Horm Metab Res 2010; 42(5): 348-352
DOI: 10.1055/s-0030-1248297
Animals, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Metabolic Effects of Free Fatty Acids During Endotoxaemia in a Porcine Model – Free Fatty Acid Inhibition of Growth Hormone Secretion as a Potential Catabolic Feedback Mechanism

M. Buhl1 , 2 , J. Gjedsted1 , 2 , A. Granfeldt2 , P. Ø. Larsen2 , O. Schmitz1 , 3 , E. Tønnesen2 , N. Møller1
  • 1Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark
  • 2Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 3Institute of Clinical Pharmacology, Aarhus University, Aarhus, Denmark
Further Information

Publication History

received 24.07.2009

accepted 21.01.2010

Publication Date:
01 March 2010 (online)

Abstract

Critical illness and severe inflammation are catabolic states characterised by breakdown of tissue and protein stores, by increased levels of free fatty acids, and by insulin resistance. These metabolic features contribute to morbidity and mortality. Growth hormone and insulin are the two major anabolic hormones. The present study was designed to test whether increased levels of free fatty acids (i) inhibit growth hormone secretion and (ii) induce insulin resistance during acute endotoxin exposure in a porcine model of critical illness. We studied 20 pigs for 6 h during combined anaesthesia and endotoxin infusion and a hyperinsulinaemic glucose clamp to control glucose, insulin, and free fatty acid concentrations. Pigs were randomised to two different continuous infusion rates of Intralipid® resulting in different, sustained, and elevated free fatty acid concentrations (1.63 mmol l–1 vs. 0.58 mmol l–1, p=0.0002). Concomitantly, we observed reduced growth hormone concentrations in the group with high free fatty acid concentrations (3.5 ng ml–1 vs. 6.6 ng ml–1, p<0.003). No difference in insulin sensitivity, measured as the glucose infusion rate necessary to maintain euglycaemia, was observed. We conclude that high levels of free fatty acids reduce circulating growth hormone concentrations in porcine endotoxaemia; this probably constitutes a negative feedback mechanism whereby growth hormone induced-stimulation of free fatty acids release inhibit growth hormone secretion. This mechanism may further contribute to protein loss in critical illness. We found no evidence that the increment of plasma free fatty acids between groups contribute to insulin resistance in critical illness.

References

  • 1 Lind L, Lithell H. Impaired glucose and lipid metabolism seen in intensive care patients is related to severity of illness and survival.  Clin Intensive Care. 1994;  5 100-105
  • 2 Nogueira AC, Kawabata V, Biselli P, Lins MH, Valeri C, Seckler M, Hoshino W, Junior LG, Bernik MM, de Andrade Machado JB, Martinez MB, Lotufo PA, Caldini EG, Martins E, Curi R, Soriano FG. Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability.  Shock. 2007;  29 342-348
  • 3 Mesotten D, Swinnen JV, Vanderhoydonc F, Wouters PJ, Van den BG. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy.  J Clin Endocrinol Metab. 2004;  89 219-226
  • 4 Streat SJ, Beddoe AH, Hill GL. Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients.  J Trauma. 1987;  27 262-266
  • 5 Van den Berghe G, de ZF, Bouillon R. Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms.  J Clin Endocrinol Metab. 1998;  83 1827-1834
  • 6 Chambrier C, Laville M, Rhzioual BK, Odeon M, Bouletreau P, Beylot M. Insulin sensitivity of glucose and fat metabolism in severe sepsis.  Clin Sci (Lond). 2000;  99 321-328
  • 7 Shangraw RE, Jahoor F, Miyoshi H, Neff WA, Stuart CA, Herndon DN, Wolfe RR. Differentiation between septic and postburn insulin resistance.  Metabolism. 1989;  38 983-989
  • 8 Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients.  N Engl J Med. 2001;  345 1359-1367
  • 9 Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van WE, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU.  N Engl J Med. 2006;  354 449-461
  • 10 Moller N, Nair KS. Diabetes and protein metabolism.  Diabetes. 2008;  57 3-4
  • 11 Moller N, Otto Lunde JJ. Effects of Growth Hormone on Glucose, Lipid and Protein Metabolism in Human Subjects.  Endocr Rev. 2009;  152-177
  • 12 Bentham J, Rodriguez-Arnao J, Ross RJ. Acquired growth hormone resistance in patients with hypercatabolism.  Horm Res. 1993;  40 87-91
  • 13 Ross R, Miell J, Freeman E, Jones J, Matthews D, Preece M, Buchanan C. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I.  Clin Endocrinol (Oxf). 1991;  35 47-54
  • 14 Norrelund H, Nair KS, Jorgensen JO, Christiansen JS, Moller N. The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown.  Diabetes. 2001;  50 96-104
  • 15 Norrelund H, Nair KS, Nielsen S, Frystyk J, Ivarsen P, Jorgensen JO, Christiansen JS, Moller N. The decisive role of free fatty acids for protein conservation during fasting in humans with and without growth hormone.  J Clin Endocrinol Metab. 2003;  88 4371-4378
  • 16 Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults.  N Engl J Med. 1999;  341 785-792
  • 17 Gallin JI, Kaye D, O’Leary WM. Serum lipids in infection.  N Engl J Med. 1969;  281 1081-1086
  • 18 Nishishita S. Studies on the fluctuation of the lipoid content of the blood in the fever period.  Jpn J Exper Med. 1941;  97-107
  • 19 Samra JS, Summers LKM, Frayn KN. Sepsis and fat metabolism.  Brit J Surg. 1996;  83 1186-1196
  • 20 Wymann MP, Schneiter R. Lipid signalling in disease.  Nat Rev Mol Cell Biol. 2008;  9 162-176
  • 21 Pilz S, Scharnagl H, Tiran B, Seelhorst U, Wellnitz B, Boehm BO, Schaefer JR, Marz W. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease.  J Clin Endocrinol Metab. 2006;  91 2542-2547
  • 22 Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias.  Lancet. 1994;  343 155-158
  • 23 Schroder NW, Heine H, Alexander C, Manukyan M, Eckert J, Hamann L, Gobel UB, Schumann RR. Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses.  J Immunol. 2004;  173 2683-2691
  • 24 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance.  J Clin Invest. 2006;  116 3015-3025
  • 25 Song MJ, Kim KH, Yoon JM, Kim JB. Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes.  Biochem Biophys Res Commun. 2006;  346 739-745
  • 26 Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans.  J Clin Invest. 1996;  97 2859-2865
  • 27 Widmaier EP. Metabolic feedback in mammalian endocrine systems.  Horm Metab Res. 1992;  24 147-153
  • 28 Quabbe HJ, Bratzke HJ, Siegers U, Elban K. Studies on the relationship between plasma free fatty acids and growth hormone secretion in man.  J Clin Invest. 1972;  51 2388-2398
  • 29 Casanueva FF, Villanueva L, Dieguez C, Diaz Y, Cabranes JA, Szoke B, Scanlon MF, Schally AV, Fernandez-Cruz A. Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary.  J Clin Endocrinol Metab. 1987;  65 634-642
  • 30 Buhl M, Gjedsted J, Granfeldt A, Larsen PO, Chew M, Moller N, Tonnesen E. Circulating free fatty acids do not contribute to the acute systemic inflammatory response. An experimental study in porcine endotoxaemia.  Basic Clin Pharmacol Toxicol. 2009;  104 1-8
  • 31 Harano Y, Ohtsuki M, Ida M, Kojima H, Harada M, Okanishi T, Kashiwagi A, Ochi Y, Uno S, Shigeta Y. Direct automated assay method for serum or urine levels of ketone bodies.  Clin Chim Acta. 1985;  151 177-183
  • 32 Orskov H, Thomsen HG, Yde H. Wick chromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone.  Nature. 1968;  219 193-195
  • 33 Carstensen E, Yudkin JS. Platelet catecholamine concentrations after short-term stress in normal subjects.  Clin Sci (Lond). 1994;  86 35-41
  • 34 Moller N, Schmitz O, Porksen N, Moller J, Jorgensen JO. Dose-response studies on the metabolic effects of a growth hormone pulse in humans.  Metabolism. 1992;  41 172-175
  • 35 Van den Berghe G. Novel insights into the neuroendocrinology of critical illness.  Eur J Endocrinol. 2000;  143 1-13
  • 36 Briard N, Rico-Gomez M, Guillaume V, Sauze N, Vuaroqueaux V, Dadoun F, Le BY, Oliver C, Dutour A. Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep.  Endocrinology. 1998;  139 4811-4819
  • 37 McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V. The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection.  Ann N Y Acad Sci. 2000;  917 4-18
  • 38 Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis.  J Endotoxin Res. 2003;  9 3-24
  • 39 Migrenne S, Magnan C, Cruciani-Guglielmacci C. Fatty acid sensing and nervous control of energy homeostasis.  Diabetes Metab. 2007;  33 177-182
  • 40 van der Poll T, Romijn JA, Endert E, Borm JJ, Buller HR, Sauerwein HP. Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans.  Am J Physiol. 1991;  261 457-465
  • 41 Moller N, Beckwith R, Butler PC, Christensen NJ, Orskov H, Alberti KG. Metabolic and hormonal responses to exogenous hyperthermia in man.  Clin Endocrinol (Oxf). 1989;  30 651-660
  • 42 Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL. Insulin resistance and substrate utilization in human endotoxemia.  J Clin Endocrinol Metab. 2000;  85 3770-3778
  • 43 Vary TC, Drnevich D, Jurasinski C, Brennan Jr WA. Mechanisms regulating skeletal muscle glucose metabolism in sepsis.  Shock. 1995;  3 403-410
  • 44 Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  1 785-789
  • 45 Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction.  Am J Respir Crit Care Med. 1998;  157 1021-1026
  • 46 Vary TC, Siegel JH. Effect of sepsis on activity of pyruvate dehydrogenase complex in skeletal muscle and liver.  Am J Physiol. 1989;  256 445

Correspondence

M. Buhl

Medical Department M (Endocrinology and Diabetes)

Århus Sygehus, NBG

Bygning 1c, 1.sal

Nørrebrogade 44

8000 Århus C

Denmark

Phone: +45 8949 2852

Fax: +45 8949 2740

Email: m.buhl@ki.au.dk