Cardiovascular Drugs and Therapy

, Volume 22, Issue 3, pp 241–251 | Cite as

Use of Insulin to Improve Glycemic Control in Diabetes Mellitus

  • Paresh Dandona
  • Ajay Chaudhuri
  • Husam Ghanim
  • Priya Mohanty
Article

Abstract

Background

The restoration of normoglycemia ensures the control of diabetic symptoms and reduction in microangiopathic complications in type 1 and type 2 diabetes. However, there is no conclusive evidence that intensive glycemic control alone will prevent macrovascular disease, the commonest cause of morbidity and mortality in type 2 diabetes. As atherosclerosis is an inflammatory condition, it is relevant that the two common insulin resistant states of obesity and type 2 diabetes have significant inflammatory processes, which promote atherosclerosis. It is also relevant that glucose has been shown to have profound effects on the endothelial cell, the leukocyte and the platelet. These effects include the induction of acute oxidative and inflammatory stress and a prothrombotic and pro-apoptotic effect following glucose intake. In contrast insulin has been shown to exert several biological effects at physiologically relevant concentrations, in relation to the endothelial cell, the platelet and leucocyte function, which may be cardioprotective and potentially anti-atherosclerotic.

Conclusion

These findings are of great interest as it is possible that the prevention of macrovascular complications in type 2 diabetes may require the use of those glucose lowering drugs which have additional anti-inflammatory effects in addition to the control of comorbid conditions (hypertension and dyslipidemia) associated with this disease. Results of future clinical trials are awaited to confirm the benefits of this approach in the primary and secondary prevention of macrovascular complications in type 2 diabetes.

Key words

diabetes mellitus glycemic control insulin inflammation 

References

  1. 1.
    Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334:952–7.PubMedGoogle Scholar
  2. 2.
    Dandona P, Mohanty P, Chaudhuri A, Garg R, Aljada A. Insulin infusion in acute illness. J Clin Invest. 2005;115:2069–72.PubMedGoogle Scholar
  3. 3.
    Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab. 2000;85:2970–3.PubMedGoogle Scholar
  4. 4.
    Aljada A, Ghanim H, Mohanty P, Syed T, Bandyopadhyay A, Dandona P. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am J Clin Nutr. 2004;80:51–7.PubMedGoogle Scholar
  5. 5.
    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–15.PubMedGoogle Scholar
  6. 6.
    Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;40:1286–92.PubMedGoogle Scholar
  7. 7.
    Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110:1564–71.PubMedGoogle Scholar
  8. 8.
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–26.PubMedGoogle Scholar
  9. 9.
    Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: “double diabetes” in the Diabetes Control and Complications Trial. Diabetes Care. 2007;30:707–12.PubMedGoogle Scholar
  10. 10.
    McGill M, Molyneaux L, Twigg SM, Yue DK. The metabolic syndrome in type 1 diabetes: does it exist and does it matter? J Diabetes Its Complicat. 2008;22:18–23.Google Scholar
  11. 11.
    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.PubMedGoogle Scholar
  12. 12.
    Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab. 1998;83:2907–10.PubMedGoogle Scholar
  13. 13.
    Mantzoros CS, Moschos S, Avramopoulos I, et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab. 1997;82:3408–13.PubMedGoogle Scholar
  14. 14.
    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19:972–8.PubMedGoogle Scholar
  15. 15.
    Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82:4196–200.PubMedGoogle Scholar
  16. 16.
    Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation. 1996;93:106–10.PubMedGoogle Scholar
  17. 17.
    Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes. 1996;45:881–5.PubMedGoogle Scholar
  18. 18.
    Crook MA, Tutt P, Pickup JC. Elevated serum sialic acid concentration in NIDDM and its relationship to blood pressure and retinopathy. Diabetes Care. 1993;16:57–60.PubMedGoogle Scholar
  19. 19.
    Duncan BB, Schmidt MI, Pankow JS, et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 2003;52:1799–805.PubMedGoogle Scholar
  20. 20.
    Pradhan AD, Cook NR, Buring JE, Manson JE, Ridker PM. C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol. 2003;23:650–5.PubMedGoogle Scholar
  21. 21.
    Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994;94:1543–9.PubMedGoogle Scholar
  22. 22.
    Aljada A, Ghanim H, Assian E, Dandona P. 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;51:487–91.PubMedGoogle Scholar
  23. 23.
    Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002;51:3391–9.PubMedGoogle Scholar
  24. 24.
    Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Diabetologia. 2007;50:278–85.PubMedGoogle Scholar
  25. 25.
    Jeschke MG, Klein D, Bolder U, Einspanier R. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology 2004;145:4084–93.PubMedGoogle Scholar
  26. 26.
    Brix-Christensen V, Andersen SK, Andersen R, et al. Acute hyperinsulinemia restrains endotoxin-induced systemic inflammatory response: an experimental study in a porcine model. Anesthesiology. 2004;100:861–70.PubMedGoogle Scholar
  27. 27.
    Jeschke MG, Einspanier R, Klein D, Jauch KW. Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med. 2002;8:443–50.PubMedGoogle Scholar
  28. 28.
    Horvath EM, Benko R, Gero D, Kiss L, Szabo C. Treatment with insulin inhibits poly(ADP-ribose) polymerase activation in a rat model of endotoxemia. Life Sci. 2008;82:205–9.PubMedGoogle Scholar
  29. 29.
    Cuschieri J, Bulger V, Grinsell R, Garcia I, Maier R. Insulin regulates macrophage activation through activin A1. Shock. 2007 (in press).Google Scholar
  30. 30.
    Shamir R, Shehadeh N, Rosenblat M, et al. Oral insulin supplementation attenuates atherosclerosis progression in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:104–10.PubMedGoogle Scholar
  31. 31.
    Kubota T, Kubota N, Moroi M, et al. Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury. Circulation. 2003;107:3073–80.PubMedGoogle Scholar
  32. 32.
    Jonassen AK, Brar BK, Mjos OD, Sack MN, Latchman DS, Yellon DM. Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. J Mol Cell Cardiol. 2000;32:757–64.PubMedGoogle Scholar
  33. 33.
    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;89:1191–8.PubMedGoogle Scholar
  34. 34.
    Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia–reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation. 2002;105:1497–502.PubMedGoogle Scholar
  35. 35.
    Tune JD, Mallet RT, Downey HF. Insulin improves contractile function during moderate ischemia in canine left ventricle. Am J Physiol. 1998;274:H1574–81.PubMedGoogle Scholar
  36. 36.
    Tune JD, Mallet RT, Downey HF. Insulin improves cardiac contractile function and oxygen utilization efficiency during moderate ischemia without compromising myocardial energetics. J Mol Cell Cardiol. 1998;30:2025–35.PubMedGoogle Scholar
  37. 37.
    Zhang HX, Zang YM, Huo JH, et al. Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs. J Cardiovasc Pharmacol. 2006;48:306–13.PubMedGoogle Scholar
  38. 38.
    Festa A, D, Agostino R Jr, Mykkanen L, et al. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol. 1999;19:562–8.PubMedGoogle Scholar
  39. 39.
    Pyorala M, Miettinen H, Laakso M, Pyorala K. Plasma insulin and all-cause, cardiovascular, and noncardiovascular mortality: the 22-year follow-up results of the Helsinki Policemen Study. Diabetes Care. 2000;23:1097–102.PubMedGoogle Scholar
  40. 40.
    Stout RW. Insulin as a mitogenic factor: role in the pathogenesis of cardiovascular disease. Am J Med. 1991;90:62S–65S.PubMedGoogle Scholar
  41. 41.
    Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states. Proc Natl Acad Sci U S A. 1991;88:9959–63.PubMedGoogle Scholar
  42. 42.
    Grover A, Padginton C, Wilson MF, Sung BH, Izzo JL Jr, Dandona P. Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study. Hypertension. 1995;25:779–84.PubMedGoogle Scholar
  43. 43.
    Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994;94:1172–9.PubMedGoogle Scholar
  44. 44.
    Aljada A, Dandona P. Effect of insulin on human aortic endothelial nitric oxide synthase. Metabolism. 2000;49:147–50.PubMedGoogle Scholar
  45. 45.
    Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996;98:894–8.PubMedGoogle Scholar
  46. 46.
    Trovati M, Anfossi G, Massucco P, et al. Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3′, 5′-cyclic monophosphate and adenosine-3′, 5′-cyclic monophosphate. Diabetes. 1997;46:742–9.PubMedGoogle Scholar
  47. 47.
    Trovati M, Massucco P, Mattiello L, Mularoni E, Cavalot F, Anfossi G. Insulin increases guanosine-3′,5′-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect. Diabetes. 1994;43:1015–9.PubMedGoogle Scholar
  48. 48.
    Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab. 2001;86:450–3.PubMedGoogle Scholar
  49. 49.
    Aljada A, Ghanim H, Mohanty P, Kapur N, Dandona P. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab. 2002;87:1419–22.PubMedGoogle Scholar
  50. 50.
    Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear NFkB and stimulates IkB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001;86:3257–65.PubMedGoogle Scholar
  51. 51.
    Dandona P, Aljada A, Mohanty P, Ghanim H, Bandyopadhyay A, Chaudhuri A. Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care. 2003;26:3310–4.PubMedGoogle Scholar
  52. 52.
    Weis S, Shintani S, Weber A, et al. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest. 2004;113:885–94.PubMedGoogle Scholar
  53. 53.
    Dandona P, Thusu K, Hafeez R, Abdel-Rahman E, Chaudhuri A. Effect of hydrocortisone on oxygen free radical generation by mononuclear cells. Metabolism. 1998;47:788–91.PubMedGoogle Scholar
  54. 54.
    Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and pro-fibrinolytic effect of insulin in acute ST-elevation myocardial infarction. Circulation. 2004;109:849–54.PubMedGoogle Scholar
  55. 55.
    Chaudhuri A, Janicke D, Wilson M, et al. Effect of modified glucose–insulin–potassium on free fatty acids, matrix metalloproteinase, and myoglobin in ST-elevation myocardial infarction. Am J Cardiol. 2007;100:1614–8.PubMedGoogle Scholar
  56. 56.
    Wong VW, McLean M, Boyages SC, Cheung NW. C-reactive protein levels following acute myocardial infarction: effect of insulin infusion and tight glycemic control. Diabetes Care. 2004;27:2971–3.PubMedGoogle Scholar
  57. 57.
    Griselli M, Herbert J, Hutchinson WL, et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med. 1999;190:1733–40.PubMedGoogle Scholar
  58. 58.
    Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440:1217–21.PubMedGoogle Scholar
  59. 59.
    Worthley MI, Holmes AS, Willoughby SR, et al. The Deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes: mediation by superoxide production, resolution with intensive insulin administration. J Am Coll Cardiol. 2007;49:304–10.PubMedGoogle Scholar
  60. 60.
    Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest. 2005;115:2277–86.PubMedGoogle Scholar
  61. 61.
    Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet. 2005;365:53–9.PubMedGoogle Scholar
  62. 62.
    Visser L, Zuurbier CJ, Hoek FJ, et al. Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery. Br J Anaesth. 2005;95:448–57.PubMedGoogle Scholar
  63. 63.
    Koskenkari JK, Kaukoranta PK, Rimpilainen J, et al. Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery. Acta Anaesthesiol Scand. 2006;50:962–9.PubMedGoogle Scholar
  64. 64.
    Malouf JF, Kanagala R, Al Atawi FO, et al. High sensitivity C-reactive protein: a novel predictor for recurrence of atrial fibrillation after successful cardioversion. J Am Coll Cardiol. 2005;46:1284–7.PubMedGoogle Scholar
  65. 65.
    Ishida K, Kimura F, Imamaki M, et al. Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg. 2006;29:501–5.PubMedGoogle Scholar
  66. 66.
    Pan W, Hindler K, Lee VV, Vaughn WK, Collard CD. Obesity in diabetic patients undergoing coronary artery bypass graft surgery is associated with increased postoperative morbidity. Anesthesiology. 2006;104:441–7.PubMedGoogle Scholar
  67. 67.
    Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004;109:1497–502.PubMedGoogle Scholar
  68. 68.
    Takebayashi K, Aso Y, Inukai T. Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. Metabolism. 2004;53:693–9.PubMedGoogle Scholar
  69. 69.
    Vehkavaara S, Yki-Jarvinen H. 3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2004;24:325–30.PubMedGoogle Scholar
  70. 70.
    Srinivasan M, Herrero P, McGill JB, et al. The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus. J Am Coll Cardiol. 2005;46:42–8.PubMedGoogle Scholar
  71. 71.
    Dhindsa S, Tripathy D, Mohanty P, et al. Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. Metabolism. 2004;53:330–4.PubMedGoogle Scholar
  72. 72.
    Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067–72.PubMedGoogle Scholar
  73. 73.
    Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7.PubMedGoogle Scholar
  74. 74.
    Dandona P. Endothelium, inflammation, and diabetes. Curr Diab Rep. 2002;2:311–5.PubMedGoogle Scholar
  75. 75.
    Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978–82.PubMedGoogle Scholar
  76. 76.
    Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol. 2002;40:1748–54.PubMedGoogle Scholar
  77. 77.
    Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000;355:773–8.PubMedGoogle Scholar
  78. 78.
    Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32:2426–32.PubMedGoogle Scholar
  79. 79.
    Iwakura K, Ito H, Ikushima M, et al. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol. 2003;41:1–7.PubMedGoogle Scholar
  80. 80.
    Timmer JR, Ottervanger JP, de Boer MJ, et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005;45:999–1002.PubMedGoogle Scholar
  81. 81.
    Corpus RA, George PB, House JA, et al. Optimal glycemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percutaneous coronary intervention. J Am Coll Cardiol. 2004;43:8–14.PubMedGoogle Scholar
  82. 82.
    Williams LS, Rotich J, Qi R, et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology. 2002;59:67–71.PubMedGoogle Scholar
  83. 83.
    Diaz R, Paolasso EA, Piegas LS, et al. Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation. 1998;98:2227–34.PubMedGoogle Scholar
  84. 84.
    Malmberg K, Ryden L, Efendic S, et al. 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.PubMedGoogle Scholar
  85. 85.
    van der Horst I, Zijlstra F, van, t Hof A, et al. Glucose–insulin–potassium infusion in patients treated with primary angioplasty for acute myocardial infarction. J Am Coll Cardiol. 2003;42:784–91.PubMedGoogle Scholar
  86. 86.
    Sodi-Pallares D, Testelli MR, Fishleder BL, et al. Effects of an intravenous infusion of a potassium–glucose–insulin solution on the electrocardiographic signs of myocardial infarction. A preliminary clinical report. Am J Cardiol. 1962;9:166–81.PubMedGoogle Scholar
  87. 87.
    Rogers WJ, Stanley AW Jr., Breinig JB, et al. Reduction of hospital mortality rate of acute myocardial infarction with glucose–insulin–potassium infusion. Am Heart J. 1976;92:441–54.PubMedGoogle Scholar
  88. 88.
    Cheung NW, Wong VW, McLean M. The hyperglycemia: intensive insulin infusion in infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care. 2006;29:765–70.PubMedGoogle Scholar
  89. 89.
    Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26:650–61.PubMedGoogle Scholar
  90. 90.
    CREATE-ECLA Trial group Investigators. Effect of glucose–insulin–potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction. JAMA. 2005;293:437–46.Google Scholar
  91. 91.
    Chaudhuri A, Miller M, Nesto R, Rosenberg N, Dandona P. Targeting glucose in acute myocardial infarction: has glucose, insulin, and potassium infusion missed the target. Diabetes Care. 2007;30:3026–8.PubMedGoogle Scholar
  92. 92.
    Diaz R, Goyal A, Mehta SR, et al. Glucose–insulin–potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA. 2007;298:2399–405.PubMedGoogle Scholar
  93. 93.
    Su H, Sun X, Ma H, et al. Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. Am J Physiol Endocrinol Metab. 2007;293:E629–35.PubMedGoogle Scholar
  94. 94.
    Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke. 2006;37:267–73.PubMedGoogle Scholar
  95. 95.
    Saposnik G, Young B, Silver B, et al. Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome. JAMA. 2004;292:1839–44.PubMedGoogle Scholar
  96. 96.
    Van den Berghe GH. Role of intravenous insulin therapy in critically ill patients. Endocr Pract. 2004;10:17–20.PubMedGoogle Scholar
  97. 97.
    Van Den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically Ill patients. NEJM. 2001;345:1359–67.PubMedGoogle Scholar
  98. 98.
    Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449–61.PubMedGoogle Scholar
  99. 99.
    Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79:992–1000.PubMedCrossRefGoogle Scholar
  100. 100.
    Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:1007–21.PubMedGoogle Scholar
  101. 101.
    Lazar HL, Philippides G, Fitzgerald C, Lancaster D, Shemin RJ, Apstein C. Glucose–insulin–potassium solutions enhance recovery after urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1997;113:354–60; discussion 360-2.PubMedGoogle Scholar
  102. 102.
    Quinn DW, Pagano D, Bonser RS, et al. Improved myocardial protection during coronary artery surgery with glucose–insulin–potassium: a randomized controlled trial. J Thorac Cardiovasc Surg. 2006;131:34–42.PubMedGoogle Scholar
  103. 103.
    Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–39.PubMedGoogle Scholar
  104. 104.
    Pinto DS, Skolnick AH, Kirtane AJ, et al. U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005;46:178–80.PubMedGoogle Scholar
  105. 105.
    Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005;26:1255–61.PubMedGoogle Scholar
  106. 106.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The diabetes control and complications trial research group. N Engl J Med. 1993;329:977–86.Google Scholar
  107. 107.
    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53.Google Scholar
  108. 108.
    Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.PubMedGoogle Scholar
  109. 109.
    Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus. N Engl J Med. 2003;348:2294–303.PubMedGoogle Scholar
  110. 110.
    Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23:B21–9.PubMedGoogle Scholar
  111. 111.
    Stettler C, Allemann S, Juni P, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J. 2006;152:27–38.PubMedGoogle Scholar
  112. 112.
    Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99:21i–33i.PubMedGoogle Scholar
  113. 113.
    Abraira C, Duckworth W, McCarren M, et al. Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: veterans affairs diabetes trial. J Diabetes Complications. 2003;17:314–22.PubMedGoogle Scholar
  114. 114.
    Sanofi-Aventis. The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention). Clinical Trials NCT 00069784 2007.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Paresh Dandona
    • 1
    • 2
    • 3
  • Ajay Chaudhuri
    • 1
  • Husam Ghanim
    • 1
  • Priya Mohanty
    • 1
  1. 1.Division of Endocrinology, Diabetes and MetabolismState University of New York at BuffaloBuffaloUSA
  2. 2.Kaleida HealthBuffaloUSA
  3. 3.Diabetes-Endocrinology Center of WNYBuffaloUSA

Personalised recommendations