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Is insulin an endogenous cardioprotector?
Critical Care volume 6, Article number: 389 (2002)
Stress hyperglycemia and diabetes mellitus with myocardial infarction are associated with increased risk for in-hospital mortality, congestive heart failure, or cardiogenic shock. Hyperglycemia triggers free radical generation and suppresses endothelial nitric oxide generation, and thus initiates and perpetuates inflammation. Conversely, insulin suppresses production of tumor necrosis factor-α and free radicals, enhances endothelial nitric oxide generation, and improves myocardial function. It is proposed that the balance between insulin and plasma glucose levels is critical to recovery and/or complications that occur following acute myocardial infarction and in the critically ill. Adequate attention should be given to maintaining euglycemia (plasma glucose ≤ 110 mg/dl) in order to reduce infarct size and improve cardiac function while using a glucose–insulin–potassium cocktail.
Patients with acute myocardial infarction (AMI) exhibit raised blood glucose concentrations [1,2,3]. In addition, a positive association between hyperglycemia and mortality from AMI has been reported , although the exact reason for this association is not clear. Intensive treatment with insulin to lower plasma glucose concentrations decreases overall mortality in patients with diabetes mellitus who have AMI. In a prospective, randomized, controlled study involving adults admitted to surgical intensive care units and receiving mechanical ventilation , intensive insulin treatment reduced mortality and morbidity. Intensive insulin treatment reduced the number of deaths from multiple organ failure with sepsis. Markers of inflammation were found to be abnormal less frequently in the intensive insulin treatment group. This suggests that hyperglycemia is harmful, whereas insulin therapy is beneficial not only in AMI but also in critical illness with or without diabetes mellitus. It is likely that lack of insulin associated with hyperglycemia causes a decrease in glycolytic substrate and an increase in free fatty acids. This induces a reduction in myocardial contractility, and promotes cardiac failure and arrhythmias , leading to poor outcomes in such patients.
Hyperglycemia is proinflammatory whereas insulin is anti-inflammatory
Capes and coworkers  showed that patients with stress hyperglycemia but without diabetes mellitus at the time of AMI are at increased risk for in-hospital mortality and congestive heart failure or cardiogenic shock. Although the exact cause for the poor prognosis is not clear, it was suggested that hyperglycemia (an indirect reflection of relative insulin deficiency) increases circulating free fatty acids, which are toxic to myocardium and induce arrhythmias . Hyperglycemia causes osmotic diuresis, and the resulting volume depletion may further compromise myocardial function.
Both in animal models of diabetes and in patients with diabetes mellitus, increased production of reactive oxygen species and consequent lipid peroxidation were noted [8,9,10]. Hyperglycemia increases the production of reactive oxygen species inside cultured aortic endothelial cells . Superoxide anion inactivates both endothelial nitric oxide (NO) and prostacyclin produced by endothelial cells, which are potent vasodilators and platelet antiaggregators [12,13]. Thus, free radicals induce endothelial dysfunction. Normalizing levels of mitochondrial reactive oxygen species was reported to prevent glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation, and nuclear factor-κB (NF-κB) activation . Glucose challenge stimulated reactive oxygen species generation and levels of p47phox (a key protein of the enzyme nicotinamide adenine dinucleotide phosphate [reduced; NADPH] oxidase), whereas α-tocopherol levels decreased significantly in polymorphonuclear leukocytes and monocytes, even in normal subjects . High glucose concentrations induced inflammatory events in rats, as evidenced by increased leukocyte rolling, leukocyte adherence, leukocyte transmigration through mesenteric venules associated with attenuation of endothelial NO release, and increased expression of P-selectin on endotheial surfaces . Local application of insulin attenuated these proinflammatory effects. Insulin infusion inhibited reactive oxygen species generation, p47phox and NF-κB in mononuclear cells, and reduced soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1 production by increasing NO synthesis [16,17,18,19,20]. These findings suggest that hyperglycemia has proinflammatory whereas insulin exhibits anti-inflammatory actions.
The exact mechanism by which glucose stimulates proinflammatory events is not clear, although indirect evidence suggests that it does so possibly by stimulating production of tumor necrosis factor (TNF)-α (a proinflammatory cytokine). A diet with a high glycemic load and hyperglycemia induced production of acute-phase reactants [21,22]. In experimental animal models of diabetes, the activity of NADPH-dependent oxidase and the levels of NADPH oxidase protein subunits p22phox, p67phox and p47phox were significantly increased , which accounted for the increased superoxide production in addition to decreased endothelial NO synthase activity. Similar to glucose, TNF-α also enhances free radical generation by augmenting polymorphonuclear leukocyte NADPH oxidase activity, activates NF-κB, and increases intercellular adhesion molecule-1 expression in endothelial cells . This similarity in the actions of glucose and TNF-α, and the ability of former to enhance acute phase reactants suggests, but does not prove, that glucose may enhance TNF-α production and brings about its proinflammatory actions.
Tumor necrosis factor-α and myocardium
TNF-α is secreted by adipose tissue, macrophages and cardiac tissue, and plays roles in the pathogeneses of insulin resistance, type 2 diabetes mellitus, inflammation, and septic shock . Release of TNF-α occurs early in the course of AMI and reduces myocardial contractility in a dose-dependent manner [25,26]. Using anti-TNF-α antibody can reduce TNF-α-induced myocardial injury and dysfunction [13,27]. Cardiac cachexia is believed to be due to an increase in the circulating levels of TNF-α , and a direct correlation between the clinical features of congestive cardiac failure (CCF) and circulating levels of TNF have been reported. Following cardiac transplantation TNF-α levels decrease [13,25]. This suggests that TNF-α is an important mediator in the pathogenesis of CCF. In addition, it causes dysfunction and apoptosis of endothelial cells, and enhances generation of free radicals (including superoxide anion), which in turn quenches NO. Damage to endothelial cells triggers procoagulant activity and fibrin deposition . These events are detrimental to the patient in the long run.
In CCF there is increased mesenteric venous pressure, which causes intestinal edema and increased bowel permeability. This causes an increase in endotoxin absorption from the gut. Increase in circulating levels of endotoxin activates macrophages and other cells to produce TNF-α . In patients with CCF, CD14 concentrations (which are indicative of endotoxin-cell interaction) are raised in relation to the elevated levels of TNF-α and cachexia . These findings suggest that methods designed to reduce TNF-α levels could be of significant benefit in inflammation, septicemia, and CCF.
Tumor necrosis factor-α and insulin
Both the American College of Cardiology and the American Heart Association recommended that intravenous glucose–insulin–potassium (GIK) be given to patients with AMI, especially those who are poor candidates for thrombolytic therapy and in whom the risk for bleeding is high , because the GIK regimen was beneficial in treating AMI [32,33,34,35,36,37,38]. It is generally believed that the GIK treatment improves the integrity and function of myocardial cells once glucose and potassium are transported in by insulin. Previously, I suggested that the GIK regimen in general and insulin in particular suppresses inflammation by inhibiting production of TNF-α, macrophage migration inhibitory factor (MIF) and superoxide anion, and by stimulating endothelial NO synthesis [16,26].
Satomi and coworkers  showed that exogenous insulin injection inhibited TNF-α production in a dose-related manner in animals after lipopolysaccharide challenge. Addition of insulin to cultures of peritoneal exudate cells from Propionibacterium acnes primed mice blocked TNF-α production, whereas in control animals it did not. Fraker and colleagues  reported that reduced food intake, decreased body weight gain, severe interstitial pneumonitis, periportal inflammation in the liver, and increases in the weights of the heart, lungs, kidney and spleen observed in TNF-α-treated animals reverted to normal levels when insulin was administered concurrently. The pneumonitis seen in these TNF-α-treated animals is somewhat similar to the adult respiratory distress syndrome that is seen in patients with septicemia and septic shock, conditions in which concentrations of interleukin-1, TNF-α, and MIF are elevated [41,42]. In addition, insulin suppresses superoxide anion generation  and enhances the production of endothelial NO . Thus, the ability of insulin to suppress TNF-α production, which decreases myocardial contractility, could be one mechanism by which the GIK regimen is beneficial in AMI.
Is it glucose or insulin that is critical to the heart?
Although several studies suggested that GIK regimen preserved systolic and diastolic function in ischemia and reperfusion  and protects the myocardium in patients undergoing open heart surgery [46,47], this is not without controversy [48,49,50,51]. Why did some studies give positive results whereas others failed to show a benefit from the GIK regimen? On closer examination, it is clear that not all studies were comparable to each other because the concentrations of glucose and insulin used in those studies were not uniform [45,46,47,48,49,50,51]. Studies in which higher concentrations of insulin were used showed better results than did those studies that employed a lesser dose. For instance, studies in which 33% glucose with 120 units of insulin  or 30% glucose with 300 units of insulin  was used yielded positive results. In contrast, the results reported by those studies that employed a lower dose (Bruemmer-Smith and coworkers  used 500 ml of 5% dextrose with 100 units of insulin, and Rao and colleagues  supplemented the cardioplegic solution with 10 units/l insulin) were less favorable. This is supported by the observation that stress hyperglycemia or even mild hyperglycemia with myocardial infarction is associated with increased mortality  and that intensive insulin treatment to maintain blood glucose levels between 80 and 110 mg/dl is highly beneficial and reduces morbidity and mortality among critically ill patients . It is possible that the negative results obtained with GIK [49,50,51] were due to the low dose of insulin used; this invariably resulted in hyperglycemia, which is detrimental to the myocardium.
It has been known for several years that continuous intravenous infusion of insulin is superior to subcutaneous administration in terms of glycemic control, especially in patients with diabetes during the perioperative and postoperative periods . During both the infusion period and the entire observation period (day of operation, and first and second postoperative days), GIK regimen resulted in lower blood glucose levels within the intended range of 90–180 mg/dl (5–10 mmol/l) as compared with conventional subcutaneous insulin administration. Improved diabetic control is believed to result in fewer wound infections and better wound healing. However, this view may be too simplistic. The beneficial effects of GIK regimen may extend beyond control of hyperglycemia alone [16,17]. As demonstrated recently [32,53], GIK infusion may salvage myocardium, improve cardiac function, and decrease mortality by an absolute 10%, provided that hyperglycemia is prevented. There is reasonable evidence to suggest that this beneficial effect may be independent of glucose [54,55,56].
These results are supplemented by those of a large trial conducted in a heterogeneous group of 1548 critically ill patients . In that trial, intensive insulin therapy to avoid hyperglycemia (blood glucose was maintained below 110 mg/dl) in predominantly nondiabetic patients led to a decrease in morbidity and mortality as compared with less intensively treated patients (blood glucose maintained between 180 and 200 mg/dl). Those findings suggest that maintaining blood glucose concentrations at 110 mg/dl or less is critical in obtaining the benefits of insulin administration. This is supported by the observation that cardiac dysfunction induced by endotoxin administration was not related to arterial blood glucose concentrations [57,58]. Furthermore, infusions of insulin reversed cardiac failure and maintained normal performance in spite of wide ranges in glucose concentrations (5–120 mg/dl), suggesting that myocardial dysfunction is not precipitated or induced by the hypoglycemia of endotoxin shock.
The ability of insulin to improve myocardial performance may be related to its capacity to suppress TNF-α, MIF, and superoxide anion generation [13,16,17,59]. Therapeutic administration of high doses of insulin results in an accumulation of myocardial glycogen stores and improvement in glucose utilization. This leads to augmented myocardial adenosine triphosphate provision and maintains cellular energy charge during coronary ischemia, resulting in better tolerance to ischemia and improved myocardial protection .
It is evident from the preceding discussion that hyperglycemia is harmful whereas insulin treatment is beneficial. Even mild hyperglycemia is associated with poor neurologic outcome after brain injury and stroke , and burns or surgery in humans [62,63]. Animal studies revealed that hyperglycemia aggravates endotoxin shock and that insulin treatment decreases mortality . What are the potential mechanisms by which insulin is able to bring about its beneficial actions?
Apart from its ability to lower blood glucose and to inhibit production of potentially dangerous proinflammatory cytokines (i.e. TNF-α, MIF, and superoxide anion), insulin has the following actions: it stimulates glucose uptake/glycolysis, pyruvate dehydrogenase and energy production; it increases muscle protein synthesis; it inhibits apoptosis and improves repair of damaged tissues; it promotes ischemic preconditioning and lessens ischemia/reperfusion damage (for review ); and it exhibits anti-inflammatory actions [16,17,65]. Because hyperglycemia induces apoptosis of myocardial cells , strict control of blood glucose is essential to preserve cardiac function both in diabetic and nondiabetic persons with stress hyperglycemia.
The ability of insulin to enhance endothelial NO synthesis is particularly significant when one considers its beneficial action in AMI, stroke, and critical illness [16,17,59]. Recent studies [67,68,69] suggested that administration of L-arginine (the precursor of NO) improves postischemic recovery of endothelial and vascular smooth muscle functions after cold cardioplegic arrest, and enhances cardioprotection and postischemic functional recovery and reduces infarct size of the myocardium. Hence, some of the beneficial actions of insulin (and therefore those of the GIK regimen) in various conditions could be attributable to an increase in endothelial NO synthesis [16,44].
In summary, GIK regimen is useful in preserving the myocardium in septicemia and septic shock, and in patients with severe burn injury [16,17], provided that blood glucose levels are maintained at 110 mg/dl or below by employing an adequate insulin dose. Thus, insulin when present in appropriate amounts preserves myocardial integrity and function.
AMI = acute myocardial infarction
CCF = congestive cardiac failure
GIK = glucose-insulin-potassium
MIF = macrophage migration inhibitory factor
NADPH = nicotinamide adenine dinucleotide phosphate (reduced)
NF-κB = nuclear factor-κB
NO = nitric oxide
TNF = tumor necrosis factor.
Cruikshank N: Coronary thrombosis and myocardial infarction, with glycosuria. BMJ 1931, 1: 618-619.
Sewdarsen M, Jialal I, Vythilingum S, Govender G, Rajput MC: Stress hyperglycemia is a predictor of abnormal glucose tolerance in Indian patients with acute myocardial infarction. Diabetes Res 1987, 6: 47-49.
Oswald GA, Smith CCT, Betteridge DJ, Yudkin JS: Determinants and importance of stress hyperglycemia in non-diabetic patients with myocardial infarction. BMJ 1986, 293: 917-922.
Yudkin JS, Oswald GA: Hyperglycemia, diabetes and myocardial infarction. Diabetes Med 1987, 4: 13-18.
Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyn-inckx F, Schetz M, Vlasselaers D, Ferdinade P, Lauwers P, Bouillon R: Intensive insulin therapy in critically ill. N Engl J Med 2001, 345: 1359-1367. 10.1056/NEJMoa011300
Oliver MF, Opie LH: Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994, 343: 155-158. 10.1016/S0140-6736(94)90939-3
Capes SE, Hunt D, Malmberg K, Gerstein HC: Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000, 355: 773-778. 10.1016/S0140-6736(99)08415-9
Mohan IK, Das UN: Oxidant stress, anti-oxidants and nitric oxide in non-insulin dependent diabetes mellitus. Med Sci Res 1997, 25: 55-57.
Das UN, Kumar KV, Mohan KI: Lipid peroxides and essential fatty acids in patients with diabetes mellitus and diabetic nephropathy. J Nutr Med 1994, 4: 149-155.
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404: 787-790. 10.1038/35008121
Giardino I, Edelstein D, Brownlee M: BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation end products in bovine endothelial cells. J Clin Invest 1996, 97: 1422-1428.
Laight DW, Kaw AV, Carrier MJ, Anggard EE: Interaction between superoxide anion and nitric oxide in the regulation of vascular endothelial function. Br J Pharmacol 1998, 124: 238-244.
Das UN: Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol Cell Biochem 2000, 215: 145-152. 10.1023/A:1026579422132
Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P: Glucose challenge stimulates reactive oxygen species (ROS) generation by leukocytes. J Clin Endocrinol Metab 2000, 85: 2970-2973.
Booth G, Stalker TJ, Lefer AM, Scalia R: Elevated ambient glucose induces acute inflammatory events in the microvasculature: effects of insulin. Am J Physiol 2001, 280: E848-E856.
Das UN: Is insulin an anti-inflammatory molecule? Nutrition 2001, 17: 409-413. 10.1016/S0899-9007(01)00518-4
Das UN: Insulin and the critically ill. Crit Care 2002, 6: 262-263. 10.1186/cc1501
Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S: Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an inflammatory effect? J Clin Endocrinol Metab 2001, 86: 3257-3265.
Aljada A, Saadesh R, Assian E, Ghanim H, Dandona P: Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab 2000, 85: 2572-2575.
Aljada A, Ghanim H, Saadeh R, Dandona P: Insulin inhibits NFκB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 2001, 86: 450-453.
Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM: Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr 2002, 75: 492-498.
Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE: Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem 2001, 276: 42077-42083. 10.1074/jbc.M107101200
Fan J, Frey RS, Rahman A, Malik AB: Role of neutrophil NADPH oxidase in the mechanism of tumor necrosis factor-α-induced NF-κB activation and intercellular adhesion molecule-1 expression in endothelial cells. J Biol Chem 2002, 277: 3404-3411. 10.1074/jbc.M110054200
Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM: Mechanisms of increased vascular superoxide production in human diabetes mellitus. Circulation 2002, 105: 1656-1662. 10.1161/01.CIR.0000012748.58444.08
Cain BS, Harken AH, Meldrum DR: Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and reperfusion. J Mol Cell Cardiol 1999, 31: 931-947. 10.1006/jmcc.1999.0924
Das UN: Possible beneficial action(s) of glucose-insulin-potassium regimen in acute myocardial infarction and inflammatory conditions: a hypothesis. Diabetologia 2000, 43: 1081-1082. 10.1007/s001250051497
Li D, Zhao L, Liu M, Du X, Ding W, Zhang J, Mehta JL: Kinetics of tumor necrosis factor alpha in plasma and the cardioprotective effect of a monoclonal antibody to tumor necrosis factor alpha in acute myocardial infarction. Am Heart J 1999, 137: 1145-1152.
Levine B, Kalman J, Mayer L, Fillit HM, Packer M: Elevated circulating levels of tumor necrosis factor in congestive heart failure. N Engl J Med 1990, 323: 236-241.
Meldrum DR, Donnahoo KK: Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome. J Surg Res 1999, 85: 185-199. 10.1006/jsre.1999.5660
Ferrari R: Tumor necrosis factor in CHF: a double facet cytokine. Cardiovasc Res 1998, 37: 554-559. 10.1016/S0008-6363(97)00309-X
Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel B, Russell RO, Smith EE III, Weaver WD, Gibbons RJ, Alpert JS, Eagle KA, Gardner TJ, Garson A Jr, Grego-ratos G, Smith SC Jr: 1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999, 100: 1016-1030.
Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latino-america) Collaborative Group. Circulation 1998, 98: 2227-2234.
Rogers WJ, Stanley AW Jr, Breinig JB, Prather JW, McDaniel HG, Moraski RE, Mantle JA, Russell RO Jr, Rackley CE: Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion. Am Heart J 1976, 92: 441-454.
Marano L, Bestetti A, Lomuscio A, Tagliabue L, Castini D, Tarricone D, Dario P, Tarolo GL, Fiorentini C: Effects of infusion of glucose-insulin-potassium on myocardial function after a recent myocardial infarction. Acta Cardiol 2000, 55: 9-15.
Lazar HL, Zhang X, Rivers S, Bernard S, Shemin RJ: Limiting ischemic myocardial damage using glucose-insulin-potassium solutions. Ann Thorac Surg 1995, 60: 411-416. 10.1016/0003-4975(95)00402-7
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L: Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995, 26: 57-65. 10.1016/0735-1097(95)00126-K
Machtey I, Syrkis I, Nissimov MR, Lobel H: Potassium, glucose and insulin administration in acute myocardial infarction: a five-year study. J Am Geriatr Soc 1976, 24: 534-537.
Malmberg K: Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (diabetes mellitus, insulin glucose infusion in acute myocardial infarction) Study Group. BMJ 1997, 314: 1512-1515.
Satomi N, Sakurai A, Haranaka K: Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: role of glucose, insulin, and macrophages. J Natl Cancer Inst 1985, 74: 1255-1260.
Fraker DL, Merino MJ, Norton JA: Reversal of the toxic effects of cachectin by concurrent insulin administration. Am J Physiol 1989,256(6 Pt 1):E725-E731.
Glauser MP, Zanetti G, Baumgartner JD, Cohen J: Septic shock: pathogenesis. Lancet 1991, 338: 732-736. 10.1016/0140-6736(91)91452-Z
Martin TR: MIF mediation of sepsis. Nature Med 2000, 6: 140-141. 10.1038/72230
Boichot E, Sannomiya P, Escofier N, Germain N, Fortes ZB, Lagente V: Endotoxin-induced acute lung injury in rats. Role of insulin. Pulm Pharmacol Ther 1999, 12: 285-290. 10.1006/pupt.1999.0212
Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL: Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action on insulin. Circulation 2000, 101: 676-681.
Zhu P, Lu L, Xu Y, Greyson C, Schwartz GG: Glucose-insulin-potassium preserves systolic and diastolic function in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 2000, 278: H595-H603.
Rudez I, Sutlic Z, Husedzinovic I, Biocina B, Ivancan V: The importance of glucose-insulin-potassium with cardiopulmonary bypass prior to cardioplegic arrest in open-heart surgery. Lijec Vjesn 1995,117(suppl 2):105-106.
Girard C, Quentin P, Bouvier H, Blanc P, Bastien O, Lehot JJ, Mikaeloff P, Estanove S: Glucose and insulin supply before cardiopulmonary bypass in cardiac surgery: a double-blind study. Ann Thorac Surg 1992, 54: 259-263.
Lell WA, Nielsen VG, McGiffin DC, Schmidt FE Jr, Kirklin JK, Stanley AW Jr: Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery. Ann Thorac Surg 2002, 73: 1246-1251. 10.1016/S0003-4975(01)03619-0
Bruemmer-Smith S, Avidan MS, Harris B, Sudan S, Sherwood R, Desai JB, Sutherland F, Ponte J: Glucose, insulin and potassium for heart protection during cadiac surgery. Br J Anaesth 2002, 88: 489-495. 10.1093/bja/88.4.489
Rao V, Christakis GT, Weisel RD, Ivanov J, Borger MA, Cohen G, for the ICT Investigators: The Insulin Cardioplegia Trial: myocardial protection for urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2002, 123: 928-935. 10.1067/mtc.2002.121686
Diaz-Arya G, Nettle D, Castro P, Miranda F, Greig D, Campos X, Chiong M, Nazzal C, Corbalan R, Lavandero S: Oxidative stress after reperfusion with primary coronary angioplasty: Lack of effect of glucose-insulin-potassium infusion. Crit Care Med 2002, 30: 417-421. 10.1097/00003246-200202000-00025
Christiansen CL, Schurizek BA, Malling B, Knudsen L, Alberti KG, Hermansen K: Insulin treatment of the insulin-dependent diabetic patient undergoing minor surgery. Continuous intravenous infusion compared with subcutaneous administration. Anaesthesia 1988, 43: 533-537.
Van Campen CMC, Klein LJ, Visser FC: Glucose-insulin-potassium imaging: the past and the future? Heart Metabol 2001, 12: 14-18.
Jonassen AK, Sack MN, Mjos OD, Yellon DM: Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell survival signaling. Circ Res 2001, 89: 1191-1198.
Rao V, Merante F, Weisel RD, Shirai T, Ikonomidis JS, Cohen G, Tumiati LC, Shiono N, Li RK, Mickle DA, Robinson BH: Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyocytes from stimulated ischemia. J Thorac Cardiovasc Surg 1998, 116: 485-494.
Girard C, Quentin P, Bouvier H, Blanc P, Bastien O, Lehot JJ, Mikkaeloff P, Estanove S: Glucose and insulin supply before cardiopulmonary bypass in cardiac surgery: a double-blind study. Ann Thorac Surg 1992, 54: 259-263.
Hinshaw LB, Archer LT, Benjamin B, Bridges C: Effects of glucose or insulin on myocardial performance in endotoxin shock. Proc Soc Exp Biol Med 1976, 152: 529-534.
Archer LT, Beller BK, Drake JK, Whitsett TL, Hinshaw LB: Reversal of myocardial dysfunction in endotoxin shock with insulin. Can J Physiol Pharmacol 1978, 56: 132-138.
Groeneveld ABJ, Beishuizen A, Visser FC: Insulin: a wonder drug in critically ill? Crit Care 2002, 6: 102-105. 10.1186/cc1463
Haider W, Benzer H, Schutz W, Wolner E: Improvement of cardiac preservation by preoperative high insulin supply. J Thorac Cardiovasc Surg 1984, 88: 294-300.
Kagansky N, Levy S, Knobler H: The role of hyperglycemia in acute stroke. Arch Neurol 2001, 58: 1209-1212. 10.1001/archneur.58.8.1209
Ljungqvist O, Nygren J, Thorell A: Insulin resistance and elective surgery. Surgery 2000, 128: 757-760. 10.1067/msy.2000.107166
Gore DC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M: Association of hyperglycemia with increased mortality after severe burn injury. J Trauma 2001, 51: 540-544.
Ling PR, Lydon E, Frederich RC, Bistrian BR: Metabolic effects of insulin and insulin-like growth factor-1 in endotoxemic rats during total parenteral nutrition feeding. Metabolism 2000, 49: 611-615.
Das UN: Insulin and inflammation: further evidence and discussion. Nutrition 2002, 18: 526-527. 10.1016/S0899-9007(02)00767-0
Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium. Diabetes 2002, 51: 1938-1948.
Nakamura K, Schmidt I, Gray CC, Dewar A, Rothery S, Severs NJ, Yacoub MH, Amrani M: The effect of chronic L-arginine administration on vascular recovery following cold cardioplegic arrest in rats. Eur J Cardiothorac Surg 2002, 21: 753-759. 10.1016/S1010-7940(02)00036-2
Suematsu Y, Ohtsuka T, Horata Y, Maeda K, Imanaka K, Takamoto S: L-arginine given after iscaemic preconditioning can enhance cardioprotection in isolated rat hearts. Eur J Cardiothorac Surg 2001, 19: 873-879. 10.1016/S1010-7940(01)00699-6
Yan Y, Davani S, Chocron S, Kantelip B, Muret P, Kantelip J-P: Effects of L-arginine administration before cardioplegic arrest on ischemia-reperfusion injury. Ann Thorac Surg 2001, 72: 1985-1990. 10.1016/S0003-4975(01)03260-X
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Das, U.N. Is insulin an endogenous cardioprotector?. Crit Care 6, 389 (2002). https://doi.org/10.1186/cc1535
- cardiac failure
- free radicals
- nitric oxide
- tumor necrosis factor
- septic shock