Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.
Grieve
David J
DJ
Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK. d.grieve@qub.ac.uk
Cassidy
Roslyn S
RS
Green
Brian D
BD
D000818:Animals; D001786:Blood Glucose; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002319:Cardiovascular System / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D052216:Glucagon-Like Peptide 1 / Q000502:physiology / Q000627:therapeutic use*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D054795:Incretins / Q000502:physiology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism / Q000627:therapeutic use; D000078790:Insulin Secretion; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism
D001786:Blood Glucose; D002317:Cardiovascular Agents; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1
Diabetologia. 2007 Feb;50(2):259-67
17160407
Circulation. 2008 May 6;117(18):2340-50
18427132
J Pharmacol Exp Ther. 2006 Feb;316(2):852-9
16221740
FEBS Lett. 1990 Mar 12;262(1):139-41
2156728
Pharmacology. 2005 Jun;74(3):119-26
15746570
Horm Metab Res. 2004 Nov-Dec;36(11-12):755-60
15655704
Endocrinology. 2005 Apr;146(4):2069-76
15618356
Diabetes Care. 1994 Sep;17(9):1039-44
7988303
Mol Endocrinol. 1996 Apr;10(4):342-55
8721980
Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8641-5
1326760
Diabet Med. 2008 Aug;25(8):889-94
18959599
Endocr Rev. 1999 Dec;20(6):876-913
10605628
Nature. 1983 Jul 28-Aug 3;304(5924):368-71
6877358
Diabetes Care. 2005 May;28(5):1083-91
15855571
J Card Fail. 2006 Dec;12(9):694-9
17174230
J Mol Model. 2009 Jan;15(1):53-65
18941807
Lancet. 2009 Feb 7;373(9662):473-81
18819705
N Engl J Med. 1992 Sep 3;327(10):685-91
1463530
Diabetes Care. 2004 Nov;27(11):2628-35
15504997
Horm Metab Res. 2004 Nov-Dec;36(11-12):761-5
15655705
Acta Physiol Scand. 1997 Aug;160(4):413-22
9338524
Regul Pept. 2004 Apr 15;118(1-2):33-8
14759554
J Clin Endocrinol Metab. 1992 Feb;74(2):379-84
1730817
Diabetes Care. 2004 Jun;27(6):1335-42
15161785
Biol Chem. 2003 Dec;384(12):1543-51
14719796
Diabetes Care. 1996 Nov;19(11):1200-6
8908380
J Am Coll Cardiol. 2009 Feb 10;53(6):501-10
19195607
Biochem Pharmacol. 2002 Mar 1;63(5):993-6
11911852
Am J Cardiol. 2007 Sep 1;100(5):824-9
17719327
J Pharmacol Exp Ther. 2006 Aug;318(2):914-21
16648370
Endocrinology. 1996 Jul;137(7):2968-78
8770921
Am J Physiol. 1999 Nov;277(5):E784-91
10567003
Diabetes. 1995 Sep;44(9):1126-31
7657039
Am J Physiol. 1997 Feb;272(2 Pt 2):R726-30
9124501
Metabolism. 1995 Sep;44(9):1231-7
7666800
J Clin Endocrinol Metab. 1996 Jan;81(1):327-32
8550773
Circ Res. 2003 Nov 14;93(10):896-906
14615493
Diabetes. 2001 Aug;50(8):1720-8
11473030
Regul Pept. 1995 Aug 22;58(3):149-56
8577927
Curr Drug Metab. 2009 Feb;10(2):125-37
19275548
J Clin Endocrinol Metab. 2005 Nov;90(11):5991-7
16144950
J Auton Nerv Syst. 2000 Apr 12;80(1-2):14-21
10742535
Endocrinology. 1987 Aug;121(2):704-13
3595539
Regul Pept. 2000 Jul 28;91(1-3):75-81
10967203
Regul Pept. 1996 Nov 14;67(1):63-8
8952007
Cell Metab. 2006 Mar;3(3):153-65
16517403
Ann Intern Med. 2007 Apr 3;146(7):477-85
17404349
Regul Pept. 2001 Dec 15;102(2-3):81-6
11730979
Diabetologia. 1996 Dec;39(12):1546-53
8960841
Endocrinology. 2003 Jun;144(6):2242-52
12746281
Peptides. 2003 Apr;24(4):569-78
12860201
JAMA. 1979 May 11;241(19):2035-8
430798
FEBS Lett. 1988 Dec 5;241(1-2):209-12
2848722
Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2401-8
16024574
Am J Physiol. 1994 Mar;266(3 Pt 1):E459-66
8166268
J Am Coll Cardiol. 2006 Feb 21;47(4):693-700
16487830
Circ Res. 2001 Aug 31;89(5):445-52
11532906
Arch Biochem Biophys. 2008 Oct 15;478(2):136-42
18708025
J Pharmacol Exp Ther. 2005 Jan;312(1):303-8
15356213
Curr Drug Targets. 2004 Aug;5(6):565-71
15270203
Horm Metab Res. 1993 Dec;25(12):612-6
8119664
Diabetologia. 1979 Feb;16(2):75-85
32119
Curr Med Res Opin. 2008 Jan;24(1):275-86
18053320
J Clin Endocrinol Metab. 2003 Jul;88(7):3082-9
12843147
Circulation. 2007 Jul 3;116(1):49-56
17576868
Am J Physiol. 1996 Sep;271(3 Pt 1):E458-64
8843738
Biochem Biophys Res Commun. 1981 Jun;100(4):1659-66
7028035
Cardiovasc Drugs Ther. 2007 Aug;21(4):253-6
17541736
Metabolism. 2004 Feb;53(2):252-9
14767880
Nucleic Acids Res. 1986 Jun 25;14(12):4719-30
3725587
Nature. 1996 Jan 4;379(6560):69-72
8538742
Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15
15353407
J Pharmacol Exp Ther. 2006 Jun;317(3):1106-13
16489128
Diabetologia. 2005 Sep;48(9):1882-90
16025254
Diabetes. 1993 Sep;42(9):1219-25
8349031
J Hypertens. 2003 Jun;21(6):1125-35
12777949
Diabetes. 2003 Jan;52(1):124-32
12502502
Diabetes. 1994 Apr;43(4):535-9
8138058
Curr Pharm Des. 2004;10(29):3651-62
15579061
Biochemistry. 2001 Mar 6;40(9):2860-9
11258897
Lancet. 1994 Nov 19;344(8934):1383-9
7968073
Diabetes. 1999 May;48(5):1045-53
10331409
Peptides. 1998;19(5):869-75
9663452
Chin Med J (Engl). 2008 Nov 5;121(21):2134-8
19080172
Diabetes. 1993 Nov;42(11):1678-82
8405712
Regul Pept. 2008 Feb 7;146(1-3):243-9
17976835
Eur J Clin Invest. 1992 Apr;22(4):283-91
1499644
Cell Biol Int. 2004;28(1):69-73
14759771
Am J Physiol Endocrinol Metab. 2002 Apr;282(4):E873-9
11882507
Diabetes. 1991 Oct;40(10):1292-6
1657666
J Endocrinol. 1993 Jul;138(1):159-66
7852887
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):943-8
17213311
Circulation. 2004 Aug 24;110(8):955-61
15313949
Circulation. 2004 Mar 2;109(8):962-5
14981009
Diabetes Care. 2005 May;28(5):1092-100
15855572
Am J Med. 1985 Nov 15;79(5A):2-7
4073075
Peptides. 1997;18(5):625-32
9213354
Arch Biochem Biophys. 2004 Aug 15;428(2):136-43
15246869
Diabetes Care. 1996 Jun;19(6):580-6
8725855
J Endocrinol. 2002 Feb;172(2):303-10
11834448
J Nippon Med Sch. 2007 Oct;74(5):338-43
17965527
FEBS Lett. 1995 Jan 30;358(3):219-24
7843404
Endocr Rev. 2004 Aug;25(4):543-67
15294881
Exp Physiol. 1997 Jul;82(4):709-16
9257113
Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1289-95
17711996
Diabetes. 2009 Apr;58(4):975-83
19151200
Endocrinology. 2003 Dec;144(12):5145-8
14645210
Circ Heart Fail. 2008 Sep;1(3):153-60
19727407
Diabetes. 1974 Feb;23(2):105-11
4359625
J Neurosci. 2003 Apr 1;23(7):2939-46
12684481
Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):497-516
18054732
Diabetes. 2005 Jan;54(1):146-51
15616022
Diabetes. 2004 Jan;53(1):5-13
14693691
J Clin Invest. 1996 Jan 1;97(1):92-103
8550855
Diab Vasc Dis Res. 2004 May;1(1):40-3
16305055
Endocrinology. 1987 Sep;121(3):1076-82
3040376
Endocrinology. 2001 Oct;142(10):4462-8
11564711
Neurobiol Aging. 2010 Sep;31(9):1495-502
18930564
Regul Pept. 2005 Feb 15;125(1-3):173-7
15582729
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):937-42
17213325
Diab Vasc Dis Res. 2006 Dec;3(3):159-65
17160910
J Biol Chem. 1993 Sep 15;268(26):19650-5
8396143
Endocrinology. 1984 Dec;115(6):2176-81
6548696
Diabetes Care. 2003 Aug;26(8):2433-41
12882875
Diabetes. 1993 Aug;42(8):1215-8
8392011
Diabetes. 2009 Feb;58(2):318-28
18984744
Eur J Pharmacol. 1996 Dec 30;318(2-3):429-35
9016935
J Clin Invest. 2002 Jul;110(1):43-52
12093887
Diabetes Care. 1998 Sep;21(9):1414-31
9727886
Br J Pharmacol. 2008 May;154(1):60-71
18311183
Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E215-22
16926376
Cardiovasc Drugs Ther. 2005 Jan;19(1):9-11
15883751
J Biol Chem. 2003 Aug 29;278(35):32517-25
12783880
Diabetes. 2001 Oct;50(10):2237-43
11574404