title: Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases.
abstract: Ghrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulin-producing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases.
authors: School of Biomedical Sciences, University of Queensland, St Lucia, QLD, 4072, Australia.
authors: Rasha Mofeed Habeeb
authors: RM
authors: Mosa
authors: Zhen
authors: Z
authors: Zhang
authors: Renfu
authors: R
authors: Shao
authors: Chao
authors: C
authors: Deng
authors: Jiezhong
authors: J
authors: Chen
authors: Chen
authors: C
authors: Chen
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000517:prevention & control; D054439:Ghrelin / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism*
chemical_list: D054439:Ghrelin; D009842:Oligopeptides; D047495:PPAR gamma; D054440:Receptors, Ghrelin; C086184:hexarelin
references: J Med Chem. 2003 Mar 27;46(7):1191-203
references: 12646029
references: FASEB J. 2005 Nov;19(13):1869-71
references: 16123174
references: Endocrinology. 2003 Mar;144(3):916-21
references: 12586768
references: Diabetes Care. 2014 Jun;37(6):1751-8
references: 24812433
references: Cell. 2001 Jun 15;105(6):745-55
references: 11440717
references: Endocrine. 2001 Jun;15(1):29-38
references: 11572322
references: Diabetologia. 2005 Feb;48(2):282-9
references: 15654602
references: Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E875-81
references: 15140754
references: Eur J Endocrinol. 1997 May;136(5):445-60
references: 9186261
references: Mol Cell. 1998 Nov;2(5):559-69
references: 9844629
references: Diabetologia. 2006 Jun;49(6):1264-73
references: 16570155
references: Cardiovasc Diabetol. 2012 Oct 15;11:129
references: 23066908
references: Am J Cardiol. 2004 Apr 1;93(7):870-5
references: 15050491
references: Cardiovasc Diabetol. 2011 Nov 21;10:100
references: 22098712
references: Curr Opin Pharmacol. 2003 Apr;3(2):146-51
references: 12681236
references: J Mol Endocrinol. 2010 Jul;45(1):9-17
references: 20382773
references: J Clin Endocrinol Metab. 2004 Nov;89(11):5535-41
references: 15531508
references: Physiol Rev. 2005 Apr;85(2):495-522
references: 15788704
references: Diabetes Obes Metab. 2013 Sep;15 Suppl 3:141-51
references: 24003931
references: Nature. 2000 Oct 19;407(6806):908-13
references: 11057670
references: J Clin Invest. 2003 Dec;112(12 ):1831-42
references: 14679178
references: Diabetes. 2008 Dec;57(12):3205-10
references: 18776138
references: Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1483-7
references: 11294772
references: Nature. 1999 Dec 9;402(6762):656-60
references: 10604470
references: Eur J Pharmacol. 1999 Sep 17;381(1):31-8
references: 10528131
references: Mol Endocrinol. 2006 Dec;20(12 ):3165-78
references: 16959872
references: J Clin Invest. 2000 Feb;105(3):271-8
references: 10675352
references: Diabetes Res Clin Pract. 1998 Jul;40 Suppl:S21-5
references: 9740498
references: Horm Metab Res. 2004 Nov-Dec;36(11-12):811-21
references: 15655713
references: J Endocrinol Invest. 1999 Apr;22(4):266-72
references: 10342360
references: Regul Pept. 2008 Feb 7;146(1-3):73-9
references: 17884193
references: Peptides. 2009 Jun;30(6):1109-16
references: 19406177
references: Peptides. 2014 Jun;56:156-62
references: 24747279
references: Endocrinology. 2003 May;144(5):1787-92
references: 12697684
references: Endocrinology. 2006 Jul;147(7):3398-407
references: 16601139
references: Diabetologia. 2002 Jan;45(1):85-96
references: 11845227
references: Semin Immunol. 2012 Dec;24(6):436-42
references: 23333525
references: Clin Endocrinol (Oxf). 1999 Sep;51(3):369-75
references: 10469018
references: J Cell Biol. 2002 Dec 23;159(6):1029-37
references: 12486113
references: Regul Pept. 2010 Sep 24;164(2-3):65-70
references: 20619300
references: J Neuroendocrinol. 2002 Jul;14(7):555-60
references: 12121492
references: Mol Cell. 2001 Jan;7(1):161-71
references: 11172721
references: Endocr Rev. 2007 Apr;28(2):187-218
references: 17353295
references: Endocr Metab Immune Disord Drug Targets. 2013 Mar;13(1):38-50
references: 23369136
references: Endocrinology. 1997 Oct;138(10):4316-23
references: 9322945
references: J Clin Invest. 2000 Aug;106(4):523-31
references: 10953027
references: Regul Pept. 2004 May 15;118(3):143-50
references: 15003830
references: Diabetes. 2003 Mar;52(3):581-7
references: 12606496
references: J Clin Invest. 2007 Jan;117(1):13-23
references: 17200702
references: Peptides. 2010 Feb;31(2):307-14
references: 19944124
references: Diabetes. 2001 Feb;50 Suppl 1:S25-9
references: 11272193
references: J Clin Invest. 1997 May 1;99(9):2100-9
references: 9151782
references: Diabetologia. 2004 May;47(5):806-15
references: 15095038
references: Eur J Endocrinol. 2009 Oct;161(4):567-73
references: 19628651
references: Diabet Med. 2004 Jan;21(1):52-8
references: 14706054
references: J Cardiovasc Pharmacol. 1999 Sep;34(3):454-60
references: 10471007
references: Circ Res. 2003 Aug 8;93(3):192-200
references: 12855674
references: PLoS One. 2012;7(4):e35265
references: 22493744
references: J Clin Invest. 1983 Jun;71(6):1544-53
references: 6134752
references: Endocrinology. 2000 Nov;141(11):4255-61
references: 11089560
references: J Gastrointest Surg. 2009 Apr;13(4):775-83
references: 19082668
references: Growth Horm IGF Res. 1998 Apr;8 Suppl B:149-52
references: 10990152
references: Am J Hypertens. 2006 Jul;19(7):764-7
references: 16814134
references: J Endocrinol. 2000 Sep;166(3):529-36
references: 10974647
references: Eur J Heart Fail. 2002 Mar;4(2):185-91
references: 11959048
references: Diabetes Care. 1990 Mar;13(3):228-43
references: 2407478
references: Am J Physiol Endocrinol Metab. 2012 May 15;302(9):E1055-62
references: 22338071
references: J Biol Regul Homeost Agents. 2010 Oct-Dec;24(4):397-402
references: 21122278
references: J Geriatr Cardiol. 2014 Sep;11(3):253-8
references: 25278975
references: Eur J Pharmacol. 1997 Sep 10;334(2-3):201-7
references: 9369349
references: Eur J Pharmacol. 2004 Sep 13;498(1-3):27-35
references: 15363972
references: Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1595-9
references: 10845877
references: Mol Endocrinol. 2004 Sep;18(9):2291-301
references: 15178745
references: Endocrinology. 2013 Oct;154(10 ):3847-54
references: 23861368
references: Circulation. 2008 Jan 1;117(1):43-51
references: 18071071
references: Peptides. 2008 Mar;29(3):448-55
references: 18215442
references: Endocrinology. 2006 May;147(5):2306-14
references: 16484324
references: Diabetes. 2002 Jan;51(1):124-9
references: 11756331
references: Biochem Biophys Res Commun. 2007 Oct 26;362(3):677-81
references: 17719561
references: Nature. 1999 Sep 2;401(6748):73-6
references: 10485707
references: Cell. 2005 Dec 16;123(6):993-9
references: 16360030
references: Nature. 2001 Dec 13;414(6865):807-12
references: 11742413
references: J Endocrinol Invest. 2003 Mar;26(3):192-6
references: 12809167
references: J Clin Endocrinol Metab. 2004 Jun;89(6):3062-5
references: 15181099
references: J Mol Endocrinol. 2007 Feb;38(1-2):193-206
references: 17293440
references: Peptides. 2014 Oct;60:86-94
references: 25102450
references: Diabetes Metab Syndr Obes. 2014 Jul 22;7:331-40
references: 25092994
references: Science. 1996 Aug 16;273(5277):974-7
references: 8688086
references: Toxicology. 2007 Jul 31;237(1-3):194-202
references: 17602820
references: J Clin Endocrinol Metab. 2008 Feb;93(2):438-44
references: 18042651
references: Circulation. 2004 May 11;109(18):2221-6
references: 15117840
references: Heart Vessels. 2013 Nov;28(6):795-801
references: 23494606
references: J Endocrinol Invest. 2000 Sep;23(8):493-5
references: 11021763
references: Diabetes. 2001 Nov;50(11):2438-43
references: 11679419
references: Annu Rev Cell Dev Biol. 2004;20:455-80
references: 15473848
references: Circ Res. 2002 May 3;90(8):844-9
references: 11988484
references: Endocrinology. 2012 Nov;153(11):5480-90
references: 22948211
references: Pancreas. 2003 Aug;27(2):161-6
references: 12883265
references: Am J Physiol Endocrinol Metab. 2013 Jun 15;304(12):E1273-80
references: 23592479
references: Pharmacol Rev. 2009 Dec;61(4):430-81
references: 20038570
references: Horm Metab Res. 2002 Nov-Dec;34(11-12):640-5
references: 12660874
references: Regul Pept. 2010 Apr 9;161(1-3):43-50
references: 20079380
references: J Clin Endocrinol Metab. 2003 Sep;88(9):4268-72
references: 12970297
references: Eur J Endocrinol. 2009 Dec;161(6):861-70
references: 19773372
references: Endocrinology. 2002 Sep;143(9):3540-7
references: 12193568
references: Endocrinology. 2007 Feb;148(2):512-29
references: 17068144
references: Eur J Endocrinol. 2002 Feb;146(2):241-4
references: 11834435
references: PLoS One. 2009 Nov 04;4(11):e7728
references: 19888469
references: Basic Res Cardiol. 2003 Nov;98(6):401-5
references: 14556085
references: J Clin Endocrinol Metab. 2005 Feb;90(2):1055-60
references: 15536157
references: J Biol Chem. 2005 Apr 15;280(15):15247-56
references: 15701644
references: J Clin Endocrinol Metab. 2001 Dec;86(12):5854-9
references: 11739451
references: FEBS Lett. 2010 Apr 16;584(8):1503-8
references: 20206170
references: J Clin Endocrinol Metab. 2001 Mar;86(3):1169-74
references: 11238504
references: J Biol Chem. 2006 Jan 13;281(2):1091-8
references: 16282329
references: Circulation. 1996 Nov 15;94(10):2597-604
references: 8921806
references: Diabetes Res Clin Pract. 2014 Feb;103(2):137-49
references: 24630390
references: Regul Pept. 2003 Jul 15;114(2-3):71-7
references: 12832093
references: J Endocrinol. 2008 Sep;198(3):511-21
references: 18541646
references: Eur J Pharmacol. 2011 Mar 5;654(2):142-9
references: 21194528
references: J Clin Endocrinol Metab. 1998 Apr;83(4):1186-9
references: 9543138
references: Peptides. 2014 Dec;62:1-5
references: 25265271
references: Diabetes Res Clin Pract. 2010 Feb;87(2):137-42
references: 19914727
references: J Gastroenterol Hepatol. 2007 Nov;22(11):1791-9
references: 17914952
references: Endocrine. 2012 Jun;41(3):398-409
references: 22322947
references: J Clin Endocrinol Metab. 2003 Apr;88(4):1537-42
references: 12679436
references: J Clin Endocrinol Metab. 2001 Dec;86(12):5992
references: 11739476
references: Mol Cell Endocrinol. 2006 Jun 7;251(1-2):103-11
references: 16647196
references: Arterioscler Thromb Vasc Biol. 2001 Mar;21(3):365-71
references: 11231915
references: J Clin Endocrinol Metab. 2001 Oct;86(10):5052-9
references: 11600584
references: Diabetes. 2001 Feb;50(2):227-32
references: 11272130
references: J Clin Endocrinol Metab. 2006 Jul;91(7):2574-81
references: 16621911
references: J Clin Endocrinol Metab. 1999 Aug;84(8):2633-7
references: 10443652
references: J Cell Biochem. 2013 Mar;114(3):525-31
references: 22991242
references: Regul Pept. 2006 Mar 15;134(1):17-22
references: 16338009
references: Life Sci. 1994;54(18):1321-8
references: 7910650
references: J Clin Endocrinol Metab. 1998 Oct;83(10):3624-30
references: 9768675
references: Hypertension. 2004 May;43(5):977-82
references: 14993197
references: Br J Pharmacol. 2002 Aug;136(8):1146-52
references: 12163347
references: Am J Physiol Heart Circ Physiol. 2012 Sep 15;303(6):H703-11
references: 22842067
references: J Med Chem. 2012 Mar 22;55(6):2585-96
references: 22352743
references: Clin Endocrinol (Oxf). 1995 Nov;43(5):631-5
references: 8548949
references: Diabetes. 2006 Dec;55(12):3486-93
references: 17130496
references: Am J Cardiol. 2001 Feb 1;87(3):320-3
references: 11165968
references: J Clin Endocrinol Metab. 2011 Feb;96(2):486-93
references: 21106712
references: J Cell Physiol. 2004 Aug;200(2):177-200
references: 15174089
references: Diabetes. 2010 Sep;59(9):2145-51
references: 20584998
references: J Clin Endocrinol Metab. 2004 Oct;89(10):5035-42
references: 15472202
references: Diabetologia. 2006 Apr;49(4):732-8
references: 16485139
references: Regul Pept. 2009 Oct 9;157(1-3):51-6
references: 19268691
references: Mol Cell Endocrinol. 2011 Jun 20;340(1):44-58
references: 21565248
references: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1063-9
references: 14615277
references: J Urol. 1999 Dec;162(6):2019-23
references: 10569560
references: Neuroendocrinology. 2007;86(3):147-64
references: 17622734
references: Clin Endocrinol (Oxf). 2001 Jun;54(6):759-68
references: 11422110
references: Development. 1993 May;118(1):33-46
references: 8104143
references: J Cardiovasc Pharmacol. 2004 Feb;43(2):165-70
references: 14716201
references: Am J Physiol Endocrinol Metab. 2012 Aug 1;303(3):E422-31
references: 22669248
references: Nature. 2001 Feb 8;409(6821):729-33
references: 11217863
references: Peptides. 2009 Dec;30(12):2286-91
references: 19747956
references: FEBS Lett. 2000 Dec 15;486(3):213-6
references: 11119706
references: Endocrinology. 2007 Mar;148(3):1009-18
references: 17138655
references: Diabetes. 2004 Dec;53(12):3142-51
references: 15561944
references: J Histochem Cytochem. 2004 Mar;52(3):301-10
references: 14966197
references: J Clin Endocrinol Metab. 2002 Aug;87(8):3997-4000
references: 12161550
references: Neuroendocrinology. 1995 May;61(5):584-9
references: 7617137
references: Endocr Dev. 2013;25:83-90
references: 23652394
references: Circulation. 2001 Sep 18;104(12):1430-5
references: 11560861
references: FASEB J. 2014 Apr;28(4):1910-23
references: 24371122
references: Diabetes. 2001 Jun;50(6):1440-8
references: 11375346
references: Circulation. 2000 Feb 8;101(5):547-52
references: 10662753
references: Diabetes Obes Metab. 1999 Sep;1 Suppl 2:S7-13
references: 11221801
references: Brain Res Mol Brain Res. 1997 Aug;48(1):23-9
references: 9379845
references: J Clin Invest. 2006 Jul;116(7):1802-12
references: 16823478
references: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16454-9
references: 17050683
references: J Clin Endocrinol Metab. 2003 Nov;88(11):5478-83
references: 14602793
references: Endocrinology. 2008 May;149(5):2191-9
references: 18218693
references: Mol Metab. 2013 Oct 17;3(1):64-72
references: 24567905
references: J Biol Chem. 2002 Dec 20;277(51):49676-84
references: 12393870
references: Diabetes. 2002 Oct;51(10):2911-4
references: 12351426
references: Development. 1994 Dec;120(12):3451-62
references: 7821214
references: Clin Sci (Lond). 2003 Oct;105(4):431-5
references: 12773196
references: Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S11-4
references: 11126232
references: Life Sci. 2001 Jan 19;68(9):991-6
references: 11212874
references: Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H426-32
references: 18024547
references: Endocrinology. 2002 Jan;143(1):185-90
references: 11751608
references: Endocr Rev. 2006 Jun;27(4):356-70
references: 16638909
references: Curr Opin Endocrinol Diabetes Obes. 2011 Feb;18(1):50-5
references: 21150588
references: Endocrinology. 1999 Sep;140(9):4024-31
references: 10465272