DPP4 in diabetes

Frontiers in Immunology

Volumn 6, Issue JUL, 2015, Pages

  Röhrborn, Diana ^a   Wronkowitz, Nina ^a   Eckel, Juergen ^a  

^a LEIBNIZ CENTER FOR DIABETES RESEARCH AT HEINRICH HEINE UNIVERSITY DÜSSELDORF   (Germany)

Author keywords

CD26 DPP4; DPP4 inhibitors gliptins; Incretins; Multifunctional enzyme; Soluble DPP4; Type 2 diabetes mellitus

Indexed keywords

ADENOSINE; BRAIN NATRIURETIC PEPTIDE; CAVEOLIN 1; CD45 ANTIGEN; DIPEPTIDYL PEPTIDASE IV; EPIDERMAL GROWTH FACTOR RECEPTOR; GASTRIC INHIBITORY POLYPEPTIDE; GLUCAGON LIKE PEPTIDE 1; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INCRETIN; INTERLEUKIN 12; METALLOPROTEINASE; NEUROPEPTIDE Y; PEPTIDE YY; STROMAL CELL DERIVED FACTOR 1; STROMAL CELL DERIVED FACTOR 1ALPHA; SUBSTANCE P; TRANSCRIPTION FACTOR AP 1; TRANSCRIPTION FACTOR SP; UNCOUPLING PROTEIN 1;

ADIPOSE TISSUE; CARDIOVASCULAR SYSTEM; CELL FUNCTION; DIABETES MELLITUS; DYSLIPIDEMIA; ENZYME ACTIVITY; GENE SEQUENCE; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; HUMAN; HYDROPHOBICITY; IMMUNE RESPONSE; INFLAMMATION; INSULIN SENSITIVITY; LIVER DISEASE; LIVER FUNCTION; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PANCREAS ISLET; PROTEIN EXPRESSION; REVIEW; UPREGULATION;

EID: 84938537260     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00386     Document Type: Review

References (209)

1. Hopsu-Havu VK, Glenner GG. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemie (1966) 7(3):197-201. doi:10.1007/BF00577838
2. Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci (2003) 40(3):209-94. doi:10.1080/713609354
3. Rohrborn D, Eckel J, Sell H. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett (2014) 588(21):3870-7. doi:10.1016/j.febslet.2014.08.029
4. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes (2011) 60(7):1917-25. doi:10.2337/db10-1707
5. Sell H, Bluher M, Kloting N, Schlich R, Willems M, Ruppe F, et al. Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care (2013) 36(12):4083-90. doi:10.2337/dc13-0496
6. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev (2014) 35(6):992-1019. doi:10.1210/er.2014-1035
7. Cordero OJ, Salgado FJ, Nogueira M. On the origin of serum CD26 and its altered concentration in cancer patients. Cancer Immunol Immunother (2009) 58(11):1723-47. doi:10.1007/s00262-009-0728-1
8. Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy-focus on alogliptin. Drug Des Devel Ther (2013) 7:989-1001. doi:10.2147/DDDT.S37647
9. Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother (2012) 13(1):81-99. doi:10.1517/14656566.2012.642866
10. Nabeno M, Akahoshi F, Kishida H, Miyaguchi I, Tanaka Y, Ishii S, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun (2013) 434(2):191-6. doi:10.1016/j.bbrc.2013.03.010
11. Chung KM, Huang CH, Cheng JH, Tsai CH, Suen CS, Hwang MJ, et al. Proline in transmembrane domain of type II protein DPP-IV governs its translocation behavior through endoplasmic reticulum. Biochemistry (2011) 50(37):7909-18. doi:10.1021/bi200605h
12. Abbott CA, McCaughan GW, Gorrell MD. Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity. FEBS Lett (1999) 458(3):278-84. doi:10.1016/S0014-5793(99)01166-7
13. Fan H, Meng W, Kilian C, Grams S, Reutter W. Domain-specific N-glycosylation of the membrane glycoprotein dipeptidylpeptidase IV (CD26) influences its subcellular trafficking, biological stability, enzyme activity and protein folding. Eur J Biochem (1997) 246(1):243-51. doi:10.1111/j.1432-1033.1997.00243.x
14. Smith RE, Talhouk JW, Brown EE, Edgar SE. The significance of hypersialylation of dipeptidyl peptidase IV (CD26) in the inhibition of its activity by Tat and other cationic peptides. CD26: a subverted adhesion molecule for HIV peptide binding. AIDS Res Hum Retroviruses (1998) 14(10):851-68. doi:10.1089/aid.1998.14.851
15. Chien CH, Huang LH, Chou CY, Chen YS, Han YS, Chang GG, et al. One site mutation disrupts dimer formation in human DPP-IV proteins. J Biol Chem (2004) 279(50):52338-45. doi:10.1074/jbc.M406185200
16. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A (1994) 91(12):5657-61. doi:10.1073/pnas.91.12.5657
17. Ghersi G, Dong H, Goldstein LA, Yeh Y, Hakkinen L, Larjava HS, et al. Seprase-dPPIV association and prolyl peptidase and gelatinase activities of the protease complex. Adv Exp Med Biol (2003) 524:87-94. doi:10.1007/0-306-47920-6_11
18. Bohm SK, Gum JR Jr, Erickson RH, Hicks JW, Kim YS. Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem J (1995) 311(Pt 3):835-43.
19. Bauvois B, Djavaheri-Mergny M, Rouillard D, Dumont J, Wietzerbin J. Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells. Oncogene (2000) 19(2):265-72. doi:10.1038/sj.onc.1203292
20. Mattern T, Reich C, Duchrow M, Ansorge S, Ulmer AJ, Flad HD. Antibody-induced modulation of CD26 surface expression. Immunology (1995) 84(4):595-600.
21. Cordero OJ, Salgado FJ, Vinuela JE, Nogueira M. Interleukin-12 enhances CD26 expression and dipeptidyl peptidase IV function on human activated lymphocytes. Immunobiology (1997) 197(5):522-33. doi:10.1016/S0171-2985(97)80084-8
22. Salgado FJ, Vela E, Martin M, Franco R, Nogueira M, Cordero OJ. Mechanisms of CD26/dipeptidyl peptidase IV cytokine-dependent regulation on human activated lymphocytes. Cytokine (2000) 12(7):1136-41. doi:10.1006/cyto.1999.0643
23. Gu N, Tsuda M, Matsunaga T, Adachi T, Yasuda K, Ishihara A, et al. Glucose regulation of dipeptidyl peptidase IV gene expression is mediated by hepatocyte nuclear factor-1alpha in epithelial intestinal cells. Clin Exp Pharmacol Physiol (2008) 35(12):1433-9. doi:10.1111/j.1440-1681.2008.05015.x
24. Morrison ME, Vijayasaradhi S, Engelstein D, Albino AP, Houghton AN. A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med (1993) 177(4):1135-43. doi:10.1084/jem.177.4.1135
25. Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, et al. The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci U S A (2003) 100(9):5063-8. doi:10.1073/pnas.0230620100
26. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci (Lond) (2005) 108(4):277-92. doi:10.1042/CS20040302
27. Yu DM, Slaitini L, Gysbers V, Riekhoff AG, Kahne T, Knott HM, et al. Soluble CD26/dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding. Scand J Immunol (2011) 73(2):102-11. doi:10.1111/j.1365-3083.2010.02488.x
28. Zhong J, Rao X, Deiuliis J, Braunstein Z, Narula V, Hazey J, et al. A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes (2013) 62(1):149-57. doi:10.2337/db12-0230
29. Belle LP, Bitencourt PE, De Bona KS, Moresco RN, Moretto MB. Association between HbA1c and dipeptidyl peptidase IV activity in type 2 diabetes mellitus. Clin Chim Acta (2012) 413(11-12):1020-1. doi:10.1016/j.cca.2012.02.021
30. Ciaraldi TP. The role of adenosine in insulin action coupling in rat adipocytes. Mol Cell Endocrinol (1988) 60(1):31-41. doi:10.1016/0303-7207(88)90117-7
31. Heseltine L, Webster JM, Taylor R. Adenosine effects upon insulin action on lipolysis and glucose transport in human adipocytes. Mol Cell Biochem (1995) 144(2):147-51. doi:10.1007/BF00944394
32. Lee JG, Kang DG, Yu JR, Kim Y, Kim J, Koh G, et al. Changes in adenosine deaminase activity in patients with type 2 diabetes mellitus and effect of DPP-4 inhibitor treatment on ADA activity. Diabetes Metab J (2011) 35(2):149-58. doi:10.4093/dmj.2011.35.2.149
33. Ohnuma K, Yamochi T, Uchiyama M, Nishibashi K, Yoshikawa N, Shimizu N, et al. CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Proc Natl Acad Sci U S A (2004) 101(39):14186-91. doi:10.1073/pnas.0405266101
34. Loster K, Zeilinger K, Schuppan D, Reutter W. The cysteine-rich region of dipeptidyl peptidase IV (CD 26) is the collagen-binding site. Biochem Biophys Res Commun (1995) 217(1):341-8. doi:10.1006/bbrc.1995.2782
35. Cheng HC, Abdel-Ghany M, Pauli BU. A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J Biol Chem (2003) 278(27):24600-7. doi:10.1074/jbc.M303424200
36. Piazza GA, Callanan HM, Mowery J, Hixson DC. Evidence for a role of dipeptidyl peptidase IV in fibronectin-mediated interactions of hepatocytes with extracellular matrix. Biochem J (1989) 262(1):327-34.
37. Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S, Chen WT. The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res (2006) 66(9):4652-61. doi:10.1158/0008-5472.CAN-05-1245
38. Ikushima H, Munakata Y, Ishii T, Iwata S, Terashima M, Tanaka H, et al. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci U S A (2000) 97(15):8439-44. doi:10.1073/pnas.97.15.8439
39. Wronkowitz N, Gorgens SW, Romacho T, Villalobos LA, Sanchez-Ferrer CF, Peiro C, et al. Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta (2014) 1842(9):1613-21. doi:10.1016/j.bbadis.2014.06.004
40. Bouchard L, Faucher G, Tchernof A, Deshaies Y, Lebel S, Hould FS, et al. Comprehensive genetic analysis of the dipeptidyl peptidase-4 gene and cardiovascular disease risk factors in obese individuals. Acta Diabetol (2009) 46(1):13-21. doi:10.1007/s00592-008-0049-4
41. Turcot V, Bouchard L, Faucher G, Tchernof A, Deshaies Y, Perusse L, et al. DPP4 gene DNA methylation in the omentum is associated with its gene expression and plasma lipid profile in severe obesity. Obesity (Silver Spring) (2011) 19(2):388-95. doi:10.1038/oby.2010.198
42. Turcot V, Tchernof A, Deshaies Y, Perusse L, Belisle A, Marceau P, et al. Comparison of the dipeptidyl peptidase-4 gene methylation levels between severely obese subjects with and without the metabolic syndrome. Diabetol Metab Syndr (2013) 5(1):4-5. doi:10.1186/1758-5996-5-4
43. Aghili N, Devaney JM, Alderman LO, Zukowska Z, Epstein SE, Burnett MS. Polymorphisms in dipeptidyl peptidase IV gene are associated with the risk of myocardial infarction in patients with atherosclerosis. Neuropeptides (2012) 46(6):367-71. doi:10.1016/j.npep.2012.10.001
44. Bailey SD, Xie C, Pare G, Montpetit A, Mohan V, Yusuf S, et al. Variation at the DPP4 locus influences apolipoprotein B levels in South Asians and exhibits heterogeneity in Europeans related to BMI. Diabetologia (2014) 57(4):738-45. doi:10.1007/s00125-013-3142-3
45. Yasuda N, Nagakura T, Yamazaki K, Inoue T, Tanaka I. Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats. Life Sci (2002) 71(2):227-38. doi:10.1016/S0024-3205(02)01637-5
46. Frerker N, Raber K, Bode F, Skripuletz T, Nave H, Klemann C, et al. Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions. Clin Chem Lab Med (2009) 47(3):275-87. doi:10.1515/CCLM.2009.064
47. Ben-Shlomo S, Zvibel I, Varol C, Spektor L, Shlomai A, Santo EM, et al. Role of glucose-dependent insulinotropic polypeptide in adipose tissue inflammation of dipeptidylpeptidase 4-deficient rats. Obesity (Silver Spring) (2013) 21(11):2331-41. doi:10.1002/oby.20340
48. Ben-Shlomo S, Zvibel I, Rabinowich L, Goldiner I, Shlomai A, Santo EM, et al. Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis. Dig Dis Sci (2013) 58(1):172-8. doi:10.1007/s10620-012-2353-7
49. Karl T, Hoffmann T, Pabst R, von Hörsten S. Extreme reduction of dipeptidyl peptidase IV activity in F344 rat substrains is associated with various behavioral differences. Physiol Behav (2003) 80(1):123-34. doi:10.1016/S0031-9384(03)00229-4
50. Stephan M, Radicke A, Leutloff S, Schmiedl A, Pabst R, von HS, et al. Dipeptidyl peptidase IV (DPP4)-deficiency attenuates diet-induced obesity in rats: possible implications for the hypothalamic neuropeptidergic system. Behav Brain Res (2011) 216(2):712-8. doi:10.1016/j.bbr.2010.09.024
51. Canneva F, Golub Y, Distler J, Dobner J, Meyer S, von HS. DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY. Psychoneuroendocrinology (2015) 53:195-206. doi:10.1016/j.psyneuen.2015.01.007
52. Kirino Y, Sato Y, Kamimoto T, Kawazoe K, Minakuchi K, Nakahori Y. Interrelationship of dipeptidyl peptidase IV (DPP4) with the development of diabetes, dyslipidaemia and nephropathy: a streptozotocin-induced model using wild-type and DPP4-deficient rats. J Endocrinol (2009) 200(1):53-61. doi:10.1677/JOE-08-0424
53. Sato Y, Koshioka S, Kirino Y, Kamimoto T, Kawazoe K, Abe S, et al. Role of dipeptidyl peptidase IV (DPP4) in the development of dyslipidemia: DPP4 contributes to the steroid metabolism pathway. Life Sci (2011) 88(1-2):43-9. doi:10.1016/j.lfs.2010.10.019
54. Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci U S A (2000) 97(12):6874-9. doi:10.1073/pnas.120069197
55. Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci U S A (2003) 100(11):6825-30. doi:10.1073/pnas.0631828100
56. Yan S, Marguet D, Dobers J, Reutter W, Fan H. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol (2003) 33(6):1519-27. doi:10.1002/eji.200323469
57. Romacho T, Indrakusuma I, Rohrborn D, Castaneda TR, Jelenik T, Weiss J, et al. Adipose-tissue specific deletion of dipeptidyl peptidase 4 (DPP4) enhances M2 macrophage markers and results in smaller adipocytes under HFD. Diabetes (2015) 64(Suppl 1):A531.
58. Sell H, Rohrborn D, Indrakusuma I, Jelenik T, Castaneda TR, Al-Hasani H, et al. Adipose-specific dipeptidyl peptidase 4 (DPP4) knockout mice display improved fasting insulin and cholesterol levels despite increased weight gain on HFD. Diabetes (2015) 64(Suppl 1):A548.
59. Engel M, Hoffmann T, Manhart S, Heiser U, Chambre S, Huber R, et al. Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV. J Mol Biol (2006) 355(4):768-83. doi:10.1016/j.jmb.2005.11.014
60. Longenecker KL, Stewart KD, Madar DJ, Jakob CG, Fry EH, Wilk S, et al. Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors. Biochemistry (2006) 45(24):7474-82. doi:10.1021/bi060184f
61. Hoffmann T, Faust J, Neubert K, Ansorge S. Dipeptidyl peptidase IV (CD 26) and aminopeptidase N (CD 13) catalyzed hydrolysis of cytokines and peptides with N-terminal cytokine sequences. FEBS Lett (1993) 336(1):61-4. doi:10.1016/0014-5793(93)81609-4
62. Lambeir AM, Proost P, Durinx C, Bal G, Senten K, Augustyns K, et al. Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J Biol Chem (2001) 276(32):29839-45. doi:10.1074/jbc.M103106200
63. van BL, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol (2014) 221(1):T1-16. doi:10.1530/JOE-13-0414
64. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care (2003) 26(10):2929-40. doi:10.2337/diacare.26.10.2929
65. Rask E, Olsson T, Soderberg S, Holst JJ, Tura A, Pacini G, et al. Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance. Metabolism (2004) 53(5):624-31. doi:10.1016/j.metabol.2003.11.011
66. 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(3):609-13. doi:10.2337/diabetes.50.3.609
67. Gautier JF, Fetita S, Sobngwi E, Salaun-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab (2005) 31(3 Pt 1):233-42. doi:10.1016/S1262-3636(07)70190-8
68. Wang W, Choi BK, Li W, Lao Z, Lee AY, Souza SC, et al. Quantification of intact and truncated stromal cell-derived factor-1alpha in circulation by immunoaffinity enrichment and tandem mass spectrometry. J Am Soc Mass Spectrom (2014) 25(4):614-25. doi:10.1007/s13361-013-0822-7
69. Busso N, Wagtmann N, Herling C, Chobaz-Peclat V, Bischof-Delaloye A, So A, et al. Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol (2005) 166(2):433-42. doi:10.1016/S0002-9440(10)62266-3
70. Tariq M, Masoud MS, Mehmood A, Khan SN, Riazuddin S. Stromal cell derived factor-1alpha protects stem cell derived insulin-producing cells from glucotoxicity under high glucose conditions in-vitro and ameliorates drug induced diabetes in rats. J Transl Med (2013) 11:115. doi:10.1186/1479-5876-11-115
71. Yano T, Liu Z, Donovan J, Thomas MK, Habener JF. Stromal cell derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes (2007) 56(12):2946-57. doi:10.2337/db07-0291
72. Humpert PM, Battista MJ, Lammert A, Reismann P, Djuric Z, Rudofsky G Jr, et al. Association of stromal cell-derived factor 1 genotype with diabetic foot syndrome and macrovascular disease in patients with type 2 diabetes. Clin Chem (2006) 52(6):1206-8. doi:10.1373/clinchem.2005.065482
73. Karimabad MN, Hassanshahi G. Significance of CXCL12 in type 2 diabetes mellitus and its associated complications. Inflammation (2015) 38(2):710-7. doi:10.1007/s10753-014-9981-3
74. Persaud SJ, Bewick GA. Peptide YY: more than just an appetite regulator. Diabetologia (2014) 57(9):1762-9. doi:10.1007/s00125-014-3292-y
75. Whim MD. Pancreatic beta cells synthesize neuropeptide Y and can rapidly release peptide co-transmitters. PLoS One (2011) 6(4):e19478. doi:10.1371/journal.pone.0019478
76. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, et al. DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabetes Obes Metab (2009) 11(4):285-92. doi:10.1111/j.1463-1326.2008.00909.x
77. Rosmaninho-Salgado J, Marques AP, Estrada M, Santana M, Cortez V, Grouzmann E, et al. Dipeptidyl-peptidase-IV by cleaving neuropeptide Y induces lipid accumulation and PPAR-gamma expression. Peptides (2012) 37(1):49-54. doi:10.1016/j.peptides.2012.06.014
78. Ahmad S, Wang L, Ward PE. Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo. J Pharmacol Exp Ther (1992) 260(3):1257-61.
79. Wang LH, Zhou SX, Li RC, Zheng LR, Zhu JH, Hu SJ, et al. Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. J Int Med Res (2012) 40(1):134-40. doi:10.1177/147323001204000114
80. Fu J, Liu B, Liu P, Liu L, Li G, Wu B, et al. Substance P is associated with the development of obesity, chronic inflammation and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes (2011) 119(3):177-81. doi:10.1055/s-0030-1261965
81. Karagiannides I, Bakirtzi K, Kokkotou E, Stavrakis D, Margolis KG, Thomou T, et al. Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. Endocrinology (2011) 152(12):4571-80. doi:10.1210/en.2011-1170
82. Yang L, Di G, Qi X, Qu M, Wang Y, Duan H, et al. Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes (2014) 63(12):4262-74. doi:10.2337/db14-0163
83. Brandt I, Lambeir AM, Ketelslegers JM, Vanderheyden M, Scharpe S, De M I. Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form. Clin Chem (2006) 52(1):82-7. doi:10.1373/clinchem.2005.057638
84. dos SL, Salles TA, Arruda-Junior DF, Campos LC, Pereira AC, Barreto AL, et al. Circulating dipeptidyl peptidase IV activity correlates with cardiac dysfunction in human and experimental heart failure. Circ Heart Fail (2013) 6(5):1029-38. doi:10.1161/CIRCHEARTFAILURE.112.000057
85. 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(6):1349-58. doi:10.1016/j.peptides.2005.11.010
86. Yada T, Nakata M, Shioda S. Insulinotropin PACAP potentiates insulin action. Stimulation of glucose uptake in 3T3-LI adipocytes. Ann N Y Acad Sci (2000) 921:473-7. doi:10.1111/j.1749-6632.2000.tb07018.x
87. Akesson L, Ahren B, Manganiello VC, Holst LS, Edgren G, Degerman E. Dual effects of pituitary adenylate cyclase-activating polypeptide and isoproterenol on lipid metabolism and signaling in primary rat adipocytes. Endocrinology (2003) 144(12):5293-9. doi:10.1210/en.2003-0364
88. Ahren B, Hughes TE. Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice. Endocrinology (2005) 146(4):2055-9. doi:10.1210/en.2004-1174
89. Mentlein R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept (1999) 85(1):9-24. doi:10.1016/S0167-0115(99)00089-0
90. Dworacka M, Krzyzagorska E, Iskakova S, Bekmukhambetov Y, Urazayev O, Dworacki G. Increased circulating RANTES in type 2 diabetes. Eur Cytokine Netw (2014) 25(3):46-51. doi:10.1684/ecn.2014.0355
91. Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes (2012) 61(7):1680-90. doi:10.2337/db11-1506
92. Baturcam E, Abubaker J, Tiss A, Abu-Farha M, Khadir A, Al-Ghimlas F, et al. Physical exercise reduces the expression of RANTES and its CCR5 receptor in the adipose tissue of obese humans. Mediators Inflamm (2014) 2014:627150. doi:10.1155/2014/627150
93. Pais R, Zietek T, Hauner H, Daniel H, Skurk T. RANTES (CCL5) reduces glucose-dependent secretion of glucagon-like peptides 1 and 2 and impairs glucose-induced insulin secretion in mice. Am J Physiol Gastrointest Liver Physiol (2014) 307(3):G330-7. doi:10.1152/ajpgi.00329.2013
94. Forssmann U, Stoetzer C, Stephan M, Kruschinski C, Skripuletz T, Schade J, et al. Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils in vivo. J Immunol (2008) 181(2):1120-7. doi:10.4049/jimmunol.181.2.1120
95. Herder C, Haastert B, Muller-Scholze S, Koenig W, Thorand B, Holle R, et al. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes (2005) 54(Suppl 2):S11-7. doi:10.2337/diabetes.54.suppl_2.S11
96. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs (2011) 71(11):1441-67. doi:10.2165/11591400-000000000-00000
97. Morishita R, Nakagami H. Teneligliptin: expectations for its pleiotropic action. Expert Opin Pharmacother (2015) 16(3):417-26. doi:10.1517/14656566.2015.1000301
98. Makdissi A, Ghanim H, Vora M, Green K, Abuaysheh S, Chaudhuri A, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab (2012) 97(9):3333-41. doi:10.1210/jc.2012-1544
99. Dobrian AD, Ma Q, Lindsay JW, Leone KA, Ma K, Coben J, et al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab (2011) 300(2):E410-21. doi:10.1152/ajpendo.00463.2010
100. Ommen ES, Xu L, O'Neill EA, Goldstein BJ, Kaufman KD, Engel SS. Comparison of treatment with sitagliptin or sulfonylurea in patients with type 2 diabetes mellitus and mild renal impairment: a post hoc analysis of clinical trials. Diabetes Ther (2015) 6(1):29-40. doi:10.1007/s13300-015-0098-y
101. Nishio S, Abe M, Ito H. Anagliptin in the treatment of type 2 diabetes: safety, efficacy, and patient acceptability. Diabetes Metab Syndr Obes (2015) 8:163-71. doi:10.2147/DMSO.S54679
102. Ervinna N, Mita T, Yasunari E, Azuma K, Tanaka R, Fujimura S, et al. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology (2013) 154(3):1260-70. doi:10.1210/en.2012-1855
103. Furuta S, Smart C, Hackett A, Benning R, Warrington S. Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans. Xenobiotica (2013) 43(5):432-42. doi:10.3109/00498254.2012.731618
104. Shinjo T, Nakatsu Y, Iwashita M, Sano T, Sakoda H, Ishihara H, et al. DPP-4 inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-kappaB activation. Am J Physiol Endocrinol Metab (2015). doi:10.1152/ajpendo.00553.2014
105. McKeage K. Trelagliptin: first global approval. Drugs (2015) 75(10):1161-4. doi:10.1007/s40265-015-0431-9
106. Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, et al. Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes. J Med Chem (2014) 57(8):3205-12. doi:10.1021/jm401992e
107. Kumar KV, Gupta AK. Clinical audit of patients using DPP4 inhibitors in longstanding type 2 diabetes. Diabetes Metab Syndr (2014):S1871-4021. doi:10.1016/j.dsx.2014.04.031
108. Aroor AR, Sowers JR, Jia G, DeMarco VG. Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system. Am J Physiol Heart Circ Physiol (2014) 307(4):H477-92. doi:10.1152/ajpheart.00209.2014
109. Pang Z, Nakagami H, Osako MK, Koriyama H, Nakagami F, Tomioka H, et al. Therapeutic vaccine against DPP4 improves glucose metabolism in mice. Proc Natl Acad Sci U S A (2014) 111(13):E1256-63. doi:10.1073/pnas.1322009111
110. Wang T, Gou Z, Wang F, Ma M, Zhai SD. Comparison of GLP-1 analogues versus sitagliptin in the management of type 2 diabetes: systematic review and meta-analysis of head-to-head studies. PLoS One (2014) 9(8):e103798. doi:10.1371/journal.pone.0103798
111. Rizos EC, Ntzani EE, Papanas N, Tsimihodimos V, Mitrogianni Z, Maltezos E, et al. Combination therapies of DPP4 inhibitors and GLP1 analogues with insulin in type 2 diabetic patients: a systematic review. Curr Vasc Pharmacol (2013) 11(6):992-1000. doi:10.2174/15701611113119990103
112. Brunton S. GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other?. Int J Clin Pract (2014) 68(5):557-67. doi:10.1111/ijcp.12361
113. de Mello AH, Pra M, Cardoso LC, de Bona SR, Rezin GT. Incretin-based therapies for obesity treatment. Metabolism (2015):S0026-0495. doi:10.1016/j.metabol.2015.05.012
114. Neumiller JJ. Incretin-based therapies. Med Clin North Am (2015) 99(1):107-29. doi:10.1016/j.mcna.2014.08.013
115. Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe?. Diabetes Care (2013) 36(7):2118-25. doi:10.2337/dc12-2713
116. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care (2013) 36(7):2126-32. doi:10.2337/dc12-2504
117. Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin (2007) 23(4):919-31. doi:10.1185/030079906X162746
118. Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes (2012) 4(1):55-67. doi:10.1111/j.1753-0407.2011.00143.x
119. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab (2004) 89(6):2548-56. doi:10.1210/jc.2004-0395
120. Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol (2007) 27(11):2276-83. doi:10.1161/ATVBAHA.107.147835
121. Pacheco R, Martinez-Navio JM, Lejeune M, Climent N, Oliva H, Gatell JM, et al. CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc Natl Acad Sci U S A (2005) 102(27):9583-8. doi:10.1073/pnas.0501050102
122. Schrader WP, West CA, Miczek AD, Norton EK. Characterization of the adenosine deaminase-adenosine deaminase complexing protein binding reaction. J Biol Chem (1990) 265(31):19312-8.
123. Focosi D, Kast RE, Galimberti S, Petrini M. Conditioning response to granulocyte colony-stimulating factor via the dipeptidyl peptidase IV-adenosine deaminase complex. J Leukoc Biol (2008) 84(2):331-7. doi:10.1189/jlb.0208109
124. Lessard J, Pelletier M, Biertho L, Biron S, Marceau S, Hould FS, et al. Characterization of dedifferentiating human mature adipocytes from the visceral and subcutaneous fat compartments: fibroblast-activation protein alpha and dipeptidyl peptidase 4 as major components of matrix remodeling. PLoS One (2015) 10(3):e0122065. doi:10.1371/journal.pone.0122065
125. Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med (2011) 17(11):1490-7. doi:10.1038/nm.2461
126. Lim J, Iyer A, Liu L, Suen JY, Lohman RJ, Seow V, et al. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J (2013) 27(12):4757-67. doi:10.1096/fj.13-232702
127. Shirakawa J, Fujii H, Ohnuma K, Sato K, Ito Y, Kaji M, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes (2011) 60(4):1246-57. doi:10.2337/db10-1338
128. Shimasaki T, Masaki T, Mitsutomi K, Ueno D, Gotoh K, Chiba S, et al. The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity. PLoS One (2013) 8(5):e63626. doi:10.1371/journal.pone.0063626
129. Fukuda-Tsuru S, Kakimoto T, Utsumi H, Kiuchi S, Ishii S. The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice. Eur J Pharmacol (2014) 723:207-15. doi:10.1016/j.ejphar.2013.11.030
130. Liu L, Omar B, Marchetti P, Ahren B. Dipeptidyl peptidase-4 (DPP-4): localization and activity in human and rodent islets. Biochem Biophys Res Commun (2014) 453(3):398-404. doi:10.1016/j.bbrc.2014.09.096
131. Omar BA, Liehua L, Yamada Y, Seino Y, Marchetti P, Ahren B. Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes. Diabetologia (2014) 57(9):1876-83. doi:10.1007/s00125-014-3299-4
132. Shah P, Ardestani A, Dharmadhikari G, Laue S, Schumann DM, Kerr-Conte J, et al. The DPP-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through GLP-1 stabilization. J Clin Endocrinol Metab (2013) 98(7):E1163-72. doi:10.1210/jc.2013-1029
133. Nagamatsu S, Ohara-Imaizumi M, Nakamichi Y, Aoyagi K, Nishiwaki C. DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice beta cells. Biochem Biophys Res Commun (2011) 412(4):556-60. doi:10.1016/j.bbrc.2011.07.119
134. Duttaroy A, Voelker F, Merriam K, Zhang X, Ren X, Subramanian K, et al. The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in neonatal rats. Eur J Pharmacol (2011) 650(2-3):703-7. doi:10.1016/j.ejphar.2010.10.062
135. Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes (2006) 55(6):1695-704. doi:10.2337/db05-1602
136. Takeda Y, Fujita Y, Honjo J, Yanagimachi T, Sakagami H, Takiyama Y, et al. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia (2012) 55(2):404-12. doi:10.1007/s00125-011-2365-4
137. Han SJ, Choi SE, Kang Y, Jung JG, Yi SA, Kim HJ, et al. Effect of sitagliptin plus metformin on beta-cell function, islet integrity and islet gene expression in Zucker diabetic fatty rats. Diabetes Res Clin Pract (2011) 92(2):213-22. doi:10.1016/j.diabres.2011.01.016
138. Akarte AS, Srinivasan BP, Gandhi S. Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates beta-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes. J Diabetes Complications (2012) 26(4):266-74. doi:10.1016/j.jdiacomp.2012.03.013
139. D'Alessio DA, Denney AM, Hermiller LM, Prigeon RL, Martin JM, Tharp WG, et al. Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes. J Clin Endocrinol Metab (2009) 94(1):81-8. doi:10.1210/jc.2008-1135
140. Foley JE, Bunck MC, Moller-Goede DL, Poelma M, Nijpels G, Eekhoff EM, et al. Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial. Diabetologia (2011) 54(8):1985-91. doi:10.1007/s00125-011-2167-8
141. Mari A, Scherbaum WA, Nilsson PM, Lalanne G, Schweizer A, Dunning BE, et al. Characterization of the influence of vildagliptin on model-assessed-cell function in patients with type 2 diabetes and mild hyperglycemia. J Clin Endocrinol Metab (2008) 93(1):103-9. doi:10.1210/jc.2007-1639
142. Leibowitz G, Cahn A, Bhatt DL, Hirshberg B, Mosenzon O, Wei C, et al. Impact of treatment with saxagliptin on glycaemic stability and beta-cell function in the SAVOR-TIMI 53 study. Diabetes Obes Metab (2015) 17(5):487-94. doi:10.1111/dom.12445
143. Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol (2010) 24(5):695-708. doi:10.1016/j.bpg.2010.08.005
144. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology (2010) 51(5):1820-32. doi:10.1002/hep.23594
145. Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res (2012) 2012:716404. doi:10.1155/2012/716404
146. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology (2008) 134(6):1655-69. doi:10.1053/j.gastro.2008.03.003
147. Guo J, Friedman SL. Hepatic fibrogenesis. Semin Liver Dis (2007) 27(4):413-26. doi:10.1055/s-2007-991517
148. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest (2005) 115(2):209-18. doi:10.1172/JCI24282
149. Mentzel S, Dijkman HB, Van Son JP, Koene RA, Assmann KJ. Organ distribution of aminopeptidase A and dipeptidyl peptidase IV in normal mice. J Histochem Cytochem (1996) 44(5):445-61. doi:10.1177/44.5.8627002
150. Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol (2013) 19(15):2298-306. doi:10.3748/wjg.v19.i15.2298
151. Miyazaki M, Kato M, Tanaka K, Tanaka M, Kohjima M, Nakamura K, et al. Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism. Mol Med Rep (2012) 5(3):729-33. doi:10.3892/mmr.2011.707
152. Gorrell MD, Wang XM, Park J, Ajami K, Yu DM, Knott H, et al. Structure and function in dipeptidyl peptidase IV and related proteins. Adv Exp Med Biol (2006) 575:45-54. doi:10.1007/0-387-32824-6_5
153. Eggstein S, Kreisel W, Gerok W, Eggstein M. [Dipeptidyl aminopeptidase IV in hospitalized patients and in galactosamine hepatitis of the rat: activity and lectin affinity chromatography in serum and hepatic plasma membranes]. J Clin Chem Clin Biochem (1989) 27(9):547-54.
154. Matsumoto Y, Bishop GA, McCaughan GW. Altered zonal expression of the CD26 antigen (dipeptidyl peptidase IV) in human cirrhotic liver. Hepatology (1992) 15(6):1048-53. doi:10.1002/hep.1840150613
155. Nilius R, Stuhec K, Dietrich R. Changes of dipeptidylpeptidase IV as a membrane marker of lymphocytes in acute and chronic liver diseases-biochemical and cytochemical investigations. Physiol Res (1991) 40(1):95-102.
156. Balaban YH, Korkusuz P, Simsek H, Gokcan H, Gedikoglu G, Pinar A, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol (2007) 6(4):242-50.
157. Firneisz G, Varga T, Lengyel G, Feher J, Ghyczy D, Wichmann B, et al. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One (2010) 5(8):e12226. doi:10.1371/journal.pone.0012226
158. Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Douhara A, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol (2014) 49(3):481-91. doi:10.1007/s00535-013-0783-4
159. Akaslan SB, Degertekin CK, Yilmaz G, Cakir N, Arslan M, Toruner FB. Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord (2013) 11(4):243-50. doi:10.1089/met.2012.0128
160. Maiztegui B, Borelli MI, Madrid VG, Del ZH, Raschia MA, Francini F, et al. Sitagliptin prevents the development of metabolic and hormonal disturbances, increased beta-cell apoptosis and liver steatosis induced by a fructose-rich diet in normal rats. Clin Sci (Lond) (2011) 120(2):73-80. doi:10.1042/CS20100372
161. Kern M, Kloting N, Niessen HG, Thomas L, Stiller D, Mark M, et al. Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS One (2012) 7(6):e38744. doi:10.1371/journal.pone.0038744
162. Klein T, Fujii M, Sandel J, Shibazaki Y, Wakamatsu K, Mark M, et al. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med Mol Morphol (2014) 47(3):137-49. doi:10.1007/s00795-013-0053-9
163. Ohyama T, Sato K, Yamazaki Y, Hashizume H, Horiguchi N, Kakizaki S, et al. MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice. World J Gastroenterol (2014) 20(43):16227-35. doi:10.3748/wjg.v20.i43.16227
164. Itou M, Kawaguchi T, Taniguchi E, Oriishi T, Sata M. Dipeptidyl peptidase IV inhibitor improves insulin resistance and steatosis in a refractory nonalcoholic fatty liver disease patient: a case report. Case Rep Gastroenterol (2012) 6(2):538-44. doi:10.1159/000341510
165. Iwasaki T, Yoneda M, Inamori M, Shirakawa J, Higurashi T, Maeda S, et al. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology (2011) 58(112):2103-5. doi:10.5754/hge11263
166. Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C, Duman DG. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg (2012) 75(2):240-4.
167. Kanazawa I, Tanaka K, Sugimoto T. DPP-4 inhibitors improve liver dysfunction in type 2 diabetes mellitus. Med Sci Monit (2014) 20:1662-7. doi:10.12659/MSM.890989
168. Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, Brown TJ, et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology (2013) 154(1):127-39. doi:10.1210/en.2012-1937
169. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab (2004) 89(6):2595-600. doi:10.1210/jc.2004-0372
170. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue. Circulation (2002) 105(3):373-9. doi:10.1161/hc0302.102143
171. Matsushita K, Blecker S, Pazin-Filho A, Bertoni A, Chang PP, Coresh J, et al. The association of hemoglobin a1c with incident heart failure among people without diabetes: the atherosclerosis risk in communities study. Diabetes (2010) 59(8):2020-6. doi:10.2337/db10-0165
172. Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation (2005) 111(16):2073-85. doi:10.1161/01.CIR.0000162472.52990.36
173. Pala L, Mannucci E, Pezzatini A, Ciani S, Sardi J, Raimondi L, et al. Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells. Biochem Biophys Res Commun (2003) 310(1):28-31. doi:10.1016/j.bbrc.2003.08.111
174. Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, et al. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and-independent actions. Circulation (2012) 126(15):1838-51. doi:10.1161/CIRCULATIONAHA.112.096479
175. Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, et al. Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood (2006) 108(5):1602-10. doi:10.1182/blood-2006-02-001016
176. Jin X, Shepherd RK, Duling BR, Linden J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest (1997) 100(11):2849-57. doi:10.1172/JCI119833
177. Chinda K, Palee S, Surinkaew S, Phornphutkul M, Chattipakorn S, Chattipakorn N. Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury. Int J Cardiol (2013) 167(2):451-7. doi:10.1016/j.ijcard.2012.01.011
178. Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol (2010) 298(5):H1454-65. doi:10.1152/ajpheart.00867.2009
179. Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, et al. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol (2012) 59(3):265-76. doi:10.1016/j.jacc.2011.07.053
180. Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation (2011) 124(21):2338-49. doi:10.1161/CIRCULATIONAHA.111.041418
181. Bhatt DL, Cavender MA. Do dipeptidyl peptidase-4 inhibitors increase the risk of heart failure?. JACC Heart Fail (2014) 2(6):583-5. doi:10.1016/j.jchf.2014.05.005
182. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med (2013) 369(14):1317-26. doi:10.1056/NEJMoa1307684
183. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med (2013) 369(14):1327-35. doi:10.1056/NEJMoa1305889
184. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med (2015) 373(3):232-42. doi:10.1056/NEJMoa1501352
185. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and-independent pathways. Circulation (2008) 117(18):2340-50. doi:10.1161/CIRCULATIONAHA.107.739938
186. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology (1996) 137(7):2968-78. doi:10.1210/endo.137.7.8770921
187. Wei Y, Mojsov S. Distribution of GLP-1 and PACAP receptors in human tissues. Acta Physiol Scand (1996) 157(3):355-7. doi:10.1046/j.1365-201X.1996.42256000.x
188. Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes (2010) 59(4):1030-7. doi:10.2337/db09-1694
189. Ku HC, Chen WP, Su MJ. DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion. Naunyn Schmiedebergs Arch Pharmacol (2011) 384(2):197-207. doi:10.1007/s00210-011-0665-3
190. Chang G, Zhang P, Ye L, Lu K, Wang Y, Duan Q, et al. Protective effects of sitagliptin on myocardial injury and cardiac function in an ischemia/reperfusion rat model. Eur J Pharmacol (2013) 718(1-3):105-13. doi:10.1016/j.ejphar.2013.09.007
191. Liu Q, Adams L, Broyde A, Fernandez R, Baron AD, Parkes DG. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats. Cardiovasc Diabetol (2010) 9:32. doi:10.1186/1475-2840-9-32
192. Erdogdu O, Nathanson D, Sjoholm A, Nystrom T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA-and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol (2010) 325(1-2):26-35. doi:10.1016/j.mce.2010.04.022
193. Fadini GP, Avogaro A. Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol (2011) 55(1-3):10-6. doi:10.1016/j.vph.2011.05.001
194. Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D. The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an "endothelial resistance" to glucagon-like peptide 1 in diabetes. Diabetes Care (2011) 34(3):697-702. doi:10.2337/dc10-1949
195. Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun (2011) 405(1):79-84. doi:10.1016/j.bbrc.2010.12.131
196. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation (2004) 109(8):962-5. doi:10.1161/01.CIR.0000120505.91348.58
197. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail (2006) 12(9):694-9. doi:10.1016/j.cardfail.2006.08.211
198. Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care (2011) 34(1):90-5. doi:10.2337/dc10-1393
199. Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de KS, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care (2010) 33(7):1607-9. doi:10.2337/dc10-0187
200. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell (2009) 4(4):313-23. doi:10.1016/j.stem.2009.02.013
201. Segers VF, Revin V, Wu W, Qiu H, Yan Z, Lee RT, et al. Protease-resistant stromal cell-derived factor-1 for the treatment of experimental peripheral artery disease. Circulation (2011) 123(12):1306-15. doi:10.1161/CIRCULATIONAHA.110.991786
202. Boerrigter G, Costello-Boerrigter LC, Harty GJ, Lapp H, Burnett JC Jr. Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation. Am J Physiol Regul Integr Comp Physiol (2007) 292(2):R897-901. doi:10.1152/ajpregu.00569.2006
203. Kawakami R, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N, et al. Overexpression of brain natriuretic peptide facilitates neutrophil infiltration and cardiac matrix metalloproteinase-9 expression after acute myocardial infarction. Circulation (2004) 110(21):3306-12. doi:10.1161/01.CIR.0000147829.78357.C5
204. Kuhn M. Endothelial actions of atrial and B-type natriuretic peptides. Br J Pharmacol (2012) 166(2):522-31. doi:10.1111/j.1476-5381.2012.01827.x
205. Palazzuoli A, Gallotta M, Quatrini I, Nuti R. Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure. Vasc Health Risk Manag (2010) 6:411-8. doi:10.2147/VHRM.S5789
206. Ikushima H, Munakata Y, Iwata S, Ohnuma K, Kobayashi S, Dang NH, et al. Soluble CD26/dipeptidyl peptidase IV enhances transendothelial migration via its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cell Immunol (2002) 215(1):106-10. doi:10.1016/S0008-8749(02)00010-2
207. Ishibashi Y, Matsui T, Maeda S, Higashimoto Y, Yamagishi S. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc Diabetol (2013) 12:125. doi:10.1186/1475-2840-12-125
208. Sanchez-Ferrer C, Vallejo S, Romacho T, Villalobos L, Wronkowitz N, Sell H, et al. Dipeptidyl peptidase-4 impairs microvascular endothelial-dependent relaxation: the role of cyclooxygenase. Diabetes (2013) 62(Suppl 1):A128.
209. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care (2014) 37(10):2884-94. doi:10.2337/dc14-0865