Hypolipidaemic effects of high-dose insulin therapy
Insulin administration in the perioperative period has been advocated for many years, for a variety of potential therapeutic benefits, but has failed to find universal application or favour. Although considerations have focused on clinical improvements, unwanted deleterious effects of insulin have been largely ignored. This is striking given that the potential for insulin to cause harm is great, especially if inadequately monitored, but unsurprising since it has many effects which are not all measurable. The study by Zuurbier and colleagues1 in this issue of the British Journal of Anaesthesia highlights potentially hazardous metabolic effects of high-dose insulin administration on lipid metabolism during cardiac surgery and provides an important and previously overlooked element of the use of insulin as a therapeutic adjunct.Confusion has arisen regarding the rationale for using insulin during and after surgery and in the various other clinical scenarios advocated for its use. Insulin may be administered in relatively low dosages to normalize blood glucose concentrations, that is, to prevent the hyperglycaemia that typically accompanies the neuroendocrine stress response to surgery and which is a consequence of counterregulatory hormone release and relative insulin resistance. Alternatively, insulin may be administered in high (supra-physiological) doses in order to utilize the multiple (potentially beneficial) effects on physiological systems over and above its effect on glucose uptake. However, insulin in doses sufficient to elicit these effects will predictably cause hypoglycaemia and hypokalaemia, hence the concomitant administration of glucose and potassium (‘GIK’) required to achieve euglycaemia and eukalaemia—the hyperinsulinaemic euglycaemic ‘clamp’. The question is, what else is all this insulin doing that we are not measuring?
The confusion regarding insulin use is compounded by the multiple clinical settings for which these therapeutic approaches to insulin administration have been used. Insulin has been advocated for amelioration of ischaemia–reperfusion injury in (cardiac) surgical and medical (acute myocardial infarction, AMI) settings, for improving left ventricular (LV) function in cardiac failure, and in postoperative surgical and medical intensive care patients. Results have been inconsistent, with several studies noting potential risks and adverse outcomes. Many studies have been underpowered and poorly designed, with hugely variable insulin dosage protocols, which may explain the lack of consensus and why insulin therapy remains controversial and contentious.
The deleterious effects of hyperglycaemia are well documented, and provide a rational basis for the administration of modest doses of insulin simply to achieve euglycaemia. Unfortunately, however, even modest doses to normalize blood glucose levels have not proved to be universally beneficial. Although surgical ICU patients (both diabetic and non-diabetic) seem to benefit from relatively long-term (
5 days) postoperative ‘intensive’ insulin therapy [i.e. closely monitored to achieve blood glucose levels of 4.4–6.1 mmol litre–1 (80–110 mg dl–1)], with improved morbidity and mortality accompanying tight glycaemic control, an effect observed in the cardiac surgical patient subgroup,2 the same benefit is not seen in medical ICU patients undergoing a similar normoglycaemic insulin regime, with no improvement in mortality.3 In the case of high-dose insulin infusion (GIK), where the rationale is to exploit the effects of insulin itself additional to its effects on blood glucose levels (i.e. at hypoglycaemic dosages), in order to optimize LV function and minimize ischaemia–reperfusion injury, the evidence in favour of its efficacy is even less clear cut, and the much greater potential for harmful side-effects needs to be carefully considered.
Benefits of insulin therapy have been reported in patients undergoing coronary artery bypass graft surgery (CABG),4 including diabetics,5 and improvement in outcome after AMI with GIK therapy has also been noted.6 However, these studies have not all used high-dose insulin regimes, and few measured plasma fatty acid (FA) levels. Furthermore, no benefits of insulin in CABG7 8 and AMI9 10 have also been reported. Insulin therapy is probably only effective in cardiac surgery when given; at optimal dose, possibly only in patients with poor LV function, and for extended periods after operation.11 Its efficacy in patients with diabetes is also uncertain.12 Worryingly, a recent study of intensive insulin therapy during cardiac surgery reported increased morbidity and mortality in the treatment group,13 highlighting the potential danger of this therapeutic approach. The assumption has been that the dangers of aggressive insulin administration are attributable solely to hypoglycaemic events, but excessive modification of other physiological parameters, including the metabolism of other substrates, such as plasma lipids, may be responsible.
Cardiac function is critically dependent on substrate utilization, and changes in myocardial fuel selection can have a major impact both positively and negatively.14 Myocardial substrate selection depends on plasma substrate availability, metabolic hormone concentrations (including insulin), and cardiac workload. The heart can oxidize carbohydrates (glucose, lactate, and pyruvate), lipids [FAs, both ‘free’ fatty acids (FFA), and esterified within triacylglycerols (TAG) in the core of lipoproteins such as chylomicrons and very low-density lipoprotein (VLDL)], and ketone bodies. Minor energy supply can be derived by glycolysis.15 The healthy heart generates about 70% of its energy requirement from FA oxidation, the remaining ATP synthesis being derived from carbohydrates. FAs are clearly important fuels for myocardial contractile function, being highly reduced they yield more ATP per mol of substrate oxidized than carbohydrates, but they are amphipathic molecules capable of causing membrane and other, intracellular effects damaging to cellular function (‘lipotoxicity’). Furthermore, being highly reduced, their oxidation requires more oxygen per mol than carbohydrate oxidation, making them less ‘efficient’ fuels, especially in an oxygen supply limited tissue such as ischaemic myocardium. In the reperfused myocardium, high concentrations of FAs decrease glucose utilization, decrease contractility, increase dysrhythmia, and increase free radical accumulation.5 By decreasing NADPH and increasing diacylglycerols, they potentially limit eNOS-mediated vasodilatation. Elevated FFA levels are also associated with increased sympathetic activity, increased oxidative stress and ROS production with endothelial dysfunction, and increased inflammatory cytokine production.5 6 A further advantage of carbohydrates over FAs is that they are anaplerotic, able to replenish Krebs cycle intermediates, which cataplerotic FAs cannot. Of critical importance here is that plasma FFA concentrations, usually low in healthy subjects, increase markedly in the stress response, and in diabetes, due to increased adipose tissue lipolysis and FA release by lipolytic hormones, such as catecholamines, and relative insulin deficiency/resistance. As a result, myocardial FA availability and utilization increase at this time. Ischaemia–reperfusion and diabetes are both associated with a marked shift in cardiac metabolism, away from carbohydrate utilization, and towards FA oxidation: increased FA utilization is closely coupled to decreased carbohydrate uptake and oxidation (Randle cycle). The cardioprotective effect of insulin on isolated hearts during reperfusion is lost in the presence of high FFA concentrations.16 Abnormally high FA utilization is associated with cardiac dysrhythmia and impaired recovery of contractile function at reperfusion; techniques to limit excessive FA utilization and increase carbohydrate oxidation therefore have the potential to ameliorate tissue injury and dysrhythmia and poor contractile function at reperfusion and provide one rationale for insulin therapy at the high, hypoglycaemic dosages required to influence lipid metabolism—GIK therapy. FA utilization may be limited by inhibitors of FA oxidation (e.g. trimetazidine and ranolazine)14—however, use of these agents carries the important caveat that FA oxidation is only partly, not totally, inhibited. FA utilization can also be decreased by lowering their plasma concentration by inhibiting adipose tissue lipolysis. Insulin achieves this by inhibiting adipose tissue hormone sensitive lipase, but it also increases tissue glucose uptake and oxidation, protecting the heart from potentially toxic levels of FAs, decreasing cardiac FA utilization, and forcing it to utilize more oxygen-efficient anaplerotic carbohydrate substrates. In the setting of ischaemia–reperfusion this should be beneficial, thus there is a clear rationale for using insulin to prevent excessively high FA concentrations and utilization, in the same way as there is a rationale to limit potentially toxic high-glucose concentrations. In addition, insulin has other potentially beneficial actions: it is positively inotropic, has a direct anti-inflammatory effect, increases glycolytic ATP, normalizes glutathione, decreases apoptosis via increased PI2K/Akt signalling, and decreases AMP-activated protein kinase (AMPK).
However, too much of a good thing can be a bad thing.17 Insulin has multiple effects on metabolism, and at the high doses of insulin advocated (and possibly required) to impact significantly on ischaemia–reperfusion injury in the cardiac surgical setting and to blunt the hyperlipidaemia of the stress response, these may be deleterious: FA concentrations may be lowered to levels below which tissues can assimilate them from the plasma,18 19 and as precursors of ketone bodies (acetoacetate, 3-hydroxybutyrate) in the liver, another quantitatively important fuel avidly oxidized by the heart, ketone body availability and utilization may also be blocked. Zuurbier and colleagues1 report that high-dose insulin administration to patients undergoing CABG does not simply prevent the rise in plasma FFA levels that occurs perioperatively, but actually decreases them to very low levels, below those seen before operation—and indeed to levels which may be too low to allow uptake by the heart.18 19 The doses of insulin used in this study are not exceptionally high compared with other GIK studies. This lowering effect was also observed with plasma triacylglycerols, notably VLDL-TAG, which may be a quantitatively more important source of FAs in vivo than free FAs.15 20 The hyper-ketonaemic response was blunted, but interestingly lactate was unaffected. What is the significance of these findings? With current knowledge, this is a difficult question to answer. The study was not designed to rigorously examine clinical outcomes, but the variable, sometimes deleterious outcomes associated with high-dose GIK usage suggest that insulin may be causing clinically significant effects by mechanisms that are not being monitored. An excess of non-cardiac deaths has been reported in one GIK study9 and this was at relatively low insulin dosage. There are few studies examining the consequences of blocking FA availability, but it is reasonable to assume that the heart may be negatively affected by the acute withdrawal of the substrate that normally provides more than two-thirds of its energy requirement, and whose effects are not limited simply to energy provision. One study of obese women found improved cardiac efficiency in non-failing hearts with insulin resistance when FFA levels were moderately lowered.21 However, plasma FFA depletion by the lipolysis inhibitor acipimox in cardiomyopathic heart failure decreased cardiac work. In healthy hearts, this was accompanied by decreased oxidative metabolism, and hence myocardial energy efficiency was maintained, but in failing hearts the decreased cardiac work was not accompanied by decreased oxidative metabolism, hence myocardial energy efficiency was worse.22 The conclusion from these authors was that both FA and glucose oxidation were required for optimal function in the failing heart. Acute increases or decreases in FFA concentrations did not alter contractile function in stunned and hibernating human myocardium.23
In the absence of conclusive clinical evidence in humans, we are obliged to examine animal models. These reveal how active the heart is in lipid metabolism. It is a major site of adipose triacylglycerol lipase (ATGL), with high lipolytic activity and FA release and assimilation.24 ATGL-deficient mice had decreased plasma FFA, TAG and ketone body levels, demonstrated increased glucose utilization and glucose tolerance and insulin sensitivity, but accumulated cardiac lipid and showed cardiac dysfunction and premature death.24 In isolated failing rat hearts, decreased FA incorporation and oxidation rates were accompanied by downregulation of cardiac FA transporters FAT/CD36, FABPpm and FATP 1 and 6, and also of the cytosolic FA binding protein cFABP. The shift away from FA metabolism correlated with functional impairment of the heart.25 FAs were also found to be beneficial in isolated diabetic rat hearts, protecting these hearts during low flow ischaemia, an effect ascribed to their ability to decrease the ATP depletion that occurs under these conditions. Furthermore, the relatively high FA levels used (1.2 mM) were not found to be detrimental to control (non-diabetic) hearts.26 Interestingly, this effect was not noted with ketone bodies.26 The shift from carbohydrate to FA oxidation in hearts from Zucker Diabetic Fatty rats did not increase myocardial oxygen consumption and was not associated with impaired response to ischaemia and reperfusion.27
Since FAs are transported in the plasma bound to albumin, decreases in plasma albumin concentrations, commonly seen in surgical and critically ill patients, could further influence FA availability.
The study by Zuurbier and colleagues also hints at the importance of TAG and ketone bodies. The roles of both in myocardial metabolism have recently been highlighted and it is now clear that both are important cardiac fuels. The heart has multiple FA/TAG pools and very high constitutive lipoprotein lipase (LPL) activity, the enzyme responsible for the hydrolysis of circulating TAG to FA before its uptake, and a key regulatory enzyme sensitive to insulin modulation. The heart also highly expresses the VLDL receptor, another route of TAG-FA entry to the heart and potentially a signalling component of cardiac metabolism. Limitation of TAG-derived FA availability may therefore be detrimental. Hearts from heart-specific LPL knockout mice show decreased FA oxidation, as expected, but also demonstrated increased glucose utilization. However, despite this compensatory increase in carbohydrate metabolism, these hearts had impaired cardiac mechanical function and all heart LPL knockout animals died within 48 h of increased cardiac workload generated by aortic constriction.28 Similarly, another model of cardiac-specific LPL inhibition showed that acute loss of LPL activity leads to rapid alterations in metabolic enzyme gene expression and cardiac dysfunction.29 Blocking TAG-rich lipoprotein uptake into isolated rat hearts via either LPL- or lipoprotein receptor-mediated routes decreases cardiac hydraulic work, despite the presence of adequate glucose.30
Besides their important role as metabolic fuels, FAs have other physiological actions. They stimulate uncoupling proteins, which are probably a cardioprotective mechanism, and are endogenous ligands for peroxisome proliferator-activated receptors (PPARs)—nuclear receptors which act as transcription factors to regulate metabolic enzyme gene expression. Activation of PPAR-
stimulates glucose metabolism and improves contractile function in type 2 diabetic rat hearts;31 FA presence is likely required for optimal carbohydrate utilization and metabolism. Critical reduction of FA concentrations may impair metabolic signalling with profound effects on tissue metabolism.
It is possible that for insulin to be effective at influencing cardiac function, it must be used at such dosages that non-glucose (e.g. FA and TAG lowering) effects become significant and potentially deleterious. Insulin may affect other substrates/systems that also influence outcome. The authors themselves have reported decreased ACTH, glucagon, cortisol,32 and acute phase proteins33 with high-dose GIK administration; the finding of raised adrenaline levels in the former study32 suggests a response to intervention indicative of metabolic stress. The pleiotropic effects of insulin may do more harm than good, or at least limit its applicability.
Strategies to lower concentrations and myocardial utilization of FAs by insulin may well have an important therapeutic application in the context of ischaemia–reperfusion during and after cardiac surgery. There is little doubt that insulin has the potential to improve cardiac status in this clinical setting, both through its effects of stimulating glucose metabolism, and its ability to limit potentially toxic rises in circulating FA levels. However, excessive lowering of FA levels to frankly hypolipidaemic levels may be deleterious. We need to distinguish between ‘tight glycaemic control’ and ‘hyperinsulinaemic’ therapy. To further complicate matters, all these considerations may be modified in the presence of pre-existing diabetes, both insulin-dependent and insulin-resistant. Until we can monitor FA concentrations with the same frequency as blood glucose levels, and until we better understand the pathophysiological consequences of extremely low FA levels, high-dose GIK therapy should be used with caution.
Nuffield Department of Anaesthetics
University of Oxford
Radcliffe Infirmary
Woodstock Road
Oxford OX2 6HE
UK
* E-mail: rhys.evans{at}nda.ox.ac.uk
References
1 Zuurbier CJ, Hoek FJ, van Dijk J, et al. Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery. Br J Anaesth (2008) 100:442–50.
2 Ingels C, Debaveye Y, Milants I, et al. Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life. Eur Heart J (2006) 27:2716–24.
3 Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU [see comment]. N Engl J Med (2006) 354:449–61.
4 Bothe W, Olschewski M, Beyersdorf F, Doenst T. Glucose–insulin–potassium in cardiac surgery: a meta-analysis. Ann Thorac Surg (2004) 78:1650–7.
5 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) 70:145–50.
6 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.
7 Bruemmer-Smith S, Avidan MS, Harris B, et al. Glucose, insulin and potassium for heart protection during cardiac surgery. Br J Anaesth (2002) 88:489–95.
8 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) 73:1246–51. discussion 51–2.
9 Ceremuzynski L, Budaj A, Czepiel A, et al. Low-dose glucose–insulin–potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther (1999) 13:191–200.[CrossRef][Web of Science][Medline]
10 Mehta SR, Yusuf S, Diaz R, et al. Effect of glucose–insulin–potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA (2005) 293:437–46.
11 Doenst T, Bothe W, Beyersdorf F. Therapy with insulin in cardiac surgery: controversies and possible solutions. Ann Thorac Surg (2003) 75:S721–8.
12 Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes (2006) 55:3151–9.
13 Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med (2007) 146:233–43.
14 Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis (2001) 12(Suppl 1):S8–11.[Web of Science][Medline]
15 Hauton D, Bennett MJ, Evans RD. Utilisation of triacylglycerol and non-esterified fatty acid by the working rat heart: myocardial lipid substrate preference. Biochim Biophys Acta (2001) 1533:99–109.[Medline]
16 Folmes CD, Clanachan AS, Lopaschuk GD. Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia. Circ Res (2006) 99:61–8.
17 Taegtmeyer H. Glucose for the heart: too much of a good thing? J Am Coll Cardiol (2005) 46:49–50.
18 Szabo Z, Arnqvist H, Hakanson E, Jorfeldt L, Svedjeholm R. Effects of high-dose glucose–insulin–potassium on myocardial metabolism after coronary surgery in patients with type II diabetes. Clin Sci (2001) 101:37–43.[Medline]
19 Stanley AW Jr, Moraski RE, Russell RO, et al. Effects of glucose–insulin–potassium on myocardial substrate availability and utilization in stable coronary artery disease. Studies on myocardial carbohydrate, lipid and oxygen arterial-coronary sinus differences in patients with coronary artery disease. Am J Cardiol (1975) 36:929–37.[CrossRef][Web of Science][Medline]
20 Augustus AS, Kako Y, Yagyu H, Goldberg IJ. Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA. Am J Physiol Endocrinol Metab (2003) 284:E331–9.
21 Peterson LR, Herrero P, Schechtman KB, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation (2004) 109:2191–6.
22 Tuunanen H, Engblom E, Naum A, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure [see comment]. Circulation (2006) 114:2130–7.
23 Wiggers H, Norrelund H, Nielsen SS, et al. Influence of insulin and free fatty acids on contractile function in patients with chronically stunned and hibernating myocardium. Am J Physiol Heart Circ Physiol (2005) 289:H938–46.
24 Haemmerle G, Lass A, Zimmermann R, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science (2006) 312:734–7.
25 Heather LC, Cole MA, Lygate CA, et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res (2006) 72:430–7.
26 King LM, Sidell RJ, Wilding JR, Radda GK, Clarke K. Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia. Am J Physiol Heart Circ Physiol (2001) 280:H1173–81.
27 Wang P, Lloyd SG, Zeng H, Bonen A, Chatham JC. Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol (2005) 288:H2102–10.
28 Augustus AS, Buchanan J, Park TS, et al. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J Biol Chem (2006) 281:8716–23.
29 Noh HL, Okajima K, Molkentin JD, Homma S, Goldberg IJ. Acute lipoprotein lipase deletion in adult mice leads to dyslipidemia and cardiac dysfunction. Am J Physiol Endocrinol Metab (2006) 291:E755–60.
30 Niu YG, Hauton D, Evans RD. Utilization of triacylglycerol-rich lipoproteins by the working rat heart: routes of uptake and metabolic fates. J Physiol (2004) 558:225–37.
31 Golfman LS, Wilson CR, Sharma S, et al. Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats. Am J Physiol Endocrinol Metab (2005) 289:E328–36.
32 van Wezel HB, Zuurbier CJ, de Jonge E, et al. Differential effects of a perioperative hyperinsulinemic normoglycemic clamp on the neurohumoral stress response during coronary artery surgery. J Clin Endocrinol Metab (2006) 91:4144–53.
33 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.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||