Download PDF
Horm Metab Res 2004; 36(11/12): 867-876
DOI: 10.1055/s-2004-826178
Review
© Georg Thieme Verlag KG Stuttgart · New York

GLP-1 Receptor Agonists and DPP-4 Inhibitors in the Treatment of Type 2 Diabetes

B.  Ahrén1 , O.  Schmitz2
  • 1Department of Medicine, Lund University, Lund, Sweden
  • 2Department of Endocrinology & Diabetes, University Hospital of Aarhus and Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
Further Information

Publication History

Received 3 August 2004

Accepted after revision 16 August 2004

Publication Date:
18 January 2005 (online)

Also available at
    Permissions and Reprints

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with antidiabetic action through its ability to stimulate insulin secretion, increase beta cell neogenesis, inhibit beta cell apoptosis, inhibit glucagon secretion, delay gastric emptying and induce satiety. It has therefore been explored as a novel treatment of type 2 diabetes. A problem is, however, that GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, which results in a short circulating half-life of the active form of GLP-1 (< 2 min). Two strategies have been employed to overcome this obstacle as a treatment of diabetes. One is to use GLP-1 receptor agonists that have a prolonged half-life due to reduced degradation by DPP-4. These GLP-1 mimetics include exenatide and liraglutide. Another strategy is to inhibit the enzyme DPP-4, which prolongs the half-life of endogenously released active GLP-1. Both these strategies have been successful in animal studies and in clinical studies of up to one year’s treatment. This review will summarize the background and the current (mid 2004) clinical experience with these two strategies.

Key words

GLP-1 - GLP-1 analogues - GLP-1 mimetics - Liraglutide - Exenatide - DPP-4 - DPP-4 inhibitors

References

  • 1 Zimmet P. The burden of type 2 diabetes: are we doing enough?.  Diabetes Metab. 2003;  29 6S9-18
    CrossrefPubMedGoogle Scholar
  • 2 Ceriello A. The possible role of postprandial hyperglyceaemia in the pathogenesis of diabetic complications.  Diabetologia. 2003;  46 M9-M16
    PubMedGoogle Scholar
  • 3 Turner R C. The U.K. Prospective Diabetes Study. A review.  Diabetes Care. 1998;  suppl 3 C35-38
    PubMedGoogle Scholar
  • 4 DeFronzo R A, Bonadonna R C, Ferrannini E. Pathogenesis of NIDDM. A balanced overview.  Diabetes Care. 1992;  15 318-368
    CrossrefPubMedGoogle Scholar
  • 5 Consoli A. Role of liver in pathophysiology of NIDDM.  Diabetes Care. 1992;  15 430-441
    PubMedGoogle Scholar
  • 6 Kahn S E. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes.  Diabetologia. 2003;  46 3-19
    CrossrefPubMedGoogle Scholar
  • 7 Maggio C A, Pi-Sunyer F X. Obesity and type 2 diabetes.  Endocrinol Metab Clin North Am. 2003;  32 805-822
    CrossrefPubMedGoogle Scholar
  • 8 Ahrén B. Glucagon-like peptide 1 (GLP-1) - a gut hormone of potential interest in the treatment of diabetes.  BioEssays. 1998;  20 642-651
    CrossrefPubMedGoogle Scholar
  • 9 Holst J J. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1.  Diabet Metab Res Rev. 2002;  18 430-441
    PubMedGoogle Scholar
  • 10 Ahrén B. Gut peptides and type 2 diabetes mellitus treatment.  Curr Diabet Rep. 2003;  3 365-372
    PubMedGoogle Scholar
  • 11 Drucker D J. Enhancing incretin action for the treatment of type 2 diabetes.  Diabetes Care. 2003;  26 2929-2940
    CrossrefPubMedGoogle Scholar
  • 12 Drucker D J. Glucagon-like peptides: rergulators of cell proliferation, differentiation and apoptosis.  Mol Endocrinol. 2003;  17 161-171
    CrossrefPubMedGoogle Scholar
  • 13 Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, di Mario U, Harlan D M, Perfetti R. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.  Endocrinology. 2003;  1344 5149-5158
    PubMedGoogle Scholar
  • 14 Gutniak M, Ørskov C, Holst J J, Ahrén B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.  N Engl J Med. 1992;  326 1316-1322
    CrossrefPubMedGoogle Scholar
  • 15 Nathan D M, Schreiber E, Fogel H, Mojsov S, Habener J F. Insulinotropic action of glucagonlike peptide-1-(7-37) in diabetic and nondiabetic subjects.  Diabetes Care. 1992;  15 270-276
    PubMedGoogle Scholar
  • 16 Nauck M A, Kleine N, Ørskov C, Holst J J, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide-1 (7-36)amide in type 2 (noninsulin-dependent) diabetic patients.  Diabetologia. 1993;  36 741-744
    CrossrefPubMedGoogle Scholar
  • 17 Nauck M A, Sauerwaldf A, Ritzel R, Holst J J, Schmiegel W. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea failure.  Diabetes Care. 1998;  21 1925-1931
    PubMedGoogle Scholar
  • 18 Rachman J, Barrow B A, Levy J C, Turner R C. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM.  Diabetologia. 1997;  40 205-211
    CrossrefPubMedGoogle Scholar
  • 19 Nauck M A, Wollschlager D, Werner J, Holst J J, Ørskov C, Creutzfeldt W, Willms B. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7 - 36amide]) in patients with NIDDM.  Diabetologia. 1996;  39 1546-1553
    CrossrefPubMedGoogle Scholar
  • 20 Juntti-Berggren L, Pigon J, Karpe F, Hamsten A, Gutniak M, Vignati L, Efendic S. The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.  Diabetes Care. 1996;  19 1200-1206
    PubMedGoogle Scholar
  • 21 Gutniak M K, Larsson H, Sanders S W, Juneskans O, Holst J J, Ahrén B. GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions.  Diabetes Care. 1997;  20 1874-1879
    PubMedGoogle Scholar
  • 22 Ritzel R, Ørskov C, Holst J J, Nauck M A. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose-response relationships.  Diabetologia. 1995;  38 720-725
    CrossrefPubMedGoogle Scholar
  • 23 Zander M, Madsbad S, Madsen J L, Holst J J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study.  Lancet. 2002;  359 824-830
    CrossrefPubMedGoogle Scholar
  • 24 Nauck M A. Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes.  Horm Metab Res. 2004;  36 852-858
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Deacon C F. Circulation and degradation of GIP and GLP-1.  Horm Metab Res. 2004;  36 761-765
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Mentlein R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides.  Regul Pept. 1999;  85 9-24
    CrossrefPubMedGoogle Scholar
  • 27 Deacon C F, Johnsen A H, Holst J J. 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.  J Clin Endocrinol Metab. 1995;  80 952-957
    CrossrefPubMedGoogle Scholar
  • 28 Rolin B, Deacon C F, Carr R D, Ahrén B. The major GLP-1 metabolite, GLP-1-(9-36) amide, does not affect glucose or insulin levels in mice.  Eur J Pharmacol. 2004;  494 283-288
    CrossrefPubMedGoogle Scholar
  • 29 Vahl T P, Paty B W, Fuller B D, Prigeon R L, D'Alessio D A. Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1-(9-36)NH2 on intravenlus glucose tolerance and glucose-induced insulin secretion in healthy humans.  J Clin Endocrinol Metab. 2003;  88 1772-1779
    CrossrefPubMedGoogle Scholar
  • 30 Knudsen L B, 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.  Eur J Pharmacol. 1996;  318 429-435
    CrossrefPubMedGoogle Scholar
  • 31 Hopsu-Havy V K, Glenner G G. A new dipeptide naphtylamidase hydrolyzing glycyl-prolyl-β-naphtylamide.  Histochemie. 1966;  7 197-201
    CrossrefPubMedGoogle Scholar
  • 32 Lojda Z. Studies on dipeptidyl (amino) peptidase IV (glycyl-proline-naphtylamidase) II Blood vessels.  Histochemistry. 1979;  59 153-166
    CrossrefPubMedGoogle Scholar
  • 33 Kurtzhals P, Havelund S, Jonassen I, Kiehr B, Larsen U D, Ribel U, Markussen J. Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo.  Biochem J. 1995;  312 (Pt 3) 725-731
    PubMedGoogle Scholar
  • 34 Bjerre Knudsen L. Glucagon-like peptide-1: The basis of a new class of treatment for type 2 diabetes.  J Med Chem. 2004;  47 4128-4134
    CrossrefPubMedGoogle Scholar
  • 35 Sturis J, Gotfredsen C F, Romer J, Rolin B, Ribel U, Brand C L, Wilken M, Wassermann K, Deacon C F, Carr R D, Bjerre Knudsen L. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics.  Br J Pharmacol. 2003;  140 123-132
    CrossrefPubMedGoogle Scholar
  • 36 Larsen P J, Fledelius C, Knudsen L B, Tang-Christensen M. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats.  Diabetes. 2001;  50 2530-2539
    PubMedGoogle Scholar
  • 37 Rolin B, Larsen M O, Gotfredsen C F, Deacon C F, Carr R D, Wilken M, Bjerre Knudsen L. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice.  Am J Physiol Endocrinol Metab. 2002;  283 E745-E752
    PubMedGoogle Scholar
  • 38 Bock T, Pakkenberg B, Buschard K. The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211.  APMIS. 2003;  111 1117-1124
    CrossrefPubMedGoogle Scholar
  • 39 Klein T, Frandsen U, Heller R S, Serup P. IMPAN cells: a pancreatic model for differentiation into endocrine cells.  Arch Biochem Biophys. 2001;  395 259-263
    CrossrefPubMedGoogle Scholar
  • 40 Ribel U, Larsen M O, Rolin B, Carr R D, Wilken M, Sturis J, Westergaard L, Deacon C F, Bjerre Knudsen L. NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs.  Eur J Pharmacol. 2002;  451 217-225
    CrossrefPubMedGoogle Scholar
  • 41 Agerso H, Jensen L B, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men.  Diabetologia. 2002;  45 195-202
    CrossrefPubMedGoogle Scholar
  • 42 Elbrond B, Jakobsen G, Larsen S, Agerso H, Jensen L B, Rolan P, Sturis J, Hatorp V, Zdravkovic M. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects.  Diabetes Care. 2002;  25 1398-1404
    CrossrefPubMedGoogle Scholar
  • 43 Juhl C B, Hollingdal M, Sturis J, Jakobsen G, Agerso H, Veldhuis J, Pørksen N, Schmitz O. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes.  Diabetes. 2002;  51 424-429
    CrossrefPubMedGoogle Scholar
  • 44 Chang A M, Jakobsen G, Sturis J, Smith M J, Bloem C J, An B, Galecki A, Halter J B. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose.  Diabetes. 2003;  52 1786-1791
    CrossrefPubMedGoogle Scholar
  • 45 Degn K B, Juhl C B, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau B R, Schmitz O. One week"s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes.  Diabetes. 2004;  53 1187-1194
    CrossrefPubMedGoogle Scholar
  • 46 Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews D R. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial.  Diabetes Care. 2004;  27 1335-1342
    CrossrefPubMedGoogle Scholar
  • 47 Feinglos M, Saad M F, Pi-Sunyer F X, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 derivative, on glycaemic control and body weight in obese subjects with Type 2 diabetes.  Diabetic Medicine. 2004;  in press
    PubMedGoogle Scholar
  • 48 Dennis M S, Zhang M, Meng Y G, Kadkhodayan M, Kirchhofer D, Combs D, Damico L A. Albumin binding as a general strategy for improving the pharmacokinetics of proteins.  J Biol Chem. 2002;  277 35 035-35 043
    PubMedGoogle Scholar
  • 49 Kim J G, Baggio L L, Bridon D P, Castaigne J P, Robitaille M F, Jette L, Benquet C, Drucker D J. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo.  Diabetes. 2003;  52 751-759
    PubMedGoogle Scholar
  • 50 Lawrence B, Dreyfus J-F, Wen S, Guivarch P-H, Drucker D J, Castaigne J-P. CJC-1131, a Long Acting GLP-1 Derivative, Exhibits an Extended Pharmacokinetic Profile in Healthy Human Volunteers.  Diabetes. 2003;  52 (Suppl. 1) A125
    PubMedGoogle Scholar
  • 51 Benquet C, Léger R, Huang X, Thibaudeau K, Bridon D, Castaigne J-P. CJC-1131 (DAC: GLP-1) binds covalently in vivo to Endogenous Albumin: Update on the DAC Technology.  Diabetes. 2004;  53 (Suppl. 2) A116
    PubMedGoogle Scholar
  • 52 Wen S, Chatenoud L, Lawrence B, Franco P, Castaigne J-P, Bach J-F. Lack of Immunogenicity of CJC-1131, a Long-Acting GLP-1 Analog for the Treatment of Type 2 diabetes.  Diabetes. 2004;  53 (Suppl. 2) A151
    PubMedGoogle Scholar
  • 53 Bloom M, Bock J, Duttaroy A, Grzegorzewski K, Moore P, Ou Y, Wojcik S, Zhou X, Bell A. Albugon(TM) Fusion Protein: A long-acting analog of GLP-1 that provides lasting antidiabetic effect in animals.  Diabetes. 2003;  52 (Suppl. 1) A112
    PubMedGoogle Scholar
  • 54 Kapitza C, Trautmann M, Heise T, Heinemann L, Patterson B. Daily administration of LY307161 SR (GLP-1 analog) normalizes blood glucose in type 2 diabetes.  Diabetes. 2002;  51 (Suppl. 2) A84
    PubMedGoogle Scholar
  • 55 Raufman J P, Jensen R T, Sutliff V E, Pisano J J, Gardner J D. Actions of Gila monster venom on dispersed acini from guinea pig pancreas.  Am J Physiol. 1982;  242 G470-G474
    PubMedGoogle Scholar
  • 56 Eng J, Kleinman W A, Singh L, Singh G, Raufman J P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas.  J Biol Chem. 1992;  267 7402-7405
    PubMedGoogle Scholar
  • 57 Thorens B, Porret A, Buhler L, Deng S P, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.  Diabetes. 1993;  42 1678-1682
    CrossrefPubMedGoogle Scholar
  • 58 Rai A, Singh G, Raffaniello R, Eng J, Raufman J P. Actions of Helodermatidae venom peptides and mammalian glucagon-like peptides on gastric chief cells.  Am J Physiol. 1993;  265 G118-G125
    PubMedGoogle Scholar
  • 59 Goke R, Fehmann H C, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta cells.  J Biol Chem. 1993;  268 19650-19655
    PubMedGoogle Scholar
  • 60 Chen K, Petrella E, Young A. Effects of functional nephrectomy on clearance of exendin-4 in rats.  Diabetes. 1999;  48 A426
    PubMedGoogle Scholar
  • 61 Parkes D, Jodka C, Smith P, Nayak S, Rinehart L, Gingerich R, Chen K, Young A. Pharmacokinetic actions of exendin-4 in the rat: Comparison with glucagon-like peptide-1.  Drug Dev Res. 2001;  53 260-267
    CrossrefPubMedGoogle Scholar
  • 62 Young A A, Gedulin B R, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).  Diabetes. 1999;  48 1026-1034
    PubMedGoogle Scholar
  • 63 Edwards C M, Stanley S A, Davis R, Brynes A E, Frost G S, Seal L J, Ghatei M A, Bloom S R. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.  Am J Physiol Endocrinol Metab. 2001;  281 E155-E161
    PubMedGoogle Scholar
  • 64 Egan J M, Clocquet A R, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes.  J Clin Endocrinol Metab. 2002;  87 1282-1290
    CrossrefPubMedGoogle Scholar
  • 65 Nielsen L L, Baron A D. Pharmacology of exenatide (synthetic exendin-4) for the treatment of type 2 diabetes.  Curr Opin Investig Drugs. 2003;  4 401-405
    PubMedGoogle Scholar
  • 66 Nielsen L L, Young A A, Parkes D G. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes.  Regul Pept. 2004;  117 77-88
    CrossrefPubMedGoogle Scholar
  • 67 Young A A. Glucagon-like peptide-1, exendin and insulin sensitivity. In: Hansen B, Shafrir E (eds.) Insulin Resistance and Insulin Resistance Syndrome. New York; Harwood Academic 2002: 235-262
    Google Scholar
  • 68 Kolterman O G, Buse J B, Fineman M S, Gaines E, Heintz S, Bicsak T A, Taylor K, Kim D, Aisporna M, Wang Y, Baron A D. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes.  J Clin Endocrinol Metab. 2003;  88 3082-3089
    CrossrefPubMedGoogle Scholar
  • 69 Egan J M, Meneilly G S, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes.  Am J Physiol Endocrinol Metab. 2003;  284 E1072-E1079
    PubMedGoogle Scholar
  • 70 Fineman M S, Bicsak T A, Shen L Z, Taylor K, Gaines E, Varns A, Kim D, Baron A D. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes.  Diabetes Care. 2003;  26 2370-2377
    CrossrefPubMedGoogle Scholar
  • 71 Degn K B, Brock B, Juhl C B, Djurhuus C B, Grubert J, Kim D, Han J, Taylor K, Fineman M, Schmitz O. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia.  Diabetes. 2004;  53 2397-2403
    CrossrefPubMedGoogle Scholar
  • 72 Vella A, Shah P, Reed A S, Adkins A S, Basu R, Rizza R A. Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans.  Diabetologia. 2002;  45 1410-1415
    PubMedGoogle Scholar
  • 73 Baron A, Poon T, Taylor K, Nielsen L, Boies S, Zhou J, Zhuang D, Varns A, Kim D, Fineman M, Kolterman O. Exenatide (synthetic exendin-4) showed marked HbA1c decline over 5 months in patients with type 2 diabetes failing oral agents in an open-label study.  Diabetes. 2003;  Suppl. 3-LB
    PubMedGoogle Scholar
  • 74 Kendall D, Riddle M, Rosenstock J, Zhuang D, Kim D, Fineman M, Baron A. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in patients with type 2 diabetes mellitus treated with metformin and a sulfonylurea.  Diabetes. 2004;  Suppl. 10-LB
    PubMedGoogle Scholar
  • 75 Buckley D I, Lundquist P. Analysis of the degradation of insulinotropin [GLP-1 (7 - 37)] in human plasma and production of degradation resistant analogs.  Regul Pept. 1992;  40 117
    PubMedGoogle Scholar
  • 76 Deacon C F, Nauck M A, Toft-Nielsen L, Pridal L, Willms B, Holst J J. 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
    CrossrefPubMedGoogle Scholar
  • 77 Kieffer T J, McIntosh C HS, Pederson R A. Degradation of glucose-dependent insulinotropic peptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.  Endocrinology. 1995;  136 3585-3596
    CrossrefPubMedGoogle Scholar
  • 78 Holst J J, Deacon C F. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes.  Diabetes. 1998;  47 1663-1670
    CrossrefPubMedGoogle Scholar
  • 79 Deacon , CF , Wamberg S, Biev P, Hughes T E, Holst J J. Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs.  J Endocrinol. 2002;  172 355-362
    CrossrefPubMedGoogle Scholar
  • 80 Deacon C F, Hughes T E, Holst J J. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide-1 in anesthetized pigs.  Diabetes. 1998;  47 764-769
    CrossrefPubMedGoogle Scholar
  • 81 Pederson R A, White H A, Schlenzig D, Pauly R P, McIntosh C H, Demuth H U. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucin thiazlodide.  Diabetes. 1998;  47 1253-1258
    PubMedGoogle Scholar
  • 82 Balkan B, Kwasnik L, Miserendino R, Holst J J, Li X. Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats.  Diabetologia. 1999;  42 1324-1331
    CrossrefPubMedGoogle Scholar
  • 83 Ahrén B, Holst J J, Mårtensson H, Balkan B. Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice.  Eur J Pharmacol. 2000;  404 239-245
    CrossrefPubMedGoogle Scholar
  • 84 Kvist Reimer M, Holst J J, Ahrén B. Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice.  Eur J Endocrinol. 2002;  146 717-727
    CrossrefPubMedGoogle Scholar
  • 85 Pospisilik J A, Stafford S G, Demuth H U, Brownsey R, Parkhouse W, Finegood D T, McIntosh C HS, Pederson R A. 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.  Diabetes. 2002;  51 943-950
    PubMedGoogle Scholar
  • 86 Sudre B, Broqua P, White R B, Ashworth D, Evans D M, Haigh R, Junien J L, Aubert M L. Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999 011 delays the occurrence of diabetes in male Zucker diabetic fatty rats.  Diabetes. 2002;  51 1461-1469
    CrossrefPubMedGoogle Scholar
  • 87 Mitani H, Takimoto M, Kimura M. Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity.  Jpn J Pharmacol. 202;  88 451-458
    PubMedGoogle Scholar
  • 88 Pederson R A, Kieffer T J, Pauly R, Kofod H, Kwong J, McIntosh C HS. The enteroinsular axis in dipeptidyl peptidase IV-negative rats.  Metabolism. 1996;  45 1335-1341
    CrossrefPubMedGoogle Scholar
  • 89 Marguet D, Baggio L, Kobayashi T, Bernard A M, Pierres M, Nielsen P F, Ribel U, Watanabe T, Drucker D J, Wagtmann N. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26.  Proc Natl Acad Sci USA. 2000;  97 6874-6879
    CrossrefPubMedGoogle Scholar
  • 90 Nagakura T, Yasuda N, Yamazaki K, Ikuta H, Yoshikawa S, Asano O, Tanaka I. Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats.  Biochem Biophys Res Commun. 2001;  284 501-506
    CrossrefPubMedGoogle Scholar
  • 91 Yasuda N, Nagakura T, Yamazaki K, Inoue T, Tanaka I. Improvement of high fat-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats.  Life Sci. 2002;  71 227-238
    CrossrefPubMedGoogle Scholar
  • 92 Demuth H U, Hoffman T, Glund K, McIntosh C HS, Pederson R A, Fueker K, Fischer S, Hanefeld M. Single dose treatment of diabetic patients by the DP IV inhibitor P32/98.  Diabetes. 2000;  49 (Suppl 1) A102
    PubMedGoogle Scholar
  • 93 Rothenburg P, Kalbag J, Smith H, Gingerich R, Nedelman J, Villhauer E, McLeod J, Hughes T. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans.  Diabetes. 2000;  49 (Suppl 1) A39
    PubMedGoogle Scholar
  • 94 Ahrén B, Simonsson E, Larsson H, Landin-Olsson M, Torgeirsson H, Jansson P A, Sandqvist M, Båvenholm P, Efendic S, Eriksson J W, Dickinson S, Holmes D. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4 week study period in type 2 diabetes.  Diabetes Care. 2002;  25 869-875
    PubMedGoogle Scholar
  • 95 Sörhede Winzell M, Ahrén B. The high-fat fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes.  Diabetes. 2004;  53 (Suppl 3) S215 - 219
    PubMedGoogle Scholar
  • 96 Ahrén B, Landin-Olsson M, Jansson P A, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduces glucagon levels in type 2 diabetes.  J Clin Endocrinol Metab. 2004;  89 2078-2084
    CrossrefPubMedGoogle Scholar
  • 97 Ahrén B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2004;  27 2874-2880
    CrossrefPubMedGoogle Scholar
  • 98 Herman G A, Zhao P L, Dietrich B, Golor G, Schrodter A, Keymuelen B, Lasseter K C, Kipnes M S, Hilliard D, Tanen M, de Lepeleire I, Cilissen C, Stevens C, Tanaka W, Gottesdiener K M, Wagner J A. The DP-IV inhibitor MK-0431 enhances GLP-1 and recues glucose following an OGTT in type 2 diabetes.  Diabetes. 2004;  53 A82
    PubMedGoogle Scholar
  • 99 Zhu L, Tamvakopoulos C, Xie D, Dragovic J, Shen X, Fenyk-Melody J E. Schmidt K, Bagchi A, Griffin PR, Thornberry NA, Sinha Roy R. The role of dopeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38).  J Biol Chem. 2003;  278 22 418-22 423
    PubMedGoogle Scholar
  • 100 Ahrén B. Autonomic regulation of islet hormone secretion. Implications for health and disease.  Diabetologia. 2000;  43 393-410
    CrossrefPubMedGoogle Scholar
  • 101 Hansotia T, Baggio L LK, Delmeire D, Hinke S A, Yamada Y, Tsukiyama K, Seino Y, Holst J J, Schuit F, Drucker D J. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing glucoregulatory actionsof DPP-IV inhibitors.  Diabetes. 2004;  53 1326-1335
    PubMedGoogle Scholar
  • 102 Caldwyll C G, Chen P, He J, Parmee E R, Leiting B, Marsilio F, Patel R A, Wu J K, Eiermann G J, Petrov A, He H, Lyons K A, Thornberry N A, Weber A E. Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors.  Bioorg Med Chem Lett. 2004;  14 1265-1268
    CrossrefPubMedGoogle Scholar
  • 103 Lankas G, Leiting B, Roy R S, Eiermann G, Biftu T, Kim D, Ok H, Weber A, Thornberry N A. Inhibition of DPP8/9 results in toxicity in preclinical species: potential importance of selective dipeptidyl peptidase IV inhibition for the treatment of type 2 DM.  Diabetes. 2004;  53 (Suppl 2) A2
    PubMedGoogle Scholar

Dr. B. Ahrén

Department of Medicine, Lund University

B11 BMC · SE-221 84 Lund · Sweden ·

Phone: + 46 (46) 222 07 58

Email: Bo.Ahren@med.lu.se