Skip to main content

Insulin: a wonder drug in the critically ill?


Stress hyperglycaemia is a common event in acute critical illness. There is increasing evidence that maintaining normoglycaemia and treatment with insulin (or with glucose–insulin–potassium [GIK]), even in non-diabetic persons, is helpful in limiting organ damage after myocardial infarction, stroke, traumatic brain injury and other conditions, even though the conditions may be accompanied by insulin resistance. A landmark study now suggests that maintaining normoglycaemia with intensive insulin treatment in a heterogeneous population of critically ill patients decreases morbidity and mortality. The potential mechanisms that underlie such a beneficial effect are discussed.


Intensive care unit patients often have complex disorders. For instance, bouts of inflammation, trauma and ischaemia/reperfusion may occur sequentially or synchronously in patients following surgery, sepsis or shock, thereby upregulating inflammatory and metabolic responses, including cytokine release, protein breakdown and insulin resistance [1,2,3,4]. In spite of elevated insulin levels, insulin resistance at the receptor and postreceptor levels may contribute to hyperglycaemia, even in non-diabetic persons, particularly when stress hormones that promote glycogenolysis are released, including catecholamines and cortisol [2,3,5]. 'Stress' hyperglycaemia can be reproduced after administration of minute amounts of endotoxin to healthy volunteers or by injecting several stress hormones at the same time [5]. Stress hyperglycaemia may occur during the acute phase of illness in 5–30% of patients with stroke, myocardial infarction, sepsis, burns, trauma, surgery and other conditions.


Recent evidence suggests that even mild hyperglycaemia is harmful in animals and humans, and aggravates ischaemia/reperfusion damage to heart and brain. Myocardial infact size in humans, with or without diabetes, is greater in the presence of hyperglycaemia [6]. That the former results from the latter (i.e. more severe stress hyperglycaemia causes greater infarct size) rather than vice versa is supported by animal studies [7]. Similarly, hyperglycaemia is associated with poor neurological outcome after traumatic brain injury and stroke [8]. In rodents hyperglycaemia aggravates endotoxin shock, and insulin treatment may decrease mortality [9,10]. Hyperglycaemia may contribute to morbidity and mortality after burns or surgery in humans [3,11]. Therefore, during the course of diabetes mellitus but also during the course of stress hyperglycaemia, untreated or insufficiently controlled hyperglycaemia may adversely impact on organ function after inflammation, trauma or ischaemia/reperfusion, and consequently may have a detrimental impact on morbidity and mortality.

Apart from the detrimental effect of even mild hyperglycaemia on bacterial defences, and wound healing and repair after ischaemia/reperfusion [11], there are various other potential mechanisms to explain the harmful effect of hyperglycaemia. They include the effect of hyperglycaemia on metabolic mitochondrial pathways, which results in oxidative stress and increased superoxide production [12]. Cytosolic oxygen radical production as a result of hyperglycaemia may arise from non-enzymatic glycation, auto-oxidation of glucose and the polyol pathway [13]. Hyperglycaemia-induced oxygen radicals may scavenge endogenous nitric oxide, thereby increasing electrical instability of the heart and peripheral vascular tone [14]. Also, in humans acute hyperglycaemia attenuates endothelial nitric oxide-dependent dilatation of the brachial artery [13]. Hyperglycaemia may increase neutrophil activation and interaction with endothelium following ischaemia/reperfusion [15]. Diabetes/hyperglycaemia may attenuate ischaemic preconditioning of the heart, possibly by inhibiting activation of ATP-sensitive potassium channels that may afford protection by activating glycolysis in the cytosol [7,16]. This may also explain why ATP-sensitive potassium channel blockers (e.g. sulfonylurea drugs) may abolish, whereas insulin may not abolish and may even enhance protection afforded by ischaemic preconditioning of the human myocardium [7]. Finally, hyperglycaemia enhances proteolysis in healthy volunteers, even during hyperinsulinaemia.

Insulin treatment

For decades it has been advocated that fasting diabetic persons be treated with a combined glucose and insulin infusion before invasive procedures or surgery [17]. The basis for this recommendation was improved diabetic control and thereby fewer wound infections and better wound healing. However, we now know that this view may be too simplistic. The effects of GIK infusion may extend beyond control of hyperglycaemia alone [4]. Indeed, the use of GIK in patients with myocardial infarction and shock was originally studied decades ago, but has recently undergone a revival. In both diabetic and non-diabetic patients with myocardial infarction, GIK infusion may salvage myocardium, improve heart function without an increase in myocardial oxygen demand, and decrease mortality by an absolute 10%, particularly in those receiving prior reperfusion therapy, provided that hyperglycaemia is prevented. This was demonstrated in a recent landmark trial [18,19]. Animal studies [20] suggest that this effect may partly be independent of glucose. Also, bolus infusion of hyperosmolar GIK improved cardiac output and heart function in canine endotoxin and human septic shock, but this may relate to the positive inotropic effect of hyperosmolarity or insulin rather than to a metabolic effect, in spite of myocardial insulin resistance [21,22]. In diabetic and non-diabetic persons, GIK infusion after cardiac surgery may improve heart function and expedite recovery [23]. Treatment with GIK may also improve outcome in stroke patients [24].

Those studies have now been supplemented by a large trial conducted in a heterogeneous group of 1548 critically ill patients [25]. That trial demonstrated that intensive insulin treatment to avoid hyperglycaemia in diabetic and non-diabetic persons is associated with a decrease in mortality, from 8% in the less intensively treated (blood glucose maintained between 10.0 and 11.1 mmol/l) to 4.6% in the intensively treated patients (blood glucose maintained below 6.1 mmol/l). The reduction in mortality was even greater in sicker patients with a duration of stay longer than 5 days. In that single-centre, landmark trial, patients with sepsis appeared to benefit the most. The effect of insulin apparently occurred even in the assumed presence of insulin resistance. Hypoglycaemia occurred somewhat more frequently in the intensive insulin group, but appeared well controlled and relatively harmless. What could underlie these beneficial effects and what are the potential mechanisms involved?

Mechanisms of the action of insulin

The basis of the beneficial effect of insulin treatment, despite potential insulin resistance in conditions associated with trauma, inflammation and ischaemia/reperfusion, may be multifactorial. On the one hand correction of hyperglycaemia may prevent its adverse effects. On the other hand insulin, whether or not combined with glucose to compensate for increased skeletal muscle glucose uptake, and even in the critically ill with insulin resistance [2], may also benefit non-diabetic or normoglycaemic patients (Table 1).

Table 1

Glucose or insulin started preoperatively may decrease postoperative insulin resistance [3]. Bolus infusion of insulin combined with glucose may have vasodilatory properties, may inhibit fatty acid, and may increase glucose uptake in ischaemic tissues for anaerobic ATP production following augmented glycolysis. Thus, insulin may limit the fall in tissue high-energy phosphates that may occur during ischaemia, despite its potential to increase lactate concentrations. Insulin may also stimulate pyruvate dehydrogenase during ischaemia, and thereby exerts a beneficial effect associated with an improved energy state and less lactate production, at least in cultures of cardiomyocytes taken from patients during cardiac surgery [26]. Similarly, pyruvate infusions and enhanced uptake thereof in the tricarboxylic acid cycle may decrease the cytosolic redox state and oxygen radical production, maintain phosphorylation potential and thus limit energy depletion during ischaemia [27]. Insulin may have anti-inflammatory properties by inhibiting production of tumour necrosis factor-α, superoxide radicals and intercellular adhesion molecule-1 in macrophages, leucocytes and endothelium; it may inhibit harmful macrophage-inhibitory factor; and it may potentiate release of endothelial nitric oxide synthase and endothelin [4].

Insulin may increase levels of insulin-like growth factor (IGF)-I, a mediator of growth hormone action, and may suppress hepatic synthesis of IGF-1-binding protein, which binds and limits free circulating IGF-I; thus, during critical illness circulating levels of IGF-I are low and those of IGF-1-binding protein are high [28,29]. Insulin may therefore increase the bioavailability of IGF-I [28].

IGF-I may mimick some of the actions of insulin and may have various beneficial actions, but the anabolic properties may not exceed those of insulin, at least in endotoxaemic rats [10]. Otherwise, muscle protein synthesis would also become relatively resistant to insulin during sepsis [30]. There have been some small trials on the value of IGF-I administration in the critically ill, but results have been disappointing thus far. Insulin may have anabolic properties in the critically ill, burned and catabolic patient [31]. It stimulates protein synthesis in skeletal muscle [31]. Both IGF-I and insulin may inhibit postischaemic apoptosis, energetic failure and damage of cardiac tissue, both in vitro and in animals [20,26]. Insulin may also potentiate ischaemic preconditioning, as described above.

Therefore, there are multiple pathways through which insulin treatment may decrease morbidity and mortality in a variety of critical conditions. Some caution is warranted, however, because hyperinsulinaemia per se may have some adverse effects, including endothelial oxygen radical production [13,32].


The finding of the beneficial effect of intensive insulin therapy in critically ill patients to maintain blood glucose levels below 6.1 mmol/l, as reported by Van den Berghe et al. [25], has a relatively firm albeit multifactorial basis. Those findings should prompt intensivists to institute strict (perhaps stricter than is commonly advocated [17]) control of blood glucose, with the help of the 'wonder drug' insulin. However, a survival benefit has also recently been shown for administration of hydrocortisone [33]. Hydrocortisone infusion may increase blood glucose levels and thereby necessitate concomitant infusion of insulin. Hence, the interaction between these hormones may be a subject for further therapeutic study. Nevertheless, the study reported by Van den Berghe et al. [25] is certainly a major step forward in the treatment of critically ill patients, particularly in the context of failure of most large trials on the value of immunomodulatory treatment of sepsis and shock to show a beneficial impact. Clearly, a limitation of intensive insulin treatment in critically ill patients on sedation is the potential occurrence of hidden hypoglycaemia [31]. Hence, intensive insulin treatment warrants intensive monitoring of blood glucose concentration.



GIK = glucose–insulin–potassium


IGF = insulin-like growth factor.


  1. 1.

    Voerman HJ, Groeneveld AB, De Boer H, Strack van Schijndel RJ, Nauta JP, Van der Veen EA, Thijs LG: Time course and variability of the endocrine and metabolic response to severe sepsis. Surgery 1993, 114: 951-959.

    CAS  PubMed  Google Scholar 

  2. 2.

    Mizock BA: Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med 1995, 98: 75-84. 10.1016/S0002-9343(99)80083-7

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Ljungqvist O, Nygren J, Thorell A: Insulin resistance and elective surgery. Surgery 2000, 128: 757-760. 10.1067/msy.2000.107166

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Das UN: Is insulin an antiinflammatory molecule? Nutrition 2001, 17: 409-413. 10.1016/S0899-9007(01)00518-4

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL: Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab 2000, 85: 3770-3778.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    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: 773-778. 10.1016/S0140-6736(99)08415-9

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Kersten JR, Montgomery MW, Ghassemi T, Gross ER, Toller WG, Pagel PS, Warltier DC: Diabetes and hyperglycemia impair activation of mitochondrial K ATP channels. Am J Physiol 2001, 280: H1744-H1750.

    CAS  Google Scholar 

  8. 8.

    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

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Losser M-R, Bernard C, Beaudeux J-L, Pison C, Payen D: Glucose modulates hemodynamic, metabolic, and inflammatory responses to lipopolysaccharide in rabbits. J Appl Physiol 1997, 83: 1566-1574.

    CAS  PubMed  Google Scholar 

  10. 10.

    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.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    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.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumara T, Kaneda Y, Yorek MA, Beebe D, Gates PJ, Hammes H-P, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000, 404: 787-790. 10.1038/35008121

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Williams SB, Goldfine AB, Timini FK, Ting HH, Roddy M-A, Simonson DC, Creager MA: Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998, 97: 1695-1701.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    D'Amico M, Marfella R, Nappo F, Di Filippo C, De Angelis L, Berrino L, Rossi F, Giugliano D: High glucose induces ventricular instability and increases vasomotor tone in rats. Diabetologia 2001, 44: 464-470. 10.1007/s001250051644

    Article  PubMed  Google Scholar 

  15. 15.

    Lin B, Ginsberg MD, Busto R, Li L: Hyperglycemia triggers massive neutrophil deposition in brain following transient ischemia in rats. Neurosci Lett 2000, 278: 1-4. 10.1016/S0304-3940(99)00889-7

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nsihioka K, Kouno Y, Umemura T, Nakamura S, Sato H: Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction. J Am Coll Cardiol 2001, 38: 1007-1011. 10.1016/S0735-1097(01)01477-2

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Jacober SJ, Sowers JR: An update on perioperative management of diabetes. Arch Intern Med 1999, 159: 2405-2411. 10.1001/archinte.159.20.2405

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Díaz R, Paolasso EC, Piegas LS, Tajer CD, Moreno MG, Coravalan R, Isea JE, Romero G, on behalf of the ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group: Metabolic modulation of acute myocardial infarction: the ECLA Glucose-insulin-potassium pilot trial. Circulation 1998, 98: 2227-2234.

    Article  PubMed  Google Scholar 

  19. 19.

    Van Campen CMC, Klein LJ, Visser FC: Glucose-insulin-potassium imaging: the past and the future? Heart Metabol 2001, 12: 14-18.

    Google Scholar 

  20. 20.

    Jonassen AK, Sack MN, Mjøs 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.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Bronsveld W, Van den Bos GC, Thijs LG: Use of glucose-insulin-potassium (GIK) in human septic shock. Crit Care Med 1985, 13: 566-570.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Law MR, McLane MP, Raymond RM: Adenosine restores myocardial responsiveness to insulin during acute endotoxin shock in vivo. Circ Shock 1989, 28: 333-345.

    CAS  PubMed  Google Scholar 

  23. 23.

    Lazar HL, Chipkin S, Philippides G, Bao Y, Apstein C: Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations. Ann Thorac Surg 2000, 70: 145-150. 10.1016/S0003-4975(00)01317-5

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Scott JF, Robinson GM, French JM, O'Connell JE, Alberti KGMM, Gray CS: Blood pressure response to glucose potassium, insulin therapy in patients with acute stroke with mild to moderate hyperglycaemia. J Neurol Neurosurg Psychiatry 2001, 70: 401-404. 10.1136/jnnp.70.3.401

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  25. 25.

    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyn-inckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in critically ill patients. N Engl J Med 2001, 345: 1359-1367. 10.1056/NEJMoa011300

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Rao V, Merante F, Weisel RD, Shirai T, Ikonomidis JS, Cohen G, Tumiati LC, Shiono N, Li R-K, Mickle DAG, Robinson BH: Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyocytes from simulated ischemia. J Thorac Cardiovasc Surg 1998, 116: 485-494.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Nygren J, Carlsson-Skwirut C, Brismar K, Thorell A, Ljungqvist O, Bang P: Insulin infusion increases levels of free IGF-1 and IGFBP-3 proteolytic activity in patients after surgery. Am J Physiol 2001, 281: E736-E741.

    CAS  Google Scholar 

  28. 28.

    Mongan PD, Capacchione J, Fontana JL, West S, Bünger R: Pyruvate improves cerebral metabolism during hemorrhagic shock. Am J Physiol 2001, 281: H854-H864.

    CAS  Google Scholar 

  29. 29.

    Timmins AC, Cotterill AM, Hughes SCC, Holly JMP, Ross RJM, Blum W, Hinds CJ: Critical illness is associated with low circulating concentrations of insulin-like growth factors-1 and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease. Crit Care Med 1996, 24: 1460-1466. 10.1097/00003246-199609000-00006

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Vary TC, Jefferson LS, Kimball SR: Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1. Am J Physiol 2001, 281: E1045-E1053.

    CAS  Google Scholar 

  31. 31.

    Ferrando AA, Chinkes DL, Wolf SE, Matin S, Herndon DN, Wolfe RR: A submaximal dose of insulin promotes net skeletal muscle protein synthesis in patients with severe burns. Ann Surg 1999, 229: 11-18. 10.1097/00000658-199901000-00002

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  32. 32.

    Kashiwagi A, Shinozaki K, Nishio Y, Maegawa H, Maeno Y, Kanazawa A, Kojima H, Haneda M, Hidaka H, Yasuda H, Kikkawa R: Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsulinemic rats. Am J Physiol 1999, 277: E976-E983.

    CAS  PubMed  Google Scholar 

  33. 33.

    Annane D: Effects of the combination of hydrocortisone (HC)-fludro-cortisone (FC) on mortality in septic shock [abstract]. Crit Care Med 2000,28(suppl):A46.

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to AB Johan Groeneveld.

Additional information

Competing interests

None declared.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Johan Groeneveld, A., Beishuizen, A. & Visser, F.C. Insulin: a wonder drug in the critically ill?. Crit Care 6, 102 (2002).

Download citation

  • Published:

  • DOI:


  • apoptosis pathways
  • critically ill
  • insulin
  • ischaemia/reperfusion
  • stress hyperglycaemia