, N.J.). 2006;231:1373–1378
  49. Siegel EG, Gallwitz B, Scharf G, et al. Biological activity of GLP-1-analogues with N-terminal modifications. Regulatory Peptides. 1999;79:93–102
  50. Gallwitz B, Ropeter T, Morys-Wortmann C, et al. GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro. Regulatory Peptides. 2000;86:103–111
  51. Gault VA, Flatt PR, Harriott P, et al. Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide. The Journal of Endocrinology. 2003;176:133–141
  52. Gault VA, Hunter K, Irwin N, et al. Characterisation and biological activity of Glu3 amino acid substituted GIP receptor antagonists. Archives of Biochemistry and Biophysics. 2007;461:263–274
  53. Marguet D, Baggio L, Kobayashi T, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:6874–6879
  54. Conarello SL, Li Z, Ronan J, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:6825–6830
  55. Nagakura T, Yasuda N, Yamazaki K, et al. Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats. Biochemical and Biophysical Research Communications. 2001;284:501–506
  56. Hansotia T, Baggio LL, Delmeire D, et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes. 2004;53:1326–1335
  57. Mentlein R. Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs. Expert Opinion on Investigational Drugs. 2005;14:57–64
  58. Green BD, Irwin N, Flatt PR. Pituitary adenylate cyclase-activating peptide (PACAP): assessment of dipeptidyl peptidase IV degradation, insulin-releasing activity and antidiabetic potential. Peptides. 2006;27:1349–1358
  59. Mentlein R. Dipeptidyl-peptidase IV and aminopeptidase P: molecular switches of NPY/PYY receptor affinities. In:  Zukowska Z,  Feuerstein GZ editor. The NPY family of peptides in immune disorders, inflammation, angiogenesis and cancer. Basel: Birkhäuser-Verlag; 2005;p. 75–84
  60. Jackson EK, Dubinion JH, Mi Z. Effects of dipeptidyl peptidase IV inhibition on arterial blood pressure. Clinical and Experimental Pharmacology & Physiology. 2008;35:29–34
  61. Van der Veken P, Haemers A, Augustyns K. Prolyl peptidases related to dipeptidyl peptidase IV: potential of specific inhibitors in drug discovery. Current Topics in Medicinal Chemistry. 2007;7:621–635
  62. Lankas GR, Leiting B, Roy RS, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005;54:2988–2994
  63. Hupe-Sodmann K, McGregor GP, Bridenbaugh R, et al. Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regulatory Peptides. 1995;58:149–156
  64. Hupe-Sodmann K, Göke R, Göke B, et al. Endoproteolysis of glucagon-like peptide (GLP)-1 (7–36) amide by ectopeptidases in RINm5F cells. Peptides. 1997;18:625–632
  65. Plamboeck A, Holst JJ, Carr RD, et al. Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia. 2005;48:1882–1890
  66. Oefner C, Pierau S, Schulz H, et al. Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV. Acta Crystallographica. Section D, Biological Crystallography. 2007;63:975–981

PII: S1521-690X(09)00024-4

doi: 10.1016/j.beem.2009.03.005

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 23, Issue 4 , Pages 443-452 , August 2009

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