Influence of GLP-1 on myocardial glucose metabolism in healthy men during normo- or hypoglycemia

Michael Gejl, Susanne Lerche, Annette Mengel, Niels Møller, Bo Martin Bibby, Kamille Smidt, Birgitte Brock, Hanne Søndergaard, Hans Erik Bøtker, Albert Gjedde, Jens Juul Holst, Søren Baarsgaard Hansen, Jørgen Rungby, Michael Gejl, Susanne Lerche, Annette Mengel, Niels Møller, Bo Martin Bibby, Kamille Smidt, Birgitte Brock, Hanne Søndergaard, Hans Erik Bøtker, Albert Gjedde, Jens Juul Holst, Søren Baarsgaard Hansen, Jørgen Rungby

Abstract

Background and aims: Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia.

Materials and methods: We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with (18)fluoro-deoxy-glucose ((18)F-FDG) as tracer.

Results: In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m(2) and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m(2). GLP-1 did not change MGU during normoglycemia (mean (+/- SD) 0.15+/-0.04 and 0.16+/-0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/-0.03 and 0.13+/-0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r(2) = 0.64 and P = 0.018, r(2) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found.

Conclusions: While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study design.
Figure 1. Study design.
Design of the normoglycemic study (n = 10) (A) and the hypoglycemic study (n = 8) (B). The studies were conducted as randomized, double-blinded, placebo-controlled, crossover studies. X1 and X2: PET and clamp data.
Figure 2. Positron emission tomography.
Figure 2. Positron emission tomography.
Myocardial glucose uptake (MGU) during normoglycemia and hypoglycemia (A and B). 18F-FDG clearance (K) during normoglycemia and hypoglycemia (C and D). Relation between placebo MGU and change in MGU during GLP-1 infusion in the normoglycemia study (E), placebo MGU and change in MGU during GLP-1 infusion in the hypoglycemia study (F). Relation between placebo K and change in K during GLP-1 infusion in the normoglycemia study (G), placebo K and change in K during GLP-1 infusion in the hypoglycemia study (H). HOMA 2IR and the change of MGU during GLP-1 infusion in the hypoglycemia study (I). HOMA 2IR and the change of K during GLP-1 infusion in the hypoglycemia study (J). Data are mean ± SD. Regression lines with 95% confidence intervals.
Figure 3. Hormones and metabolites - normoglycemia…
Figure 3. Hormones and metabolites - normoglycemia study.
Plasma glucose, glucose infusion rates (GIR), total GLP-1, insulin, cortisol, free fatty acid (FFA), glucagon and epinephrine concentrations during GLP-1 (black dots) and placebo infusion (white dots). Data are means ± SEM. * P≤0.05.
Figure 4. Hormones and metabolites - hypoglycemia…
Figure 4. Hormones and metabolites - hypoglycemia study.
Plasma glucose, glucose infusion rates (GIR), total GLP-1, insulin, cortisol, free fatty acid (FFA), glucagon and epinephrine concentrations during GLP-1 (black dots) and placebo infusion (white dots). Data are means ± SEM. * P≤0.05.

References

    1. Smyth S, Heron A (2006) Diabetes and obesity: the twin epidemics. Nat Med 12: 75–80 nm0106-75 [pii];10.1038/nm0106-75 [doi].
    1. DeFronzo RA (2004) Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 88: 787–835, ix.
    1. Guz Y, Nasir I, Teitelman G (2001) Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes. Endocrinology 142: 4956–4968.
    1. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ (2011) Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54: 10–18 10.1007/s00125-010-1896-4 [doi].
    1. van den Brom CE, Bulte CS, Loer SA, Bouwman RA, Boer C (2013) Diabetes, perioperative ischaemia and volatile anaesthetics: consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol 12: 42 1475-2840-12-42 [pii];10.1186/1475-2840-12-42 [doi].
    1. Taegtmeyer H, McNulty P, Young ME (2002) Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation 105: 1727–1733.
    1. Holst JJ (2004) On the Physiology of GIP and GLP-1. Horm Metab Res 36: 747–754.
    1. Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, et al. (2012) Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 33: 1491–1499 ehr309 [pii];10.1093/eurheartj/ehr309 [doi].
    1. Ravassa S, Zudaire A, Diez J (2012) GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res 94: 316–323 cvs123 [pii];10.1093/cvr/cvs123 [doi].
    1. Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, et al. (2004) Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 53: 2397–2403 53/9/2397 [pii].
    1. Gejl M, Sondergaard HM, Stecher C, Bibby BM, Moller N, et al. (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 jc.2011-3456 [pii];10.1210/jc.2011-3456 [doi].
    1. Toft-Nielsen MB, Madsbad S, Holst JJ (1999) Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 22: 1137–1143.
    1. Espelund U, Hansen TK, Hojlund K, Beck-Nielsen H, Clausen JT, et al. (2005) Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. J Clin Endocrinol Metab 90: 741–746 jc.2004-0604 [pii];10.1210/jc.2004-0604 [doi].
    1. Eriksson BM, Persson BA (1982) Determination of catecholamines in rat heart tissue and plasma samples by liquid chromatography with electrochemical detection. J Chromatogr 228: 143–154.
    1. Orskov H, Thomsen HG, Yde H (1968) Wick chromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone. Nature 219: 193–195.
    1. Wilken M, Larsen FS, Buckley D, Holst JJ (1999) New highly specific immunoassays for glucacon-like peptide 1 (GLP-1). Diabetologia 42: A196.
    1. Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43: 535–539.
    1. Gjedde A (1981) High- and low-affinity transport of D-glucose from blood to brain. J Neurochem 36: 1463–1471.
    1. Gjedde A (1982) Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: a re-examination. Brain Res 257: 237–274.
    1. Lerche S, Brock B, Rungby J, Botker HE, Moller N, et al. (2008) Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans. Diabetes 57: 325–331 db07-1162 [pii];10.2337/db07-1162 [doi].
    1. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27: 1487–1495 27/6/1487 [pii].
    1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90: 207–258 90/1/207 [pii];10.1152/physrev.00015.2009 [doi].
    1. Owen P, Dennis S, Opie LH (1990) Glucose flux rate regulates onset of ischemic contracture in globally underperfused rat hearts. Circ Res 66: 344–354.
    1. Mallet RT, Hartman DA, Bunger R (1990) Glucose requirement for postischemic recovery of perfused working heart. Eur J Biochem 188: 481–493.
    1. Finfer S, Chittock DR, Su SY, Blair D, Foster D, et al. (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360: 1283–1297 NEJMoa0810625 [pii];10.1056/NEJMoa0810625 [doi].
    1. 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 S1071-9164(06)01109-2 [pii];10.1016/j.cardfail.2006.08.211 [doi].
    1. Nielsen R, Wiggers H, Halbirk M, Botker H, Holst JJ, et al. (2012) Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients. Exp Clin Endocrinol Diabetes 120: 266–272 10.1055/s-0032-1304605 [doi].
    1. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, et al. (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87: 1239–1246.
    1. Gejl M, Lerche S, Egefjord L, Brock B, Moller N, et al. (2013) Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain. Front Neuroenergetics 5: 2 10.3389/fnene.2013.00002 [doi].
    1. Ahren B, Schweizer A, Dejager S, Dunning BE, Nilsson PM, et al. (2009) Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes. J Clin Endocrinol Metab 94: 1236–1243 jc.2008-2152 [pii];10.1210/jc.2008-2152 [doi].
    1. Vella A, Shah P, Basu R, Basu A, Camilleri M, et al. (2001) Effect of glucagon-like peptide-1(7–36)-amide on initial splanchnic glucose uptake and insulin action in humans with type 1 diabetes. Diabetes 50: 565–572.
    1. Vella A, Shah P, Reed AS, Adkins AS, Basu R, et al. (2002) Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans. Diabetologia 45: 1410–1415.
    1. Ryan AS, Egan JM, Habener JF, Elahi D (1998) Insulinotropic hormone glucagon-like peptide-1-(7–37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia. J Clin Endocrinol Metab 83: 2399–2404.
    1. Larsen PJ, Tang-Christensen M, Jessop DS (1997) Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology 138: 4445–4455.
    1. Choi Y, Brunken RC, Hawkins RA, Huang SC, Buxton DB, et al. (1993) Factors affecting myocardial 2-[F-18]fluoro-2-deoxy-D-glucose uptake in positron emission tomography studies of normal humans. Eur J Nucl Med 20: 308–318.
    1. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, et al. (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 CIRCULATIONAHA.107.739938 [pii];10.1161/CIRCULATIONAHA.107.739938 [doi].
    1. Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, et al. (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 CIRCHEARTFAILURE.109.900282 [pii];10.1161/CIRCHEARTFAILURE.109.900282 [doi].
    1. Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, et al. (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 en.2012-1937 [pii];10.1210/en.2012-1937 [doi].
    1. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, et al. (2013) GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med nm.3128 [pii];10.1038/nm.3128 [doi].
    1. Pyke C, Knudsen LB (2013) The glucagon-like peptide-1 receptor–or not? Endocrinology 154: 4–8 154/1/4 [pii];10.1210/en.2012-2124 [doi].
    1. Chinda K, Chattipakorn S, Chattipakorn N (2012) Cardioprotective effects of incretin during ischaemia-reperfusion. Diab Vasc Dis Res 9: 256–269 1479164112440816 [pii];10.1177/1479164112440816 [doi].
    1. Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, et al. (2011) Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care 34: 90–95 dc10-1393 [pii];10.2337/dc10-1393 [doi].
    1. Sun F, Yu K, Wu S, Zhang Y, Yang Z, et al. (2012) Cardiovascular safety and glycemic control of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus: A pairwise and network meta-analysis. Diabetes Res Clin Pract S0168-8227(12)00308-7 [pii];10.1016/j.diabres.2012.09.004 [doi].
    1. Sivertsen J, Rosenmeier J, Holst JJ, Vilsboll T (2012) The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol 9: 209–222 nrcardio.2011.211 [pii];10.1038/nrcardio.2011.211 [doi].
    1. Kudoh A, Katagai H, Takazawa T (2002) Atrial natriuretic peptide increases glucose uptake during hypoxia in cardiomyocytes. J Cardiovasc Pharmacol 40: 601–610.
    1. Moberly SP, Mather KJ, Berwick ZC, Owen MK, Goodwill AG, et al. (2013) Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus. Basic Res Cardiol 108: 365 10.1007/s00395-013-0365-x [doi].
    1. Nishino Y, Miura T, Miki T, Sakamoto J, Nakamura Y, et al. (2004) Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection. Cardiovasc Res 61: 610–619 10.1016/j.cardiores.2003.10.022 [doi];S0008636303006874 [pii].
    1. Kainulainen H, Breiner M, Schurmann A, Marttinen A, Virjo A, et al. (1994) In vivo glucose uptake and glucose transporter proteins GLUT1 and GLUT4 in heart and various types of skeletal muscle from streptozotocin-diabetic rats. Biochim Biophys Acta 1225: 275–282.
    1. Hall JL, Sexton WL, Stanley WC (1995) Exercise training attenuates the reduction in myocardial GLUT-4 in diabetic rats. J Appl Physiol (1985 ) 78: 76–81.
    1. Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, et al. (2011) Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy. PLoS One 6: e17178 10.1371/journal.pone.0017178 [doi].
    1. Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, et al. (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 jpet.106.100982 [pii];10.1124/jpet.106.100982 [doi].
    1. Ding SY, Nkobena A, Kraft CA, Markwardt ML, Rizzo MA (2011) Glucagon-like peptide 1 stimulates post-translational activation of glucokinase in pancreatic beta cells. J Biol Chem 286: 16768–16774 M110.192799 [pii];10.1074/jbc.M110.192799 [doi].
    1. Van Dyke DA, Walters L, Frieswyk D, Kokmeyer D, Louters LL (2003) Acute effects of troglitazone and nitric oxide on glucose uptake in L929 fibroblast cells. Life Sci 72: 2321–2327 S002432050300119X [pii].
    1. Etgen GJ Jr, Fryburg DA, Gibbs EM (1997) Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. Diabetes 46: 1915–1919.
    1. Gejl M, Egefjord L, Lerche S, Vang K, Bibby BM, et al. (2012) Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. J Cereb Blood Flow Metab jcbfm2012118 [pii];10.1038/jcbfm.2012.118 [doi].
    1. Botker HE, Bottcher M, Schmitz O, Gee A, Hansen SB, et al. (1997) Glucose uptake and lumped constant variability in normal human hearts determined with [18F]fluorodeoxyglucose. J Nucl Cardiol 4: 125–132.
    1. Botker HE, Goodwin GW, Holden JE, Doenst T, Gjedde A, et al. (1999) Myocardial glucose uptake measured with fluorodeoxyglucose: a proposed method to account for variable lumped constants. J Nucl Med 40: 1186–1196.

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