Skip to main content Accessibility help

Insulin resistance and glucose-induced thermogenesis in critical illness

  • Gordon L. Carlson (a1)


Critical illness is associated with a marked increase in metabolic rate and progressive wasting, despite aggressive nutritional support. The metabolic events which are responsible for these phenomena are unclear, but are characterised by marked impairment of the anabolic effects of insulin on glucose metabolism and excessive activation of the sympathetic nervous system. It has been suggested that critical illness may be associated with impaired carbohydrate oxidation and a marked increase in the loss of heat energy associated with glucose administration (glucose-induced thermogenesis). This situation may result in impaired efficiency of nutrient assimilation. Studies employing combinations of nutrient infusions both at clinically-relevant rates and in association with euglycaemic hyperinsulinaemia have, however, demonstrated that nutrient-induced thermogenesis is unaffected in critical illness in human subjects, and that defective glucose utilization occurs as a consequence of impaired insulin-mediated glucose storage rather than oxidation. Although the cellular and molecular mechanisms underlying these changes are controversial, the recent validation of a human model of insulin resistance in critical illness should provide a means of studying this response in future, and allow the identification of therapeutic targets. This information should increase the efficacy of nutritional support in some of our most seriously-ill patients.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Insulin resistance and glucose-induced thermogenesis in critical illness
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Insulin resistance and glucose-induced thermogenesis in critical illness
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Insulin resistance and glucose-induced thermogenesis in critical illness
      Available formats


Corresponding author

Corresponding Author: Mr Gordon Carlson, fax +44 161 707 9708, email


Hide All
Acheson, KJ, Jequier, E & Wahren, J (1983) Influence of beta adrenergic blockade on glucose-induced thermogenesis. Journal of Clinical Investigation 72, 981986.
Acheson, KJ, Ravussin, E, Wahren, J & Jéquier, E (1984) Thermic effect of glucose in man. Obligatory and facultative thermogenesis. Journal of Clinical Investigation 73, 15721580.
Agwunobi, AO, Reid, C, Maycock, P, Little, RA & Carlson, GL (2000) Insulin resistance and substrate utilization in human endotoxaemia. Journal of Clinical Endocrinology and Metabolism 85, 37703778.
Allard, JP, Jeejeebhoy, KN, Whitwell, J, Pashutinski, L & Peters, WJ (1988) Factors influencing energy expenditure in patients with burns. Journal of Trauma 28, 199202.
Arnold, J, Leinhardt, D, Carlson, G, Gray, P, Little, RA & Irving, MH (1992) Thermogenic and hormonal responses to amino acid infusion in septic humans. American Journal of Physiology 263, E129E135.
Arnold, J, Shipley, K, Scott, NA, Little, RA & Irving, MH (1989) Thermic effect of parenteral nutrition in septic and non-septic individuals. American Journal of Clinical Nutrition 53, 853863.
Arnold, J, Shipley, KA, Scott, NA, Little, RA & Irving, MH (1991) Lipid infusion increases oxygen consumption similarly in septic and nonseptic patients. American Journal of Clinical Nutrition 53, 143148.
Askanazi, J, Carpentier, YA, Elwyn, DH, Nordenstrom, J, Jeevanandam, M, Rosenbaum, SH, Gump, FE & Kinney, JM (1980) Influence of total parenteral nutrition on fuel utilization in injury and sepsis. Annals of Surgery 291, 4046.
Barton, RN (1987) The neuroendocrinology of physical injury. Clinical Endocrinology and Metabolism 1, 355374.
Bedard, S, Marcotte, B & Marette, A (1997) Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase. Biochemical Journal 325, 487493.
Begum, N & Ragolia, L (1996) Effect of tumor necrosis factor-alpha on insulin action in cultured rat skeletal muscle cells. Endocrinology 137, 24412446.
Benedict, FG & Carpenter, TM (1918) Food ingestion and energy transformations with special reference to the stimulating effects of nutrients. Carnegie Institute of Washington 355382.
Bessey, PQ, Watters, JM, Aoki, TT & Wilmore, DW (1984) Combined hormonal infusion simulates the metabolic response to injury. Annals of Surgery 200, 264281.
Bjorntorp, P & Sjostrom, L (1978) Carbohydrate storage in man: speculations and some quantitative considerations. Metabolism 27, 18531865.
Bornstein, SR, Licinio, J, Tauchnitz, R, Engelmann, L, Negrao, AB, Gold, P & Chrousos, GP (1998a) Plasma leptin levels are increased in survivors of acute sepsis: Associated loss of diurnal rhythm in cortisol and leptin secretion. Journal of Clinical Endocrinology and Metabolism 83, 280283.
Bornstein, SR, Preas, HL, Chrousos, GP & Suffredini, AF (1998b) Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans. Journal of Infectious Diseases 178, 887890.
Carlson, GL (1998) Nutrient induced thermogenesis. In Baillière's Clinical Endocrinology and Metabolism: Energy Metabolism in Trauma, pp. 603615 [Little, RA and Werrneman, J, editors]. London: Baillière-Tindall.
Carlson, GL, Gray, P, Arnold, J, Little, RA & Irving, MH (1994) Thermogenic, hormonal and metabolic effects of a TPN mixture. Influence of glucose and amino acids. American Journal of Physiology 266, E845E851.
Carlson, GL, Gray, P, Arnold, J, Little, RA & Irving, MH (1997) Thermogenic, hormonal and metabolic effects of intravenous glucose infusion in human sepsis. British Journal of Surgery 84, 14541459.
Carlson, GL & Little, RA (1992) The pathophysiology and pattern of the hormonal response to severe sepsis. In Endocrine Consequences of Critical Illness, pp. 5769 [Boles, JM, editor]. Paris: Arnette.
Carlson, GL & Little, RA (1994) Insulin resistance and tissue fuels. In Organ Metabolism and Nutrition: Ideas for Critical Care, pp. 4969 [Kinney, JM, editor]. New York: Raven Press.
Carlson, GL, Saeed, M, Little, RA & Irving, MH (1999) Serum leptin concentrations and their relation to metabolic abnormalities in human sepsis. American Journal of Physiology 276, E658E662.
Carpenter, TM & Fox, EL (1930) The gaseous exchange of the human subject III. As affected by small quantities of levulose. Journal of Nutrition ii, 389408.
Catania, RA, Schwacha, MG, Cioffi, WG, Bland, KI & Chaudry, IH (1999) Does uninjured skin release proinflammatory cytokines following trauma and hemorrhage? Archives of Surgery 134, 368374.
Christin, L, Nach, C-A, Vernet, O, Ravussin, E, Jéquier, E & Acheson, K (1986) Insulin – its role in the thermic effect of glucose. Journal of Clinical Investigation 77, 17471755.
Cohen, B, Novick, D & Rubinstein, M (1996) Modulation of insulin activities by leptin. Science 274, 11851188.
DeFronzo, R, Thorin, D, Felber, J, Simonson, D, Thiebaud, D, Jequier, E & Golay, A (1984) Effect of beta and alpha adrenergic blockade on glucose-induced thermogenesis in man. Journal of Clinical Investigation 73, 633639.
Elwyn, DH, Kinney, JM, Jeevanandam, M, Gump, FE & Broell, JR (1978) Influence of increasing carbohydrate intake on glucose kinetics in injured patients. Annals of Surgery 190, 117126.
Evans, EI & Butterfield, WJH (1951) The stress response in the severely burned. Annals of Surgery 134, 588613.
Fan, J, Li, YH, Wojnar, MM & Lang, CH (1996) Endotoxin-induced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1 and MAP kinase in skeletal muscle. Shock 6, 164170.
Ferrannini, E, Smith, JD, Cobelli, C, Toffolo, G, Pilo, A & DeFronzo, RA (1985) Effect of insulin on the distribution and disposition of glucose in man. Journal of Clinical Investigation 76, 357364.
Fischer, P (1862) Du diabete consecutif aux traumatismes (Diabetes following traumas). Archives Generale de Medecine 20, 413443.
Flatt, JP (1977) The biochemistry of energy expenditure. In Recent Advances in Obesity Research, pp. 211228 [Bray, GA, editor]. Washington, DC: Newman.
Furnsinn, C, Neschen, S, Wagner, O, Roden, M, Bisschop, M & Waldhausl, W (1997) Acute and chronic exposure to tumor necrosis factor-alpha fails to affect insulin-stimulated glucose metabolism of isolated rat soleus muscle. Endocrinology 138, 26742679.
Gelfand, RA, Matthews, DE, Bier, DM & Sherwin, RS (1984) Role of counterregulatory hormones in the catabolic response to stress. Journal of Clinical Investigation 74, 22382248.
Giovannini, I, Chiarla, C, Boldrini, G, Castiglioni, G & Castagneto, M (1988) Calorimetric response to amino acid infusion in sepsis and critical illness. Critical Care Medicine 16, 667670.
Green, CJ, Campbell, IT, O'Sullivan, E, Underhill, S, McLaren, DPM, Hipkin, LJ, MacDonald, IA & Russell, J (1995) Septic patients in multiple organ failure can oxidize infused glucose but non-oxidative disposal (storage) is impaired. Clinical Science 89, 601609.
Grunfeld, C, Zhao, C, Fuller, J, Pollock, A, Moser, A, Friedman, J & Feingold, K (1996) Endotoxin and cytokines induce expression of leptin the ob gene product in hamsters. Journal of Clinical Investigation 97, 21522157.
Howard, JM (1955) Studies of the absorption and metabolism of glucose following injury. Annals of Surgery 141, 321.
Krebs, HA (1964) The metabolic fate of amino acids. In Mammalian Protein Metabolism, pp. 125176 [Munro, HN and Allison, JB, editors]. New York and London: Academic Press.
Lang, CH, Dobrescu, C & Bagby, GJ (1992) Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130, 4352.
Lavoisier, AL & LaPlace, P (1784) Memoire sur la chaleur (Memoir on heat). Histoires Academie Royale Science 355408.
Leinhardt, DJ, Arnold, J, Shipley, KA, Mughal, MM, Little, RA & Irving, MH (1993) Plasma NE concentrations do not accurately reflect sympathetic nervous system activity in human sepsis. American Journal of Physiology 265, E284E288.
Liu, YL, Emilsson, V & Cawthorne, MA (1997) Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese ob/ob mice. FEBS Letters 411, 351355.
Lusk, G (1912) Animal calorimetry. The influence of the ingestion of amino acids upon metabolism. Journal of Biological Chemistry XIII, 155183.
Lusk, G (1922) The specific dynamic action of various food factors. Medicine 1, 311354.
Lusk, G (1931) The specific dynamic action. Journal of Nutrition iii, 519530.
McCall, JL, Tuckey, JA & Parry, BR (1992) Serum tumor necrosis factor alpha and insulin resistance in gastrointestinal cancer. British Journal of Surgery 79, 13611363.
Magnus-Levy, A (1894) Über die Grosse des respiratorischen Gaswechsels unter dem einfluss der nahrungsaufnahme (On the extent of respiratory gaseous exchange in relation to food intake). Pflugers Archiv 46, 1126.
Moan, A, Hoieggen, A, Nordby, G, Birkeland, K, Eide, I & Kjeldsen, SE (1995) The glucose clamp procedure activates the sympathetic nervous system even in the absence of hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism 80, 31513154.
Molina, PE, Malek, S, Lang, CH, Qian, L, Naukam, R & Abumrad, NN (1997) Early organ-specific hemorrhage-induced increases in tissue cytokine content: Associated neurohormonal and opioid alterations. Neuroimmunomodulation 4, 2836.
Moshyedi, AK, Josephs, MD, Abdalla, EK, Mackay, SL, Edwards, CK III, Copeland, EM III & Moldawer, LL (1998) Increased leptin expression in mice with bacterial peritonitis is partially regulated by tumor necrosis factor alpha. Infection and Immunity 66, 18001802.
Newsholme, EA & Crabtree, B (1976) Substrate cycles in metabolic regulation and in heat generation. Biochemical Society Symposia 41, 61109.
Ng, LL & Hockaday, TD (1989) The effect of environmental temperature on prandial changes in leucocyte sodium transport. British Journal of Nutrition 62, 639645.
Noguchi, Y, Yoshikawa, T, Marat, D, Doi, C, Makino, T, Fukuzawa, K, Tsuburaya, A, Satoh, S, Ito, T & Mitsuse, S (1998) Insulin resistance in cancer patients is associated with enhanced tumor necrosis factor alpha expression in skeletal muscle. Biochemical and Biophysical Research Communications 253, 887892.
Nordenström, JM, Jeevanandam, M, Elwyn, DH, Carpentier, YA, Askanazi, J, Arnold, R & Kinney, JM (1981) Increasing glucose intake during total parenteral nutrition increases norepinephrine in trauma and sepsis. Clinical Physiology 1, 525534.
Randle, PJ, Garland, PB, Hales, CN & Newsholme, EA (1963) The glucose fatty acid cycle, its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet i, 787788.
Ravussin, E & Bogardus, C (1982) Thermogenic response to insulin and glucose infusions in man: a model to evaluate the different components of the thermic effect of carbohydrate. Life Science 31, 20112018.
Robertson, RP & Porte, D Jr (1974) Plasma catecholamine responses to intravenous glucose in normal man. Journal of Clinical Endocrinology and Metabolism 39, 403405.
Rubner, M (1902) Die Gesetze die Energieverbrauchs bei der Ernahrung (The laws of energy consumption with nutrition). Leipzig and Vienna: Rubner.
Saeed, M & Carlson, GL (1995) Substrate utilisation after injury. International Journal of Orthopaedic Trauma 5, 152157.
Saeed, M, Carlson, GL, Little, RA & Irving, MH (1999) Selective impairment of glucose storage in human sepsis. British Journal of Surgery 86, 813821.
Segal, KR, Landt, M & Klein, S (1996) Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45, 988991.
Shulman, RG, Bloch, G & Rothman, DL (1995) In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proceedings of the National Academy of Sciences USA 92, 85358542.
Smith, E (1859) Experiments on respiration-second communication. On the action of foods upon the respiration during the primary processes of digestion. Philosophical Transactions of the Royal Society 149, 715742.
Stoner, HB, Little, RA, Frayn, KN, Elebute, EA, Tresadern, J & Gross, E (1983) The effect of sepsis upon the oxidation of carbohydrate and fat. British Journal of Surgery 70, 3235.
Stratton, RJ, Dewit, O, Crowe, E, Jennings, G, Villar, RN & Elia, M (1997) Plasma leptin, energy intake and hunger following total hip replacement surgery. Clinical Science 93, 113117.
Thiebaud, D, Schutz, Y, Acheson, K, Jacot, E, DeFronzo, R, Felber, J-P, & Jequier, E (1983) Energy cost of glucose storage in human subjects during glucose-insulin infusions. American Journal of Physiology 244, E216E221.
Thorell, A, Efendic, S, Gutniak, M, Haggmark, T & Ljungqvist, O (1994) Insulin resistance after abdominal surgery. British Journal of Surgery 81, 5963.
Uysal, KT, Wiesbrock, SM, Marino, MW & Hotamisligil, GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–4.
Vary, TC, Drnevich, D, Jurasinski, C & Brennan, WA (1995) Mechanisms regulating skeletal muscle glucose metabolism in sepsis. Shock 3, 403410.
Virkamaki, A, Puhakainen, I, Koivisto, VA, Vuorinen-Markkola, H & Yki-Jarvinen, H (1992) Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans. Journal of Clinical Endocrinology and Metabolism 74, 673679.
Virkamaki, A & Yki-Jarvinen, H (1994) Mechanisms of insulin resistance during acute endotoxaemia. Endocrinology 134, 20722078.
Welle, S, Lilavivat, U & Campbell, RG (1981) Thermic effect of feeding in man: increased plasma norepinephrine levels following glucose but not protein or fat consumption. Metabolism 30, 953958.
White, RH, Frayn, KN, Little, RA, Threlfall, CJ, Stoner, HB & Irving, MH (1987) Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycaemic glucose clamp technique. Journal of Parenteral and Enteral Nutrition 11, 345353.
Winkler, G, Salamon, F, Salamon, D, Speer, G, Simon, K & Cseh, K (1998) Elevated serum tumour necrosis factor alpha levels can contribute to the insulin resistance in Type II (non- insulin-dependent) diabetes and in obesity. Diabetologia 41, 860861.
Wolfe, RR, Jahoor, F, Herndon, D & Miyoshi, H (1991) Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion. Surgery 110, 5467.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed