Insulinresistenz: Bedeutung in Anästhesie und Intensivmedizin – Pathophysiologie der perioperativ gestörten Insulinsensitivität

Zusammenfassung

Hyperglykämie und Insulinresistenz treten gehäuft perioperativ und bei kritisch kranken Patienten auf. Die zugrundeliegende Pathophysiologie ist bislang nur in Ansätzen bekannt, obwohl Hyperglykämien mit erhöhter postoperativer Morbidität und Mortalität assoziiert sind. Die Insulinresistenz ist offenkundig ein komplexes Geschehen, wobei auch gewebsspezifische Unterschiede berücksichtigt werden müssen. Verschiedene Auslöser wie auch unterschiedliche intrazellulär beteiligte Signalkaskaden liegen der perioperativen Insulinresistenz zugrunde. Dieser Review fokussiert auf Mechanismen, welche die klassische Insulinsignalkaskade betreffen.

Abstract

Hyperglycemia and insulin resistance are frequently observed during critical illness. The underlying pathophysiology is not yet fully understood, although hyperglycemia predicts post-surgical morbidity and mortality. Apparently perioperative insulin resistance has a complex pathophysiology and tissue-specific differences have to be considered. Multiple causative factors and intracellular signalling pathways have been identified driving the development of systemic perioperative insulin resistance. This review will focus on mechanisms involving the classical insulin signalling cascade.

Perioperative Insulinresistenz - Insulinsignalweg - Critical-Illness

perioperative insulin resistance - insulin signalling - critical illness

Kernaussagen

• Bei insulinresistenten Patienten führt eine reduzierte Glukoseaufnahme zu gesteigerter Morbidität und Mortalität.

• Hyperglykämie und Insulinresistenz sind mit erhöhten postoperativen Komplikationen verbunden.

• Physische Inaktivität ist assoziiert mit dem Auftreten von Insulinresistenz und Mikrozirkulationsstörungen.

• Kortisol, Wachstumshormone und endogene wie exogene Katecholaminspiegel hemmen die Wirkung von Insulin.

• Hypocholesterinämie wird bei Verletzungen und Infektionen häufig beobachtet; es besteht eine Korrelation zwischen Hypocholesterinämie und Mortalität.

• Nach Operationen und Verletzungen können erhöhte inflammatorische Zytokinspiegel nachgewiesen werden, welche mit Insulinresistenz, Diabetes-mellitus Typ 2 und Adipositas in Verbindung gebracht werden.

Literatur

• 1 van den Berghe G et al.. Intensive insulin therapy in the critically ill patients.  N Engl J Med. 2001;  345 1359-1367
• 2 Furnary AP et al.. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting.  J Thorac Cardiovasc Surg. 2003;  125 1007-1021
• 3 Van den Berghe G et al.. Intensive insulin therapy in the medical ICU.  N Engl J Med. 2006;  354 449-461
• 4 Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients.  Mayo Clin Proc. 2004;  79 992-1000
• 5 Bruning JC et al.. Role of brain insulin receptor in control of body weight and reproduction.  Science. 2000;  289 2122-2125
• 6 DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes.  Diabetes Review. 1997;  5 177-269
• 7 White MF, Yenush L. The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action.  Curr Top Microbiol Immunol. 1998;  228 179-208
• 8 Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action.  Nat Rev Mol Cell Biol. 2006;  7 85-96
• 9 Sale EM, Sale GJ. Protein kinase B: signalling roles and therapeutic targeting.  Cell Mol Life Sci. 2008;  65 113-127
• 10 Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes.  Exp Biol Med (Maywood). 2005;  230 593-605
• 11 Sano H et al.. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.  J Biol Chem. 2003;  278 14599-14602
• 12 Le Marchand-Brustel Y et al.. Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin-resistant obese mice.  Nature. 1985;  315 676-679
• 13 Kim YB et al.. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes.  J Clin Invest. 1999;  104 733-741
• 14 McGuire MC et al.. Abnormal regulation of protein tyrosine phosphatase activities in skeletal muscle of insulin-resistant humans.  Diabetes. 1991;  40 939-942
• 15 Ahmad F, Considine RV, Goldstein BJ. Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects.  J Clin Invest. 1995;  95 2806-2812
• 16 Ahmad F, and BJ Goldstein. Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus.  Metabolism. 1995;  44 1175-1184
• 17 Ahmad F, Goldstein BJ. Functional association between the insulin receptor and the transmembrane protein-tyrosine phosphatase LAR in intact cells.  J Biol Chem. 1997;  272 448-457
• 18 Garvey WT et al.. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.  J Clin Invest. 1998;  101 2377-2386
• 19 Stuart CA et al.. Insulin-stimulated translocation of glucose transporter (GLUT) 12 parallels that of GLUT4 in normal muscle.  J Clin Endocrinol Metab. 2009;  94 3535-3542
• 20 Cusi K et al.. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.  J Clin Invest. 2000;  105 311-320
• 21 Bajaj M, Defronzo RA. Metabolic and molecular basis of insulin resistance.  J Nucl Cardiol. 2003;  10 311-323
• 22 Bouzakri K, Koistinen HA, Zierath JR. Molecular mechanisms of skeletal muscle insulin resistance in type 2 diabetes.  Curr Diabetes Rev. 2005;  1 167-174
• 23 Karlsson HK, Zierath JR. Insulin signaling and glucose transport in insulin resistant human skeletal muscle.  Cell Biochem Biophys. 2007;  48 103-113
• 24 Black PR et al.. Mechanisms of insulin resistance following injury.  Ann Surg. 1982;  196 420-435
• 25 Little RA et al.. The disposal of intravenous glucose studied using glucose and insulin clamp techniques in sepsis and trauma in man.  Acta Anaesthesiol Belg. 1987;  38 275-279
• 26 Bernard C. Lecons sur les Phenomenes de la Vie Communs aux Animaux et aux Vegetaux. Paris: JB Bailliere et Fils; 1878: 564
• 27 McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia.  Crit Care Clin. 2001;  17 107-124
• 28 Thorell A, Nygren J, Ljungqvist O. Insulin resistance: a marker of surgical stress.  Curr Opin Clin Nutr Metab Care. 1999;  69-78
• 29 Thorell A et al.. The metabolic response to cholecystectomy: insulin resistance after open compared with laparoscopic operation.  Eur J Surg. 1996;  162 187-191
• 30 Sato H et al.. The association of preoperative glycemic control, intraoperative insulin sensitivity, and outcomes after cardiac surgery.  J Clin Endocrinol Metab. 2010;  95 4338-4344
• 31 Langouche L, Van den Berghe G. Glucose metabolism and insulin therapy.  Crit Care Clin. 2006;  22
• 32 Manson JE et al.. A prospective study of exercise and incidence of diabetes among US male physicians.  JAMA. 1992;  268 63-67
• 33 Stuart CA et al.. Bed-rest-induced insulin resistance occurs primarily in muscle.  Metabolism. 1988;  37 802-806
• 34 Mitchell GF et al.. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study.  Hypertension. 2004;  44 134-139
• 35 Higashi Y et al.. A noninvasive measurement of reactive hyperemia that can be used to assess resistance artery endothelial function in humans.  Am J Cardiol. 2001;  87
• 36 Meredith IT et al.. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide.  Am J Physiol. 1996;  270
• 37 Wheatcroft SB et al.. Pathophysiological implications of insulin resistance on vascular endothelial function.  Diabet Med. 2003;  20 255-268
• 38 Ruderman NB et al.. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes.  Biochem Soc Trans. 2003;  31 202-206
• 39 Baron AD et al.. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans.  J Clin Invest. 1995;  96 786-92
• 40 Hamburg NM et al.. Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers.  Arterioscler Thromb Vasc Biol. 2007;  27 2650-2656
• 41 Desborough JP. The stress response to trauma and surgery.  Br J Anaesth. 2000;  85 109-117
• 42 Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action.  J Clin Endocrinol Metab. 1982;  54 131-138
• 43 Kollind M et al.. Diabetogenic action of GH and cortisol in insulin-dependent diabetes mellitus. Aspects of the mechanisms behind the Somogyi phenomenon.  Horm Metab Res. 1987;  156-159
• 44 Deibert DC, DeFronzo RA. Epinephrine-induced insulin resistance in man.  J Clin Invest. 1980;  65 717-721
• 45 Shamoon H, Hendler R, Sherwin RS. Synergistic interactions among antiinsulin hormones in the pathogenesis of stress hyperglycemia in humans.  J Clin Endocrinol Metab. 1981;  52 1235-1241
• 46 Li L et al.. Tissue-specific difference in the molecular mechanisms for the development of acute insulin resistance after injury.  Endocrinology. 2009;  150 24-32
• 47 Dimitriadis G et al.. Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle.  Biochem J. 1997;  321 707-712
• 48 Smith TR et al.. Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4.  Am J Physiol. 1997;  272
• 49 Dominici FP et al.. Alterations in the early steps of the insulin-signaling system in skeletal muscle of GH-transgenic mice.  Am J Physiol. 1999;  277
• 50 Stumvoll M et al.. Renal glucose production and utilization: new aspects in humans.  Diabetologia. 1997;  40 749-757
• 51 Leboeuf B, Flinn RB, Cahill Jr GF. Effect of epinephrine on glucose uptake and glycerol release by adipose tissue in vitro.  Proc Soc Exp Biol Med. 1959;  102 527-529
• 52 Khovidhunkit W et al.. Infection and inflammation-induced proatherogenic changes of lipoproteins.  J Infect Dis. 2000;  181 (S 03) 462-472
• 53 Alvarez C, Ramos A. Lipids, lipoproteins, and apoproteins in serum during infection.  Clin Chem. 1986;  32 142-145
• 54 Akgun S et al.. Postsurgical reduction of serum lipoproteins: interleukin-6 and the acute-phase response.  J Lab Clin Med. 1998;  131 103-108
• 55 Gordon BR et al.. Relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients.  Crit Care Med. 2001;  29 1563-1568
• 56 Windler E et al.. The prognostic value of hypocholesterolemia in hospitalized patients.  Clin Investig. 1994;  72 939-943
• 57 Gallin JI, Kaye D, O'Leary WM. Serum lipids in infection.  N Engl J Med. 1969;  281 1081-1086
• 58 Randle PJ et al.. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  1 785-789
• 59 Boden G et al.. Mechanisms of fatty acid-induced inhibition of glucose uptake.  J Clin Invest. 1994;  93 2438-2446
• 60 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 61 McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes.  Science. 1992;  258 766-770
• 62 Bergman RN, Ader M. Free fatty acids and pathogenesis of type 2 diabetes mellitus.  Trends Endocrinol Metab. 2000;  11 351-356
• 63 Massillon D et al.. Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion.  Diabetes. 1997;  46 153-157
• 64 Dresner A et al.. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
• 65 Avramoglu RK, Basciano H, Adeli K. Lipid and lipoprotein dysregulation in insulin resistant states.  Clin Chim Acta. 2006;  368 1-19
• 66 Ozcan U et al.. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.  Science. 2004;  306 457-461
• 67 Cruickshank AM et al.. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity.  Clin Sci (Lond). 1990;  79 161-165
• 68 Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives.  Trends Cell Biol. 2001;  11 372-377
• 69 Hirosumi J et al.. A central role for JNK in obesity and insulin resistance.  Nature. 2002;  420 333-336
• 70 Feinstein R et al.. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.  J Biol Chem. 1993;  268 26055-26058
• 71 Emanuelli B et al.. SOCS-3 is an insulin-induced negative regulator of insulin signaling.  J Biol Chem. 2000;  275 15985-15991
• 72 Rui L et al.. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2.  J Biol Chem. 2002;  277 42394-42398
• 73 Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms.  Mol Cell Biol. 2004;  24 5434-5446
• 74 Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects.  J Biol Chem. 2003;  278 45777-45784
• 75 Aljada A et al.. Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells.  Metabolism. 2002;  51 487-491
• 76 Stephens JM, Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha.  J Biol Chem. 1991;  266 21839-21845
• 77 de lAguila LF, Claffey KP, Kirwan JP. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells.  Am J Physiol. 1999;  276
• 78 Fan J et al.. Endotoxin-induced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1, and MAP kinase in skeletal muscle.  Shock. 1996;  6 164-170
• 79 Mesotten D et al.. 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
• 80 Langouche L et al.. Effect of intensive insulin therapy on insulin sensitivity in the critically ill.  J Clin Endocrinol Metab. 2007;  92 3890-3897
• 81 Langouche L et al.. Intensive insulin therapy protects the endothelium of critically ill patients.  J Clin Invest. 2005;  115 2277-2286
• 82 Langouche L et al.. Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients.  Crit Care Med. 2008;  36 1475-80
• 83 Vanhorebeek I et al.. Cortisol response to critical illness: effect of intensive insulin therapy.  J Clin Endocrinol Metab. 2006;  91 3803-3813
• 84 Soop M et al.. Randomized clinical trial of the effects of immediate enteral nutrition on metabolic responses to major colorectal surgery in an enhanced recovery protocol.  Br J Surg. 2004;  91 1138-1145
• 85 Ljungqvist O. Modulating postoperative insulin resistance by preoperative carbohydrate loading.  Best Pract Res Clin Anaesthesiol. 2009;  23 401-409
• 86 Ljungqvist O. Insulin resistance and outcomes in surgery.  J Clin Endocrinol Metab. 2010;  95 4217-4219
• 87 Braga M et al.. ESPEN Guidelines on Parenteral Nutrition: surgery.  Clin Nutr. 2009;  28 378-386
• 88 Truong AD et al.. Bench-to-bedside review: mobilizing patients in the intensive care unit--from pathophysiology to clinical trials.  Crit Care. 2009;  13 216