Abstract
Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.
Similar content being viewed by others
References
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. doi:10.1161/CIRCULATIONAHA.107.739938
Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, Barzilai N, Oren R, Fishman S (2011) Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 54:1214–1223. doi:10.1016/j.jhep.2010.09.032
Berwick ZC, Dick GM, Tune JD (2012) Heart of the matter: coronary dysfunction in metabolic syndrome. J Mol Cell Cardiol 52:848–856. doi:10.1016/j.yjmcc.2011.06.025
Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen YT, Shannon RP (2010) Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail 3:512–521. doi:10.1161/CIRCHEARTFAILURE.109.900282
Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM (2005) Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 54:146–151. doi:10.2337/diabetes.54.1.146
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. doi:10.1007/s10557-005-6892-4
Dokken BB, Hilwig WR, Teachey MK, Panchal RA, Hubner K, Allen D, Rogers DC, Kern KB (2010) Glucagon-like peptide-1 (GLP-1) attenuates post-resuscitation myocardial microcirculatory dysfunction. Resuscitation 81:755–760. doi:10.1016/j.resuscitation.2010.01.031
Drucker DJ (2006) The biology of incretin hormones. Cell Metab 3:153–165. doi:10.1016/j.cmet.2006.01.004
Feigl EO, Neat GW, Huang AH (1990) Interrelations between coronary artery pressure, myocardial metabolism and coronary blood flow. J Mol Cell Cardiol 22:375–390
Fox CS, Pencina MJ, Wilson PW, Paynter NP, Vasan RS, D’Agostino RB Sr (2008) Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study. Diabetes Care 31:1582–1584. doi:10.2337/dc08-0025
Gejl M, Sondergaard HM, Stecher C, Bibby BM, Moller N, Botker HE, Hansen SB, Gjedde A, Rungby J, Brock B (2012) Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. J Clin Endocrinol Metab 97:E1165–E1169. doi:10.1210/jc.2011-3456
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. doi:10.1007/s00125-010-1831-8
Hicks RJ, Herman WH, Kalff V, Molina E, Wolfe ER, Hutchins G, Schwaiger M (1991) Quantitative evaluation of regional substrate metabolism in the human heart by positron emission tomography. J Am Coll Cardiol 18:101–111. doi:10.1016/2050912
Holst JJ (2003) Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors. Adv Exp Med Biol 524:263–279. doi:10.1007/0-306-47920-6_33
Huisamen B, Genade S, Lochner A (2008) Signalling pathways activated by glucagon-like peptide-1 (7–36) amide in the rat heart and their role in protection against ischaemia. Cardiovasc J Afr 19:77–83. doi:10./18516352
Hutchins GD, Chen T, Carlson KA, Fain RL, Winkle W, Vavrek T, Mock BH, Zipes DP (1999) PET imaging of oxidative metabolism abnormalities in sympathetically denervated canine myocardium. J Nucl Med 40:846–853. doi:10.2967/10319760
Knudson JD, Dincer UD, Bratz IN, Sturek M, Dick GM, Tune JD (2007) Mechanisms of coronary dysfunction in obesity and insulin resistance. Microcirculation 14:317–338. doi:10.1080/10739680701282887
Krijnen PA, Hahn NE, Kholova I, Baylan U, Sipkens JA, van Alphen FP, Vonk AB, Simsek S, Meischl C, Schalkwijk CG, van Buul JD, van Hinsbergh VW, Niessen HW (2012) Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients. Basic Res Cardiol 107:233. doi:10.1007/s00395-011-0233-5
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716. doi:10.1001/jama.288.21.2709
Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR 3rd, Young LH (2005) AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB 1 in the ischemic heart. Circ Res 97:872–879. doi:10.1161/01.RES.0000187458.77026.10
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. doi:10.1186/1475-2840-9-76
Lonborg J, Kelbaek H, Vejlstrup N, Botker HE, Kim WY, Holmvang L, Jorgensen E, Helqvist S, Saunamaki K, Terkelsen CJ, Schoos MM, Kober L, Clemmensen P, Treiman M, Engstrom T (2012) Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 5:288–295. doi:10.1161/CIRCINTERVENTIONS.112.968388
Lopaschuk GD (2001) Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis 12(Suppl 1):S8–S11
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258. doi:10.1152/physrev.00015.2009
Matsubara M, Kanemoto S, Leshnower BG, Albone EF, Hinmon R, Plappert T, Gorman JH 3rd, Gorman RC (2011) Single dose GLP-1-Tf ameliorates myocardial ischemia/reperfusion injury. J Surg Res 165:38–45. doi:10.1016/j.jss.2009.03.016
Moberly SP, Berwick ZC, Kohr M, Svendsen M, Mather KJ, Tune JD (2012) Intracoronary glucagon-like peptide 1 preferentially augments glucose uptake in ischemic myocardium independent of changes in coronary flow. Exp Biol Med (Maywood) 237:334–342. doi:10.1258/ebm.2011.011288
Ng Y, Moberly SP, Mather KJ, Brown-Proctor C, Hutchins GD, Green MA (2013) Equivalence of arterial and venous blood for [(11)C]CO(2)-metabolite analysis following intravenous administration of 1-[(11)C]acetate and 1-[(11)C]palmitate. Nucl Med Biol. doi:10.1016/j.nucmedbio.2012.11.011
Nikolaidis LA, Doverspike A, Hentosz T, Zourelias L, Shen YT, Elahi D, Shannon RP (2005) Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther 312:303–308. doi:10.1124/jpet.104.073890
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. doi:10.1161/01.CIR.0000139339.85840.DD
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. doi:10.1152/ajpheart.00347.2005
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. doi:10.1161/01.CIR.0000120505.91348.58
Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, Brown TJ, Streutker C, Holland D, Cao X, Baggio LL, Drucker DJ (2013) GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(−/−) mice. Endocrinology 154:127–139. doi:10.1210/en.2012-1937
Penna C, Pasqua T, Perrelli MG, Pagliaro P, Cerra MC, Angelone T (2012) Postconditioning with glucagon like peptide-2 reduces ischemia/reperfusion injury in isolated rat hearts: role of survival kinases and mitochondrial KATP channels. Basic Res Cardiol 107:272. doi:10.1007/s00395-012-0272-6
Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109:2191–2196. doi:10.1161/01.CIR.0000127959.28627.F8
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. doi:10.1161/CIRCHEARTFAILURE.108.766402
Pyke C, Knudsen LB (2013) The glucagon-like peptide-1 receptor—or not? Endocrinology 154:4–8. doi:10.1210/en.2012-2124
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2012) Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125:e2–e220. doi:10.1161/CIR.0b013e31823ac046
Schelbert HR (2004) Positron emission tomography of the heart: methodology, findings in the normal and diseased heart, and clinical applications. In: Phelps ME (ed) PET: molecular imaging and its biological applications. Springer, New York, pp 389–508
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. doi:10.1016/j.cardfail.2006.08.211
Sonne DP, Engstrom 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. doi:10.1016/j.regpep.2007.10.001
Sun KT, Yeatman LA, Buxton DB, Chen K, Johnson JA, Huang SC, Kofoed KF, Weismueller S, Czernin J, Phelps ME, Schelbert HR (1998) Simultaneous measurement of myocardial oxygen consumption and blood flow using [1-carbon-11]acetate. J Nucl Med 39:272–280. doi:10.2967/9476935
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. doi:10.1161/hh1701.095716
Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613. doi:11246881
Yan W, Zhang H, Liu P, Wang H, Liu J, Gao C, Liu Y, Lian K, Yang L, Sun L, Guo Y, Zhang L, Dong L, Lau WB, Gao E, Gao F, Xiong L, Qu Y, Tao L (2013) Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1alpha signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol 108:329. doi:10.1007/s00395-013-0329-1
Zhang H, Dellsperger KC, Zhang C (2012) The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol 107:237. doi:10.1007/s00395-011-0237-1
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. doi:10.1124/jpet.106.100982
Acknowledgments
This work was supported by NIH grants HL092245 (JDT), HL092799 (KJM), HL117620 (KJM and JDT), the Indiana Clinical and Translational Sciences Institute (TR000006) and the IU Medical Scientist Training Program (for SPM).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moberly, S.P., Mather, K.J., Berwick, Z.C. et al. Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus. Basic Res Cardiol 108, 365 (2013). https://doi.org/10.1007/s00395-013-0365-x
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-013-0365-x