Cardiovascular biology of the incretin system

Endocrine Reviews

Volumn 33, Issue 2, 2012, Pages 187-215

  Ussher, John R ^a   Drucker, Daniel J ^a  

^a MOUNT SINAI HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

3 ISOPROPYLAMINO 1 (7 METHYL 4 INDANYLOXY) 2 BUTANOL; AC 3174; APOLIPOPROTEIN B48; CHOLESTEROL; CHYLOMICRON; CNT 0736; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; ENDOTHELIAL NITRIC OXIDE SYNTHASE; EXENDIN 4; FATTY ACID; GASTRIC INHIBITORY POLYPEPTIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; GLUCOSE TRANSPORTER 4; INCRETIN; INSULIN; LIPOPROTEIN; LIRAGLUTIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MITOGEN ACTIVATED PROTEIN KINASE P38; NITRIC OXIDE; PFK 275 055; PHENTOLAMINE; PLERIXAFOR; PROPRANOLOL; SITAGLIPTIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERY LOW DENSITY LIPOPROTEIN; VILDAGLIPTIN;

ACUTE HEART INFARCTION; ADIPOCYTE; ADIPOSE TISSUE; ATHEROSCLEROSIS; BLOOD PRESSURE REGULATION; BLOOD VESSEL; BODY WEIGHT; CARDIOMYOPATHY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CARDIOVASCULAR SYSTEM; CONGESTIVE HEART FAILURE; CONTINUOUS INFUSION; DIABETIC PATIENT; DYSLIPIDEMIA; ENDOTHELIUM CELL; ENZYME INHIBITION; GLYCEMIC CONTROL; HEART FAILURE; HEART MUSCLE CELL; HEART PROTECTION; HEART RATE; HUMAN; HYPERTENSION; HYPOGLYCEMIA; INFLAMMATION; INSULIN RELEASE; ISCHEMIC HEART DISEASE; LIPOPROTEIN SECRETION; MORNING DOSAGE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; POSTPRANDIAL STATE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECEPTOR UPREGULATION; REVIEW; RISK BENEFIT ANALYSIS;

ANIMALS; CARDIOVASCULAR DISEASES; DIPEPTIDYL PEPTIDASE 4; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RECEPTORS, GLUCAGON;

EID: 84860204551     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2011-1052     Document Type: Review

References (231)

1. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M 1998 Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229-234
2. Killilea T 2002 Long-term consequences of type 2 diabetes mellitus: economic impact on society and managed care. Am J Manag Care 8:S441-S449
3. Mazzone T, Chait A, Plutzky J 2008 Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371:1800-1809
4. Brown JC, Dryburgh JR 1971 A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can J Biochem 49:867-872
5. Cataland S, Crockett SE, Brown JC, Mazzaferri EL 1974 Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man. J Clin Endocrinol Metab 39:223-228
6. Dupre J, Ross SA, Watson D, Brown JC 1973 Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 37:826-828
7. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF 1987 Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 84:3434-3438
8. Kreymann B, Ghatei MA, Williams G, Bloom SR 1987 Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2:1300-1304
9. Mojsov S, Weir GC, Habener JF 1987 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 79:616-619
10. Orskov C, Holst JJ, Nielsen OV 1988 Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123:2009-2013
11. Drucker DJ 2006 The biology of incretin hormones. Cell Metab 3:153-165
12. Baggio LL, Drucker DJ 2007 Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131-2157
13. Brubaker PL 2010 Minireview: update on incretin biology: focus on glucagon-like peptide-1. Endocrinology 151: 1984-1989
14. Barrera JG, Sandoval DA, D'Alessio DA, Seeley RJ 2011 GLP-1 and energy balance: an integrated model of shortterm and long-term control. Nat Rev Endocrinol 7:507- 516
15. Asmar M, Holst JJ 2010 Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances. Curr Opin Endocrinol Diabetes Obes 17:57-62
16. Mayo KE, Miller LJ, Bataille D, Dalle S, Göke B, Thorens B, Drucker DJ 2003 International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55: 167-194
17. Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C 1993 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 42:1678-1682
18. Bullock BP, Heller RS, Habener JF 1996 Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide 1 receptor. Endocrinology 137:2968-2978
19. Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D 2009 Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. J Clin Endocrinol Metab 94:1843-1852
20. Holz 4th GG, Kühtreiber WM, Habener JF 1993 Pancreatic β-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature 361:362-365
21. Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC 1996 Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1(7-36)amide in patients with NIDDM. Diabetes 45: 1524-1530
22. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W 1993 Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:741-744
23. de Heer J, Rasmussen C, Coy D.H.,Holst JJ 2008 Glucagonlike peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia 51:2263-2270
24. Kulkarni RN 2010 GIP: no longer the neglected incretin twin? Sci Transl Med 2:49ps47
25. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI 1993 Gastric inhibitory polypeptide receptor, a member of the secretin- vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133:2861-2870
26. Irwin N, Flatt PR 2009 Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications. Diabetologia 52:1724-1731
27. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia-Naji N, Dupuis J, Jackson AU, Kao WH, Li M, Glazer NL, Manning AK, Luan J, Stringham HM, Prokopenko I, Johnson T, Grarup N, Boesgaard TW, Lecoeur C, Shrader P, O'Connell J, Ingelsson E, Couper DJ, et al. 2010 Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142-148
28. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J,Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, et al. 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937-948
29. Zhu L, Tamvakopoulos C, Xie D, Dragovic J, Shen X, Fenyk-Melody JE, Schmidt K, Bagchi A, Griffin PR, Thornberry NA, Sinha Roy R 2003 The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 278:22418-22423
30. Brandt I, Lambeir AM, Maes MB, Scharpé S, De Meester I 2006 Peptide substrates of dipeptidyl peptidases.AdvExp Med Biol 575:3-18
31. Drucker DJ 2007 Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30:1335-1343
32. Mentlein R, Gallwitz B, Schmidt WE 1993 Dipeptidylpeptidase 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 J Biochem 214:829 -835
33. Kieffer TJ, McIntosh CH, Pederson RA 1995 Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585-3596
34. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ 1995 Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44:1126-1131
35. Holst JJ, Deacon CF 1998 Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663-1670
36. Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, Ribel U, Watanabe T, Drucker DJ, Wagtmann N 2000 Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 97:6874-6879
37. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M 2008 Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117:2340-2350
38. Wei Y, Mojsov S 1996 Distribution of GLP-1 and PACAP receptors in human tissues. Acta Physiol Scand 157:355- 357
39. Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen YT, Shannon RP 2010 Glucagon-like peptide-1 increases myocardial glucose uptake via p38α MAP kinasemediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail 3:512- 521
40. Vila Petroff MG, Egan JM, Wang X, Sollott SJ 2001 Glucagon-like peptide-1 increases cAMP but fails to augment. contraction in adult rat cardiac myocytes. Circ Res 89: 445-452
41. Xiao YF, Nikolskaya A, Jaye DA, SiggDC2011 Glucagonlike peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway. Cardiovasc Diabetol 10:6
42. Ban K, Kim KH, Cho CK, Sauvé M, Diamandis EP, Backx PH, Drucker DJ, Husain M 2010 GLP-1(9-36) protects cardiomyocytes and endothelial cells from ischemia-reperfusion injury via cytoprotective pathways independent of the GLP-1 receptor. Endocrinology 151:1520-1531
43. Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B, Quijada P, Mason M, Konstandin MH, Malhowski A, Cheng Z, Khan M, McGregor M 2011 Myocardial AKT: the omnipresent nexus. Physiol Rev 91:1023-1070
44. Rose BA, Force T, Wang Y 2010 Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507-1546
45. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ 2009 GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 58: 975-983
46. Wang SX, Xie Y, Zhou X, Sha WW, Wang WL, Han LP, Wang JC, Yu DM 2010 [Effect of glucagon-like peptide-1 on hypoxia-reoxygenation induced injury in neonatal rat cardiomyocytes]. Zhonghua Xin Xue Guan Bing Za Zhi 38:72-75 (Chinese)
47. Ravassa S, Zudaire A, Carr RD, Díez 2011 Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes. Am J Physiol Heart Circ Physiol 300:H1361-H1372
48. Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen YT, Shannon RP 2006 Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther 317:1106-1113
49. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP 2004 Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 110:955-961
50. Gros R, You X, Baggio LL, Kabir MG, Sadi AM, Mungrue IN, Parker TG, Huang Q, Drucker DJ, Husain M 2003 Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology 144:2242-2252
51. Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, Sjöholm A 2004 Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 287:E1209-E1215
52. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S 2010 Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun 391:1405-1408
53. Hattori Y, Jojima T, Tomizawa A, Satoh H, Hattori S, Kasai K, Hayashi T 2010 A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia 53:2256-2263
54. Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q 2010 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 325:26-35
55. Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Silljé HH 2010 Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol 30:1407-1414
56. Liu H, Dear AE, Knudsen LB, Simpson RW 2009 A longacting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol 201:59-66
57. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ 2007 Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab 293:E1289- E1295
58. Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D 2011 The possible protective role of glucagonlike peptide 1 on endothelium during the meal and evidence for an " endothelial resistance" to glucagon-like peptide 1 in diabetes. Diabetes Care 34:697-702
59. Nathanson D, Erdogdu O, Pernow J, Zhang Q, Nyström T 2009 Endothelial dysfunction induced by triglycerides is not restored by exenatide in rat conduit arteries ex vivo. Regul Pept 157:8-13
60. Barragán JM, Rodríguez RE, Blázquez E 1994 Changes in arterial blood pressure and heart rate induced by glucagonlike peptide-1-(7-36 amide) in rats. Am J Physiol 266: E459-E466
61. Barragán JM, Rodríguez RE, Eng J, Blázquez E 1996 Interactions of exendin-(9-39) with the effects of glucagonlike peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regulatory Peptides 67:63-68
62. Barragán JM, Eng J, Rodríguez R, Blázquez E 1999 Neural contribution to the effect of glucagon-like peptide-1-(7- 36) amide on arterial blood pressure in rats. Am J Physiol 277:E784-E791
63. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB, Drucker DJ, Elmquist JK 2002 Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest 110:43-52
64. Gardiner SM, March JE, Kemp PA, Bennett T 2006 Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats. J Pharmacol Exp Ther 316:852-859
65. Gardiner SM, March JE, Kemp PA, Bennett T 2008 Autonomic nervous system-dependent and -independent cardiovascular effects of exendin-4 infusion in conscious rats. Br J Pharmacol 154:60-71
66. Osaka T, Endo M, Yamakawa M, Inoue S 2005 Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system. Peptides 26:1623-1631
67. Griffioen KJ, Wan R, Okun E, Wang X, Lovett-Barr MR, Li Y, Mughal MR, Mendelowitz D, Mattson MP 2011 GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons. Cardiovascular research 89:72-78
68. Isbil-Buyukcoskun N, Gulec G 2004 Effects of centrally injected GLP-1 in various experimental models of gastric mucosal damage. Peptides 25:1179-1183
69. Edwards CM, Edwards AV, Bloom SR 1997 Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf. Exp Physiol 82:709-716
70. Bharucha AE, Charkoudian N, Andrews CN,Camilleri M, Sletten D, Zinsmeister AR, Low PA 2008 Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans. Am J Physiol Regul Integr Comp Physiol 295:R874-R880
71. Edwards CM, Todd JF, Ghatei MA, Bloom SR 1998 Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci (Lond) 95:719-724
72. Qin X, Shen H, Liu M, Yang Q, Zheng S, Sabo M, D'Alessio DA, Tso P 2005 GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol 288: G943-G949
73. Hsieh J, Longuet C, Baker CL, Qin B, Federico LM, Drucker DJ, Adeli K 2010 The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion. Diabetologia 53:552-561
74. Flock G, Baggio LL, Longuet C, Drucker DJ 2007 Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 56:3006-3013
75. Ding X, SaxenaNK,Lin S, Gupta NA, Gupta N, Anania FA 2006 Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43:173-181
76. Mells JE, Fu PP, Sharma S, Olson D, Cheng L, Handy JA, Saxena NK, Sorescu D, Anania FA 2012 GLP-1 analogue, liraglutide ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol 302:G225-G335
77. Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA 2011 GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 6:e25269
78. Parlevliet ET, Schröder-van der Elst JP, Corssmit EP, Picha K, O'Neil K, Stojanovic-Susulic V, Ort T, Havekes LM, Romijn JA, Pijl H 2009 CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice. J Pharmacol Exp Ther 328:240-248
79. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, Faraci G, Pacetti D, Vivarelli M, Nicolini D, Garelli P, Casini A, Manco M, Mingrone G, Risaliti A, Frega GN, Benedetti A, Gastaldelli A 2011 Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 31:1285-1297
80. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA 2010 Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51: 1584-1592
81. Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S 2009 Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem 284:33509-33520
82. Tomas E, Stanojevic V, Habener JF 2010 GLP-1 (9-36) amide metabolite suppression of glucose production in isolated mouse hepatocytes. Horm Metab Res 42:657-662
83. Valverde I,Mérida E, Delgado E, Trapote MA,Villanueva-Peñacarrillo ML 1993 Presence and characterization of glucagon-like peptide-1(7-36) amide receptors in solubilized membranes of rat adipose tissue. Endocrinology 132: 75-79
84. Mérida E, Delgado E, Molina LM,Villanueva-Peñacarrillo ML, Valverde I 1993 Presence of glucagon and glucagonlike peptide-1-(7-36)amide receptors in solubilized membranes of human adipose tissue. J Clin Endocrinol Metab 77:1654-1657
85. Ruiz-Grande C, Alarcón C, Mérida E, Valverde I 1992 Lipolytic action of glucagon-like peptides in isolated rat adipocytes. Peptides 13:13-16
86. Villanueva-Peñacarrillo ML, Márquez L, González N, Díaz-Miguel M, Valverde I 2001 Effect of GLP-1 on lipid metabolism in human adipocytes. Horm Metab Res 33: 73-77
87. Bertin E, Arner P, Bolinder J, Hagström-Toft E 2001 Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo. J Clin Endocrinol Metab 86:1229- 1234
88. Meier JJ, Gethmann A, Götze O, Gallwitz B, Holst JJ, Schmidt WE, Nauck MA 2006 Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 49:452-458
89. Juntti-Berggren L, Pigon J, Karpe F, Hamsten A, Gutniak M, Vignati L, Efendic S 1996 The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia inNIDDMpatients. Diabetes Care 19:1200-1206
90. Toft-Nielsen MB,Madsbad S, Holst JJ 2001 Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab 86:3853-3860
91. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D 2003 Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 26:2835-2841
92. Schwartz EA, Koska J, Mullin MP, Syoufi I, Schwenke DC, Reaven PD 2010 Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus. Atherosclerosis 212:217-222
93. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L 2008 Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372: 1240-1250
94. Nauck MA, Kemmeries G, Holst JJ, Meier JJ 2011 Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60: 1561-1565
95. Matikainen N, Mänttäri S, Schweizer A, Ulvestad A, Mills D, Dunning BE, Foley JE, Taskinen MR 2006 Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 49:2049-2057
96. Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P 2011 Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab 13:366-373
97. Brownsey RW, Boone AN, Allard MF 1997 Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc Res 34:3-24
98. Ji L, Fu F, Zhang L, Liu W, Cai X, Zhang L, Zheng Q, Zhang H, Gao F 2010 Insulin attenuates myocardial ischemia/ reperfusion injury via reducing oxidative/nitrative stress. Am J Physiol Endocrinol Metab 298:E871-880
99. Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, Schlattner U, Wallimann T, Carling D, Hue L, Rider MH 2006 Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 281:5335-5340
100. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS 2007 Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79-101
101. Ahmed K, Tunaru S, Tang C,Müller M, Gille A, Sassmann A, Hanson J, Offermanns S 2010 An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 11:311-319
102. Zhao YT, Weng CL, Chen ML, Li KB, Ge YG, Lin XM, Zhao WS, Chen J, Zhang L, Yin JX, Yang XC 2010 Comparison of glucose-insulin-potassium and insulin-glucose as adjunctive therapy in acute myocardial infarction: a contemporary meta-analysis of randomised controlled trials. Heart 96:1622-1626
103. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, Drucker DJ 1996 Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide receptor gene. Nat Med 2:1254- 1258
104. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR 1996 A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69-72
105. Flint A, Raben A, Astrup A, Holst JJ 1998 Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101:515-520
106. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS 2002 Obesity and the risk of heart failure. N Engl J Med 347:305-313
107. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N, Walsh K 2005 Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11:1096-1103
108. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K 2004 Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384-1389
109. Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP 2008 Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail 1:153-160
110. KimChung le T, Hosaka T, Yoshida M, Harada N, Sakaue H, Sakai T, Nakaya Y 2009 Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression. Biochem Biophys Res Commun 390: 613-618
111. Horton ES, Silberman C, Davis KL, Berria R 2010 Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care 33:1759-1765
112. Deacon CF, Johnsen AH, Holst JJ 1995 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 80:952-957
113. Rolin B, Deacon CF, Carr RD, Ahrén B 2004 The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice. Eur J Pharmacol 494:283-288
114. Deacon CF, Plamboeck A, Møller S, Holst JJ 2002 GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am J Physiol Endocrinol Metab 282:E873-E879
115. Meier JJ, Gethmann A, Nauck MA, Götze O, Schmitz F, Deacon CF, Gallwitz B, Schmidt WE, Holst JJ 2006 The glucagon-like peptide 1 metabolite GLP-1 (9-36)amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans. Am J Physiol Endocrinol Metab 290:E1118-E1123
116. 2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab 88:1772-1779
117. Elahi D, Egan JM, Shannon RP, Meneilly GS, Khatri A, Habener JF, Andersen DK 2008 GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide. Obesity (Silver Spring) 16:1501-1509
118. Tomas E, Stanojevic V, Habener JF 2011 GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept 167:177-184
119. Tomas E, Wood JA, Stanojevic V, Habener JF 2011 Glucagon-like peptide-1(9 -36)amide metabolite inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice. Diabetes Obes Metab 13:26 -33
120. Nikolaidis LA, Elahi D, Shen YT, Shannon RP 2005 Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289:H2401-H2408
121. Sonne DP, Engstrøm T, Treiman M 2008 Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart. Regul Pept 146:243-249
122. Ossum A, van Deurs U, Engstrøm T, Jensen JS, Treiman M 2009 The cardioprotective and inotropic components of the postconditioning effects of GLP-1 and GLP-1(9-36)a in an isolated rat heart. Pharmacol Res 60:411-417
123. Sauvé M, Ban K,Momen MA,Zhou YQ, Henkelman RM, Husain M, Drucker DJ 2010 Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes following myocardial infarction in mice. Diabetes 59:1063-1073
124. Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y 2010 The myocardial infarct size limiting effects of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol 298:H1454-H1465
125. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP 2010 DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging 3:195-201
126. Hirata K, Kume S, Araki S, Sakaguchi M, Chin-Kanasaki M, Isshiki K, Sugimoto T, Nishiyama A, Koya D, Haneda M, Kashiwagi A, Uzu T 2009 Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem Biophys Res Commun 380:44-49
127. Laugero KD, Stonehouse AH, Guss S, Landry J, Vu C, Parkes DG 2009 Exenatide improves hypertension in a rat model of the metabolic syndrome. Metab Syndr Relat Disord 7:327-334
128. Halbirk M, Nørrelund H, Møller N, Holst JJ, Schmitz O, Nielsen R, Nielsen-Kudsk JE, Nielsen SS, Nielsen TT,Eiskjaer H, Bøtker HE, Wiggers H 2010 Cardiovascular and metabolic effects of 48-hour glucagon-like peptide 1 infusion in compensated chronic heart failure patients. Am J Physiol Heart Circ Physiol 298:H1096-H1102
129. Gill A, Hoogwerf BJ, Burger J, Bruce S, Macconell L, Yan P, Braun D, Giaconia J, Malone J 2010 Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol 9:6
130. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, Thomsen AB, Søndergaard RE, Davies M 2010 Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, openlabel trial. Lancet 375:1447-1456
131. Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, Garber A, Thomsen AB, Hartvig H, Davies M 2011Oneyear of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract 65:397- 407
132. Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, Gonzalez JG, Chan M, Wolka AM, Boardman MK 2012 Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 35:252- 258
133. Gustavson SM, Chen D, Somayaji V, Hudson K, Baltrukonis DJ, Singh J, Boyden TL, Calle RA 2011 Effects of a long-acting GLP-1 mimetic (PF-04603629) on pulse rate and diastolic blood pressure in patients with type 2 diabetes mellitus. Diabetes Obes Metab 13:1056-1058
134. Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, Wilhelm K, Trautmann M, Shen LZ, Porter LE 2010 DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 33:1255-1261
135. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM 2006 Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 8:436-447
136. Yang W, Chen L, Ji Q, Liu X, Ma J, Tandon N, Bhattacharyya A, Kumar A, Kim KW, Yoon KH, Bech OM, Zychma M 2011 Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, doubleblind, active control trial. Diabetes Obes Metab 13:81-88
137. Varanasi A, Patel P, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P 2011 Clinical use of liraglutide in type 2 diabetes, and its effects on cardiovascular risk factors. Endocr Pract 19:1-13
138. Gallwitz B, Vaag A, Falahati A, Madsbad S 2010 Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract 64:267-276
139. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rossner S, Savolainen MJ, Van Gaal L 16 August 2011 Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 10.1038/ijo.2011.158
140. Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H 2010 Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59:1030-1037
141. Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, Arakawa M, Jin WL, Kanazawa A, Kawamori R, Fujitani Y, Hirose T, Watada H 2011 Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun 405:79-84
142. Nagashima M, Watanabe T, Terasaki M, Tomoyasu M, Nohtomi K,Kim-Kaneyama J, Miyazaki A, Hirano T 2011 Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia 54:2649-2659
143. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM 2005 Glucagon-like peptide-1 (GLP-1) can directly protect the heart against ischemia/reperfusion injury. Diabetes 54: 146-151
144. Bose AK, Mocanu MM, Carr RD, Yellon DM 2005 Glucagon like peptide-1 is protective against myocardial ischemia/ reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther 19:9-11
145. Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA, Pasterkamp G, Hoefer IE 2009 Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol 53:501-510
146. Kavianipour M, Ehlers MR, Malmberg K, Ronquist G, Ryden L, Wikström G, Gutniak M 2003 Glucagon-like peptide-1 (7-36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium. Peptides 24:569-578
147. Kristensen J, Mortensen UM, Schmidt M, Nielsen PH, Nielsen TT,Maeng M 2009 Lack of cardioprotection from subcutaneously and preischemic administered liraglutide in a closed chest porcine ischemia reperfusion model.BMC Cardiovasc Disord 9:31
148. Bao W, Aravindhan K, Alsaid H, Chendrimada T, Szapacs M, Citerone DR, Harpel MR, Willette RN, Lepore JJ, Jucker BM 2011 Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/ reperfusion injury: evidence for improving cardiac metabolic efficiency. PLoS One 6:e23570
149. Matsubara M, Kanemoto S, Leshnower BG, Albone EF, Hinmon R, Plappert T, Gorman 3rd JH, Gorman RC 2011 Single dose GLP-1-Tf ameliorates myocardial ischemia/ reperfusion injury. J Surg Res 165:38-45
150. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP 2004 Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109:962-965
151. Read PA, Khan FZ, Dutka DP 10 May 2011 Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart 10.1136/hrt.2010.219345
152. Read PA, Hoole SP, White PA, Khan FZ, O'Sullivan M, West NE, Dutka DP 2011 A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv 4:266- 272
153. Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, Jorgensen E, Helqvist S, Saunamaki K, Clemmensen P, Holmvang L, Thuesen L, Krusell LR, Jensen JS, Kober L, Treiman M, Holst JJ, Engstrom T 14 September 2011 Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 10.1093/eurheartj/ehr309
154. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP 2006 Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 12:694-699
155. Liu Q, Anderson C, Broyde A, Polizzi C, Fernandez R, Baron A, Parkes DG 2010 Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc Diabetol 9:76
156. Palmieri FE, Ward PE 1989 Dipeptidyl(amino)peptidase IV and post proline cleaving enzyme in cultured endothelial and smooth muscle cells. Adv Exp Med Biol 247A:305- 311
157. Matheeussen V, Baerts L, De Meyer G, De Keulenaer G, Van der Veken P, Augustyns K, Dubois V, Scharpé S,De Meester I 2011 Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries. Biol Chem 392:189-198
158. Pala L, Pezzatini A, Dicembrini I, Ciani S, Gelmini S, Vannelli BG, Cresci B, Mannucci E, Rotella CM 9 May 2010 Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells. Acta Diabetol 10.1007/s00592-010-0195-3
159. Ikushima H, Munakata Y, Iwata S, Ohnuma K, Kobayashi S, Dang NH, Morimoto C 2002 Soluble CD26/dipeptidyl peptidase IV enhances transendothelial migration via its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cell Immunol 215:106-110
160. Kim SJ, Nian C, McIntosh CH 2007 Resistin is a key mediator of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes. J Biol Chem 282:34139-34147
161. Kim SJ, Nian C, McIntosh CH 2010 GIP increases human adipocyte LPL expression throughCREBandTORC2-mediated trans-activation of the LPL gene. J Lipid Res 51: 3145-3157
162. Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y 2002 Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738-742
163. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, Drucker DJ 2007 Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest 117:143-152
164. Zhong Q, Bollag RJ, Dransfield DT, Gasalla-Herraiz J, Ding KH, Min L, Isales CM 2000 Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides 21:1427-1432
165. Ding KH, Zhong Q, Isales CM 2003 Glucose-dependent insulinotropic peptide stimulates thymidine incorporation in endothelial cells: role of endothelin-1. Am J Physiol Endocrinol Metab 285:E390-E396
166. Ding KH, Zhong Q, Xu J, Isales CM 2004 Glucosedependent insulinotropic peptide: differential effects on hepatic artery vs. portal vein endothelial cells. Am J Physiol Endocrinol Metab 286:E773-E779
167. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T 1996 Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/ SDF-1. Nature 382:635-638
168. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR 1998 Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595-599
169. Zaruba MM,Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM 2009 Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4:313-323
170. Tang YL, Qian K, Zhang YC, Shen L, Phillips MI 2005 Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1α (SDF-1α ) treatment. Regul Pept 125:1-8
171. Vagima Y, Lapid K, Kollet O, Goichberg P, Alon R, Lapidot T 2011 Pathways implicated in stem cell migration: the SDF-1/CXCR4 axis. Methods Mol Biol 750:277-289
172. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC 2004 Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858-864
173. McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM 2001 Matrix metalloproteinase activity inactivates the CXC chemokine stromal cellderived factor-1. J Biol Chem 276:43503-43508
174. Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A 2010 The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes mellitus. Possible role of stromal derived factor-1α. Diabetes Care 33:1607-1609
175. Theiss HD, Brenner C, Engelmann MG, Zaruba MM, Huber B, Henschel V, Mansmann U, Wintersperger B, Reiser M, Steinbeck G, Franz WM 2010 Safety and efficacy of sitagliptin plus granulocyte-colony-stimulating factor in patients suffering from acute myocardial infarction (SITAGRAMI-Trial): rationale, design and first interim analysis. Int J Cardiol 145:282-284
176. Mentlein R, Dahms P, Grandt D, Krüger R 1993 Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept 49:133-144
177. Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T 1998 XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 50: 143-150
178. Pellieux C, Sauthier T, Domenighetti A, Marsh DJ, Palmiter RD, Brunner HR, Pedrazzini T 2000 Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogenactivated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors. Proc Natl Acad Sci USA 97:1595-1600
179. Bryant SM, Hart G 1996 Effects of neuropeptide Y on L-type calcium current in guinea-pig ventricular myocytes. Br J Pharmacol 118:1455-1460
180. 2+ sparks in adult rat ventricular myocytes through Y1 receptor and PLC activation. J Mol Cell Cardiol 38:205-212
181. Tseng CJ, Robertson D, Light RT, Atkinson JR, Robertson RM 1988 Neuropeptide Y is a vasoconstrictor of human coronary arteries. Am J Med Sci 296:11-16
182. Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H, Yeh Y, Chen WT, Kleinman HK, Grouzmann E, Grant DS 1998 Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83:187-195
183. Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z 2007 Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 13:803-811
184. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, Carlsson L, Kumar S, McTernan PG 2009 DPP-IV inhibition enhances the antilipolytic action ofNPY in human adipose tissue. Diabetes Obes Metab 11:285- 292
185. Jackson EK, Zhang M, Liu W, Mi Z 2007 Inhibition of renal dipeptidyl peptidase IV enhances peptide YY1-36-induced potentiation of angiotensin II-mediated renal vasoconstriction in spontaneously hypertensive rats. J Pharmacol Exp Ther 323:431-437
186. Hasegawa K, Fujiwara H, Doyama K, Miyamae M, Fujiwara T, Suga S, Mukoyama M, Nakao K, Imura H, Sasayama S 1993 Ventricular expression of brain natriuretic peptide in hypertrophic cardiomyopathy. Circulation 88: 372-380
187. Ogawa T, Linz W, Stevenson M, Bruneau BG, Kuroski de Bold ML, Chen JH, Eid H, Schölkens BA, de Bold AJ 1996 Evidence for load-dependent and load-independent determinants of cardiac natriuretic peptide production. Circulation 93:2059-2067
188. Brandt I, Lambeir AM, Ketelslegers JM, Vanderheyden M, Scharpé S,De Meester I 2006 Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form. Clin Chem 52:82-87
189. Moilanen AM,Rysä J, Mustonen E, Serpi R, Aro J, Tokola H, Leskinen H, Manninen A, Levijoki J, Vuolteenaho O, Ruskoaho H 2011 Intramyocardial BNP gene delivery improves cardiac function through distinct context-dependent mechanisms. Circ Heart Fail 4:483-495
190. Pleister AP, Baliga RR, Haas GJ 2011 Acute study of clinical effectiveness of nesiritide in decompensated heart failure: nesiritide redux. Curr Heart Fail Rep 8:226-232
191. Drucker DJ, Shi Q, Crivici A, Sumner-Smith M, Tavares W, Hill M, DeForest L, Cooper S, Brubaker PL 1997 Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV. Nat Biotechnol 15:673- 677
192. Bremholm L, Hornum M, Andersen UB, Holst JJ 2010 The effect of glucagon-like peptide-2 on arterial blood flow and cardiac parameters. Regul Pept 159:67-71
193. Angelone T, Filice E, Quintieri AM, Imbrogno S, Amodio N, Pasqua T, Pellegrino D, Mule F, Cerra MC 24 December 2010 Receptor identification and physiological characterisation of glucagon-like peptide-2 in the rat heart. Nutr Metab Cardiovasc Dis 10.1016/j.numecd.2010.07.014
194. Yusta B, Huang L, Munroe D, Wolff G, Fantaske R, Sharma S, Demchyshyn L, Asa SL, Drucker DJ 2000 En-teroendocrine localization of GLP-2 receptor expression. Gastroenterology 119:744-755
195. Wang LH,AhmadS, Benter IF,ChowA, Mizutani S, Ward PE 1991 Differential processing of substance P and neurokinin A by plasma dipeptidyl(amino)peptidase IV, aminopeptidase M and angiotensin converting enzyme. Peptides 12:1357-1364
196. Chiao H, Caldwell RW 1995 Local cardiac effects of substance P: roles of acetylcholine and noradrenaline. Br J Pharmacol 114:283-288
197. Byrd JB, Touzin K, Sile S, Gainer JV, Yu C, Nadeau J, Adam A, Brown NJ 2008 Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 51:141-147
198. Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, Pinto R, Garrido P, Sereno J, Fernandes R, Santos P, Velada I, Melo A, Nunes S, Teixeira F, Reis F 2010 Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm 2010: 592760
199. Pacheco BP, Crajoinas RO, Couto GK, Davel AP, Lessa LM, Rossoni LV, Girardi AC 2011 Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats. J Hypertens 29:520-528
200. Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, Herman GA 2008 Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol 48:592-598
201. Ogawa S, Ishiki M, Nako K, Okamura M, Senda M, Mori T, Ito S 2011 Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. Tohoku J Exp Med 223: 133-135
202. Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE 2010 Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376:431-439
203. Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B, Moffatt-Bruce S, Durairaj R, Sun Q, Mihai G, Maiseyeu A, Rajagopalan S 2011 Long-term dipeptidylpeptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124:2338-2349
204. Hocher B, Sharkovska Y,MarkM,Klein T, Pfab T 2 January 2012 The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Int J Cardiol 10.1016/j.ijcard.2011.12.007
205. Huisamen B, Genis A, Marais E, Lochner A 2011 Pretreatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drugs Ther 25: 13-20
206. Theiss HD, Vallaster M, Rischpler C, Krieg L, Zaruba MM,Brunner S, Vanchev Y, Fischer R, Gröbner M, Huber B, Wollenweber T, Assmann G, Mueller-Hoecker J, Hacker M, Franz WM 2011 Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res 7:244-255
207. Zaruba MM, Zhu W, Soonpaa MH, Reuter S, Franz WM, Field LJ 2012 Granulocyte colony-stimulating factor treatment plus dipeptidylpeptidase-IV inhibition augments myocardial regeneration in mice expressing cyclin D2 in adult cardiomyocytes. Eur Heart J 33:129-137
208. Kanki S, Segers VF, Wu W, Kakkar R, Gannon J, Sys SU, Sandrasagra A, Lee RT 2011 Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium. Circ Heart Fail 4:509-518
209. Gomez N, Touihri K, Matheeussen V, Mendes Da Costa A, Mahmoudabady M, Mathieu M, Baerts L, Peace A, Lybaert P, Scharpé S, De Meester I, Bartunek J, Vanderheyden M, Mc Entee K 2012 Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur J Heart Fail 14:14-21
210. Yin M, Silljé HH, Meissner M, van Gilst WH, de Boer RA 2011 Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure. Cardiovasc Diabetol 10:85
211. Lenski M, Kazakov A, Marx N, Böhm M, Laufs U 2011 Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J Mol Cell Cardiol 51:906-918
212. Fonseca VA 2011 Ongoing clinical trials evaluating the cardiovascular safety and efficacy of therapeutic approaches to diabetes mellitus. The American journal of cardiology 108:52B-58B
213. Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, Chen R, Wolf R, Mahaffey KW 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 122:16-27
214. Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA 2011 Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the GLP-1 receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care 34:90-95
215. Monami M, Dicembrini I, Martelli D, Mannucci E 2011 Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin 27(SUPPL 3):57-64
216. Drucker DJ, Sherman SI, Bergenstal RM, Buse JB 2011 The safety of incretin-based therapies: review of the scientific evidence. J Clin Endocrinol Metab 96:2027-2031
217. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, Gotfredsen C, Egerod FL, Hegelund AC, Jacobsen H, Jacobsen SD, Moses AC, Mølck AM, Nielsen HS, Nowak J, Solberg H, Thi TD, Zdravkovic M 2010 Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 151:1473-1486
218. Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH 2011 GLP-1 and Calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab 96:853-860
219. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm Jr RH, Probstfield JL, Simons-Morton DG, Frie-dewald WT 2008 Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545-2559
220. Romero-Corral A, Montori VM, Somers VK, Korinek J, Thomas RJ, Allison TG, Mookadam F, Lopez-Jimenez F 2006 Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 368:666-678
221. Futter JE, Cleland JG, Clark AL 2011 Body mass indices and outcome in patients with chronic heart failure. Eur J Heart Fail 13:207-213
222. Adamopoulos C, Meyer P, Desai RV,Karatzidou K, Ovalle F, White M, Aban I, Love TE, Deedwania P, Anker SD, Ahmed A 2011 Absence of obesity paradox in patients with chronic heart failure and diabetes mellitus: a propensity-matched study. Eur J Heart Fail 13:200-206
223. Drucker DJ, Nauck MA 2006 The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696-1705
224. Boerrigter G, Costello-Boerrigter LC, Harty GJ, Lapp H, Burnett Jr JC 2007 Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation.AmJ Physiol Regul Integr Comp Physiol 292:R897-R901
225. Wang LL, Guo Z, Han Y, Wang PF, Zhang RL, Zhao YL, Zhao FP, Zhao XY 2011 Implication of substance P in myocardial contractile function during ischemia in rats. Regul Pept 167:185-191
226. Clark JT, Kalra PS, Crowley WR, Kalra SP 1984 Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115:427-429
227. Yang K, Guan H, Arany E, Hill DJ, Cao X 2008 Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J 22:2452-2464
228. Kos K, Harte AL, James S, Snead DR, O'Hare JP, McTernan PG, Kumar S 2007 Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass. Am J Physiol Endocrinol Metab 293: E1335-E1340
229. Cruze CA, Su F, Limberg BJ, Deutsch AJ, Stoffolano PJ, Dai HJ, Buchanan DD, Yang HT, Terjung RL, Spruell RD, Mittelstadt SW, Rosenbaum JS 2007 The Y2 receptor mediates increases in collateral-dependent blood flow in a model of peripheral arterial insufficiency. Peptides 28: 269-280
230. Valet P, Berlan M, Beauville M, Crampes F, Montastruc JL, Lafontan M 1990 Neuropeptide Y and peptide YY inhibit lipolysis in human and dog fat cells through a pertussis toxin-sensitive G protein. The Journal of clinical investigation 85:291-295
231. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR 2002 Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418:650-654