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Review

Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes?

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Pages 1091-1102 | Published online: 24 Feb 2005

Bibliography

  • AHREN B, SIMONSSON E, LARSSON H et al.: Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in Type 2 diabetes. Diabetes Care (2002) 25:869–975.
  • ••The first demonstration of a clinical effectof DPP IV inhibition in Type 2 diabetes.
  • AHREN B, LANDIN-OLSSON M, JANSSON PA, SVENSSON M, HOLMES D, SCHWEIZER A: Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduced glucagon levels in Type 2 diabetes. Clin. Endocrinol Metab. (2004) 89:2078–2084.
  • ORSKOV C, HOLST JJ, KNUHTSEN S, BALDISERRA FG, POULSEN SS, NIELSEN OV: Glucagon-like peptides GLP-1 and GLP-2, predicted products of the proglucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology (1986) 119:1476–1475.
  • 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. J. Clin. Invest. (1987). 79:616–619.
  • HOLST JJ, ORSKOV C, NIELSEN OV, SCHWARTZ TW: Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Lett. (1987) 211:169–174.
  • ORSKOV C, HOLST JJ, NIELSEN OV: Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology (1988) 123: 2009-2013.
  • FRIDOLF T, BOTTCHER G, SUNDLER F, AHREN B: GLP-1 and GLP-1(7-36) amide: influences on basal and stimulated insulin and glucagon in the mouse. Pancreas (1991) 6:208–215.
  • HOLST JJ: Therapy of Type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab. Res. Rev (2002) 18:430–441.
  • GUTNIAK M, ORSKOV C, HOLST JJ, AHREN B, EFENDIC S: Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl Med. (1992) 326:1316–1322.
  • •The first description of an effect of GLP-1 in Type 2 diabetes.
  • NATHAN DM, SCHREIBER E, H, MOJSOV S, HABENERJF: Insulinotropic action of glucagonlike peptide-I (7-37) in diabetic and nondiabetic subjects. Diabetes Care (1992) 15:270–276.
  • NAUCK MA, KLEINE N, ORSKOV C, HOLST JJ, WILLMS B, CREUTZFELDT C: Normalization of fasting hyperglycemia by exogenous GLP-1 (7-36 amide) in Type 2 diabetic patients. Diabetologia (1993) 36:741–744.
  • ••An important study demonstrating that-1 can normalise fasting glucose concentrations in diabetic patients.
  • RACHMAN J, GRIBBLE FM, BA, LEVY JC, KD, TURNER RC: Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1/7-36) amide in patients with NIDDM. Diabetes (1996) 45:1524–1530.
  • LARSEN J, HYLLEBERG B, NG K, DAMSBO P: Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in Type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care (2001) 24:1416–1421.
  • NAUCK MA, SAUERWALD A, RITZEL R, HOLST JJ, SCHMIEGEL W: Influence of glucagon-like peptide 1 on fasting glycemia inType 2 diabetic patients treated with insulin after sulfonylurea failure. Diabetes Care (1998) 21: 1925-1931.
  • NAUCK MA, WOLLSCHLAGER D, WERNER J et al.: Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia (1996) 39:1546–1553.
  • JUNTTI-BERGGREN L, PIGON J, KARPE F et al: 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.
  • ZANDER M, MADSBAD S, JL, HOLST JJ: Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and 13-cell function in Type 2 diabetes: a parallel-group study. Lancet (2002) 359:824–830.
  • ••First demonstration of a long-term effectof GLP-1 in patients with Type 2 diabetes.
  • GUTNIAK MK, LARSSON H, HEIBER SJ, JUNESKANS OT, HOLST JJ, AHREN B: Potential therapeutic levels of glucagon-like peptide-1 achieved in humans by a buccal tablet. Diabetes Care (1996) 19:843–848.
  • GUTNIAK MK, LARSSON H, SANDERS SVV, JUNESKANS 0, HOLST JJ, AHREN B: GLP-1 tablet in Type 2 diabetes in fasting and postprandial conditions. Diabetes Care (1997) 20: 1874-1879.
  • BUCKLEY DI, LUNDQUIST P: Analysis of the degradation of insulinotropin [GLP-1 (7–37)] in human plasma and production of degradation resistant analogs. Regal. Pept (1992) 40:117 (Abstract).
  • 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. Eur. Biochein. (1993) 214:829–835.
  • ••A kinetic study indicating that DPP IV inplasma can cleave GLP-1.
  • DEACON CE JOHNSEN AH, JJ: Degradation of glucagon-like peptide-1 by human plasma in vitroyields an N-terminally truncated peptide which is a major endogenous metabolite in vivo.. Endocrinol Metab. (1995) 80:952–957.
  • DEACON CE NAUCK MA, TOFT-NIELSEN M-B, PRIDAL L, WILLMS B, HOLST JJ: Both subcutaneously and intravenously administered glucagon-like peptide-1 are rapidly degraded from the amino-acid terminus in Type 2 diabetic patients and in healthy subjects. Diabetes (1995) 44:1126–1131.
  • ••Demonstration that GLP-1 is degraded byDPP IV in humans, leading to the first suggestion that DPP IV inhibition may be therapeutically useful.
  • KIEFFER TJ, McINTOSH CHS, PEDERSON RA: Degradation of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide 1 (tGLP-1) M vitro and in vivo by dipeptidyl peptidase IV. Endocrinology (1995) 136:3585–3596.
  • DEACON CE DANIELSEN P, KLARSKOV L, OLESEN M, HOLST Dipeptidyl peptidase IV inhibition reduces the degradation, and clearance of GIP, and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs. Diabetes (2001) 50:1588–1597.
  • DEACON CE HUGHES TE, HOLST JJ: Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide-1 in anesthetized pigs. Diabetes (1998) 47:764–769.
  • ••Demonstration that DPP IV inhibitionin vivo is capable of preventing GLP-1 degradation.
  • MARGUET D, BAGGIO L, T et al.: Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc. Natl Acad. Sd. USA (2000) 97:6874–6879.
  • DEACON CE WAMBERG S, BIE P, HUGHES TE, HOLST JJ: Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. (2002) 172:355–362.
  • HOLST JJ, DEACON CF: Inhibition of the activity of dipeptidyl peptidase IV as a treatment for Type 2 diabetes. Diabetes (1998) 47: 1663-1670.
  • WEIR GC, MOJSOV S, HENDRICK GK,HABENERJF: Glucagonlike peptide I (7-37) actions on endocrine pancreas. Diabetes (1989) 38:338–342.
  • NAGAKURA T, YASUDA N, YAMAZAKI K et al.: Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IV-deficient Fischer rats. Biochem. Biophys. Res. Commun. (2001) 284:501–506.
  • PEDERSON RA, WHITE HA, SCHLENZIG D, PAULY RP, MCINTOSH CH, DEMUTH HU: Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes (1998) 47:1253–1258.
  • •Demonstration that DPP IV inhibition in vivo is capable of improving glucose tolerance in rodents.
  • BALKAN B, KWASNIK L, R, HOLST JJ, 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.
  • AHREN B, HOLST JJ, H, BALKAN B: Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Pim j Pharmacol. (2000) 404:239–245.
  • POSPISILIK JA, STAFFORD SG, DEMUTH HU et al.: Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/09 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia and I3-cell responsiveness in VDF (fa/fa) Zucker rats. Diabetes (2002) 51:943–950.
  • ••First demonstration that chronic DPP IVinhibition improves glucose tolerance in diabetic rodents.
  • SUDRE B, BROQUA P, WHITE RB et al.:Chronic Inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male Zucker diabetic fatty rats. Diabetes (2002) 51:1461–1469.
  • POSPISILIK JA, STAFFORD SG, DEMUTH HU, McINTOSH CH, PEDERSON RA: Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a-hyperinsulinemic clamp study. (2002) 51:2677–2683.
  • POSPISILIK JA, MARTIN J, DOTY T et al.: Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes (2003) 52:741–750.
  • REIMER MK, HOLST JJ, AHREN B: Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Ear. J. Endocrinol (2002) 146:717–727.
  • AHREN B, GOMIS R, STANDL E, MILLS D, SCHWEIZER A: Prolonged efficacy of LAF237 in patients with Type 2 diabetes (T2DM) inadequately controlled with metformin. 64th Scientific Sessions of the American Diabetes Association. Orlando, USA (2004) Late-breaking 7-LB (Abstract).
  • CONARELLO SL, LI Z, RONAN J et al: Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Natl Acad. Sci. USA (2003) 100:6825–6830.
  • YASUDA N, NAGAKURA T, YAMAZAKI K, INOUE T, TANAKA I: Improvement of high fat-diet-induced insulin resistance in dipeptidyl IV-deficient Fischer rats. Life ScL (2002) 71:227–238.
  • PRATLEY R, GALBREATH E: Twelve-week monotherapy with the DPP-4 inhibitor, LAF237 improves glycemic control in patients with Type 2 diabetes (T2DM). Diabetes (2004) 53\(Suppl. 2):A83, 355-OR (Abstract).
  • AHREN B, GOMIS R, MILLS D, SCHWEIZER A: The DPP-4 inhibitor, LAF237, improves glycemic control in patients with Type 2 diabetes (T2DM) inadequately treated with metformin. Diabetes (2004) 53\(Suppl. 2):A83, 354-OR (Abstract).
  • FESTA A, D'AGOSTINO R Jr, HANLEY AJ, KARTER AJ, SAAD ME HAFFNER SM: Differences in insulin resistance in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose. Diabetes (2004) 53:1549–1555.
  • CHIASSON JL, JOSSE RG, GOMIS R, HANEFELD M, KARASIK A, M: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA (2003) 290:486–494.
  • LAMBEIR A-M, DURINX C, S, DE MEESTER I: Dipeptidyl-peptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPPIV. Crit. Rev Clin. Lab. Sci. (2003) 40:209–294.
  • •A good review of DPP IV.
  • ABBOTT CA, YU DM, WOOLLATT E, SUTHERLAND GR, GW, GORRELL MD: Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur. Biotbem. (2000) 267:6140–6150.
  • OLSEN C, WAGTMANN N: Identification and characterization of human DPP9, a novel homologue of dipeptidyl peptidase IV. Gene (2002) 299:185–193.
  • LETTING B, NICHOLS E, BIFTU T et al.: Inhibition of dipeptidyl peptidase IV does not attenuate T cell activation in vitro. Diabetes (2004) 53\(Suppl. 2):A2, 6-OR (Abstract).
  • LANKAS G, LETTING B, ROY RS et al: 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, 7-OR (Abstract).
  • MENTLEIN R: Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept. (1999) 85:9–24.
  • AHREN B: Autonomic regulation of islet hormone secretion. Implications for health and disease. Diabetologia (2000) 43:393–410.
  • LAMBEIR AM, DURINX C, PROOST P, VAN DAMME J, SCHARPE S, DE MEESTER I: Kinetic study of the processing by dipeptidyl-peptidase IV/ CD26 of neuropeptides involved in pancreatic insulin secretion. FEBS Lett. (2001) 507:327–330.
  • 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 activarting polypeptide-1(1–38).. (2003) 278:22418–22423.
  • FILIPSSON K, REIMER MK, AHREN B: The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function. Diabetes (2001) 50:1959–1969.
  • SCHAFER H, ZHENGJ, GUNDLACH F et al.: Pituitary adenylate-cyclase-activating polypeptide stimulates protooncogene expression and activates the AP-1 (c-Fos/c-Jun) transcription factor in ARA-2J pancreatic carcinoma cells. Eur. Biotbem. (1996) 242:467–476.
  • HASHIMOTO H, KUNUGI A, ARAKAWA N et al: Possible involvement of a cyclic AMP-dependent mechanism in PACAP-induced proliferation and ERK activation in astrocytes. Biotbem. Biophys. Res. Commun. (2003) 311:337–343.
  • DIETRICH JB: Neuropeptides, antagonistsand cell proliferation: bombesin as an example. Cell MM. Biol. (1994) 40:731–746.
  • BHAVE SV, HOFFMAN PL: Phosphatidylinositol 3 "-OH kinase and protein kinase A pathways mediate the anti-apoptotic effect of pituitary adenylyl cyclase-activating polypeptide in cultured cerebellar granule neurons: modulation by ethanol. Neurotbem. (2004) 88:359–369.
  • YAMAMOTO K, HASHIMOTO H, TOMIMOTO S et al.: Overexrpession of PACAP in transgenic mouse pancreatic I3-cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes. Diabetes (2003) 82:1155–1162.
  • YADA T, SAKURADA M, FILIPSSON K, KIKUCHI M, AHREN B: Intraperitoneal PACAP administration decreases blood glucose in GK rats, and in normal and high-fat diet mice. Ann. NY Acad. Sci. (2000) 921:259–263.
  • MADSBAD S, SCHMITZ 0, RANSTAM J, JAKOBSEN G, MATTHEWS DR: 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.
  • FINEMAN MS, BICSAK TA, SHEN LZ et al.: 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.
  • DEFRONZO R, RATNER R, HAN J, KIM D, FINEMAN M, BARON A: Effects of exenatide (synthetic exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with Type 2 diabetes. 64th Scientific Sessions of the Diabetes Association. Orlando, USA (2004) Late-breaking 6-LB (Abstract).
  • NAUCK MA, HOMPESCH M, FILIPCZAK R et al.: Liraglutide significantly improves glycemic control and reduces body weight compared with glimepiride as add-on to metformin in Type 2 diabetes. Diabetes (2004) 53\(Suppl. 2):A83, 356-OR (Abstract).
  • HANSOTIA T, BAGGIO LL, 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.
  • NAGAKURA T, YASUDA N, YAMAZAKI K, IKUTA H, TANAKA I: Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition. Metabolism (2003) 52:81–86.
  • YASUDA N, INOUE T, NAGAKURA T et al.: 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. Pliarmacol Exp.Ther. (2004) 310(2):614–619.
  • TAKASAKI K, NAKAJIMA T, UENO K, NOMOTO Y, HIGO K: Effects of combination treatment with dipeptidyl peptidase IV inhibitor and sulfonylurea on glucose levels in rats. J. Pliarmacol. (2004) 95:291–293.
  • BURKEY BE LI X, BOLOGNESE L et al: Combination treatment of a DPP-IV inhibitor NVP-LAF237 with pioglitazone completely normalized glucose tolerance in adult obese Zucker rats. Diabetes (2002) 51 (Suppl. 2):A338 (Abstract).
  • WEBER A, KIM D, BECONI M et al: MK-0431 is a potent, selective dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes. Diabetes (2004) 53\(Suppl. 2): A151, 633-P (Abstract).
  • LI Y, HANSOTIA T, YUSTA B, RIS F, HALBAN PA, DRUCKER DJ: Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. Biol. Chem. (2003) 278:471–478.
  • BOSE AK, MOCANU MM, KN, BRAND CL, CARR RD, YELLON DM: GLP-1 protects ischemic and reperfused myocardium via PI3 kinase and p42/p44 MAPK signalling pathways. Diabetes (2004) 53 (Suppl. 2):A1, 2-OR (Abstract).
  • VILSBOLL T, KRARUP T, DEACON CF, MADSBAD S, HOLST JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in Type 2 diabetic patients. Diabetes (2001) 50:609–613.
  • MEIER JJ, NAUCK MA, KRANZ D et al:Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes (2004) 53:654–662.
  • HERMAN GA, ZHAO P-L, B et al.: The DP-IV inhibitor MK-0431 enhances active GLP-1 and reduces glucose following an OGTT in Type 2 diabetics. Diabetes (2004) 53\(Suppl. 2):A82, 353-OR (Abstract).
  • LARSEN MO, ROLIN B, RIBEL U et al:Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass. Exp. Diabesig Res. (2003) 4:93–105.
  • NAUCK MA, HEIMESAAT MM, ORSKOV C, HOLST JJ, EBERT R, CREUTZFELDT W: Preserved incretin activity of glucagon-like peptide 1 (7-36 amide) but not of synthetic human gastric inhibitory polypeptide in patients with Type II diabetes mellitus. J. Gin. Invest. (1993) 91:301–307.
  • ELAHI D, MCALOON-DYKE M, FUKAGAWA NK et al.: The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. (1994) 51:63–74.
  • MENEILLY GS, BRYER-ASH M, ELAHI D: The effect of glyburide on 13-cell sensitivity to glucose-dependent insulinotropic polypeptide. Diabetes Care (1993) 16:110–114.
  • LYNN FC, PAMIR N, NG EH, MCINTOSH CH, KIEFFER TJ, PEDERSON RA: Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes (2001) 50:1004–1011.
  • LYNN FC, THOMPSON SA, JA et al.: A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor in beta cells. EASEB J. (2003) 17:91–93.
  • TANAKA S, MURAKAMI T, N, OHNUKI T, YAMADA M, SUGITA T: Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225. Immunopharmacology (1998) 40:21–26.
  • WILLIAMS YN, BABA H, HAYASHI S et al.: Dipeptidyl peptidase IV on activated T cells as a target molecule for therapy of rheumatoid arthritis. Clin. Exp. Immunol (2003) 131:68–74.
  • JONES B, ADAMS S, MILLER GT, JESSON MI, WATANABE T, BP: Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. Blood (2003) 102:1641–1648.
  • KOROM S, DE MEESTER I, STADLBAUER TH et al.: Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients. Transplantation (1997) 63:1495–1500.
  • STEINBRECHER A, REINHOLD D, QUIGLEY L et al.: Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo. (2001) 166:2041-2048.
  • RASMUSSEN H B, BRANNER S, WIBERG FC, WAGTMANN N: Crystal structure of human dipeptidyl peptidase IV/ CD26 in complex with a substrate analog. Nat. Smuct. Biol. (2003) 10:19–25.
  • •First description of the crystal structure of human DPP IV.
  • OEFNER C, D'ARCY A, A, PIERAU S, GARDINER R, DALE GE: High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1- [([2- [(5-iodopyridin-2-yl)amino]-ethyl[amino)-acetyl[-2-cyano-(5)-pyrrolidine. Acta. Crystallogr. D. Biol. Crystallogr. (2003) 59:1206–1212.
  • THOMA R, LOFFLER B, STIHLE M, HUBER W, RUF A, HENNIG M: Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure (2003) 1:947–959.
  • HUPE-SODMANN K, McGREGOR GP, BRIDENBAUGH R et at 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. Regal. Pept. (1995) 58:149–156.
  • GEE NS, BOWES MA, BUCK P, KENNY AJ: An immunoradiometric assay for endopeptidase-24.11 shows it to be a widely distributed enzyme in pig tissues. Biochem. J. (1985) 228:119–126.
  • PLAMBOECK A, HOLST JJ, CARR RD, DEACON CF: Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both involved in regulating the metabolic stability of glucagon-like peptide-1 in vivo. Adv. Exp. Med. Biol. (2002) 524:303–312.
  • OEFNER C, PIERAU S, DALE GE: Ectopeptidases and Type II diabetes. 11th Protein Structure Determination in Industry Cambridge, UK (2003) T001 (Abstract).
  • ZHANG BB, WOODS JVV,LI Z et al: Chronic inhibition of dipeptidyl peptidase IV increases pancreatic beta cell mass in a murine model of Type 2 diabetes. 64th Scientific Sessions of the American Diabetes Association. Orlando, USA (2004) Late-breaking 58-LB (Abstract).
  • STOCKEL-MASCHEK A,-KLAUS C, STIEBITZ B, DEMUTH HU, NEUBERT K: Thioxo aminoacid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases. Biochim Biophys Acta (2000) 1479:15–31.
  • VILLHAUER EB, BRINKMAN JA, NADERI GB et al.:1- [[(3-hydroxy4-adamanty0amino]acetyl[-2-cyano-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. (2003) 46:2774–2789.

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