REVIEW
Mechanisms underlying stress-induced hyperglycemia in critically ill patients
Farshad Kajbaf1, Critical illnesses associate with alteration in metabolic status. Insulin resistance and Mojtaba Mojtahedzadeh1 enhanced blood glucose levels occur during stressful situations, such as acute illnesses. & Mohammad Abdollahi1† These disturbances associate with poor prognostic events. Intensive insulin therapy and maintaining normoglycemia reduce the morbidity and mortality rate in critically ill †Author for correspondence 1Faculty of Pharmacy, and patients. We aim to give an overview of the current insights in hyperglycemia and insulin Pharmaceutical Sciences resistance in critical illnesses. A search of the literature was conducted using Pubmed Research Center, articles in English. Most of the recent and relevant articles were studied, reviewed and Tehran University of Medical Sciences, Tehran, summarized with categorization of causes, pathophysiology and adverse events. To PO Box 14155–6451 introduce better conception regarding stress-induced hyperglycemia and its management, Iran the most viable mechanisms and therapeutic goals are discussed. Hyperglycemia and Tel.: +98 216 695 9104 Fax: +98 216 695 9104 insulin resistance are common in critically ill patients, particularly in trauma, E-mail: mohammad@ postmyocardial infarction, following major surgery and among those with sepsis. These tums.ac.ir complications occur in patients with or without a history of diabetes. Multiple pathogenic mechanisms, such as increased release of proinflammatory cytokines and counter- regulatory hormones, have been suggested. The resulting metabolic alteration is associated with significant adverse events and poor prognostic outcomes. Strict glycemic control and intensive insulin therapy could improve the survival rate in critically ill patients. Tight glycemic control by intensive insulin therapy has a pivotal role in the treatment of such patients. Every medication or intervention that could prevent the inflammatory process and insulin resistance might be considered as therapeutic strategies for the improvement of critically ill patients with acute hyperglycemia.
Hyperglycemia in critical illnesses of systemic infection, frequency of acute renal The relationship between stressful situations in failure requiring dialysis or hemofiltration, red critically ill patients (CIPs) and acute hyperglyc- blood cell (RBC) transfusion, polyneuropathy emia was first described in the late 19th Century and overall hospital mortality. Currently, the [1]. Stress-induced hyperglycemia was thought of use of insulin is an approved therapeutic strat- as an adaptive and even beneficial neurohormo- egy in the management of CIPs [2,3,6]. Earlier nal response to support the energy requirements studies in diabetic patients who underwent of insulin-independent cell types, such as brain open heart surgery or those with acute myocar- cells and phagocytes [1]. With high prevalence, dial infarction (AMI) showed that hyperglyc- hyperglycemia and insulin resistance are associ- emia could be a predictor of poor prognosis ated with poor outcome in a wide spectrum of [7,8]. Other clinical investigations in both medi- CIPs [2–5]. Therefore, tight glycemic control cal and surgical ICUs in the diabetic and could improve the prognosis of these patients nondiabetic population have confirmed the and decrease adverse events. beneficial effects of glycemic control using intensive insulin therapy [4,5,9,10]. Intensive insulin therapy & tight glycemic control in CIPs Adverse effects of acute hyperglycemia Keywords: antihyperglycemic Previously, glycemic control has not been seri- in critical illnesses reagents, critical illnesses, ously considered in the intensive care unit CIPs, such as diabetic patients, are susceptible to hyperglycemia, insulin resistance, intensive (ICU), except in diabetic patients or those with infection due to the deleterious effects of hyper- insulin therapy a persistently high glucose level above glycemia on the immune system [11]. Hyperglyc- 200 mg/dl. Results from studies after 2000 emia is found to be associated with a higher risk part of demonstrated that tight glycemic control may of sepsis and septic shock among patients who improve the outcomes of CIPs via a reduction need intensive care support, even for a short
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period of time [12,13]. It has been demonstrated activation of the corticotropin-releasing factor that intensive insulin therapy reduces the rate of (CRF)–adrenocorticotrophic hormone (ACTH) bacteremia and wound infection in burn axis via cytokines such as interleukin (IL)-1, IL-6 patients [14,15]. Control of blood glucose and tumor necrosis factor (TNF)α, which are decreased the rate of deep sternal wound infec- primed by monocytes, lymphocytes and other tion in diabetic patients following open heart chief endocrine factors, and eventually results in surgery [16]. The rate of worse outcome in increased secretion of glucocorticoids from the nondiabetic patients with acute ischemic events, adrenal cortex, which influence the immune- such as stroke or AMI, has been reported as accessory cells, a bidirectional interaction of higher in hyperglycemic states [17–19]. In addi- immunoneuroendocrine systems [26,28,29]. Fur- tion, hyperglycemia accompanies poor outcomes thermore, stimulation of the sympathetic nervous in traumatic events [20,21]. system leads to release of ChAs and hormonal modulation [30,31]. New approach to glycemic control Increased level of counter regulatory hor- Several pathogenic mechanisms are thought to mones (e.g., glucagone and growth hormone), be involved in this metabolic phenomenon. cortisol, ChAs and proinflammatory cytokines Understanding these mechanisms would pro- cause insulin resistance and hyperglycemia by vide knowledge to better manage hyperglyc- different mechanisms. emia in critical illnesses using additional therapeutic targets. Counter-regulatory hormones & hyperglycemia Pathophysiology of Blood glucose level is normally regulated by an stress-induced hyperglycemia interaction between neurohormonal and hepatic Major causes of acute hyperglycemia autoregulatory mechanisms. Glycogenolysis and Insulin resistance and hyperglycemia are com- gluconeogenesis are involved in hepatic glucose mon in critical illness due to an alteration in the metabolisms [1,32,33]. Cortisol increases transcrip- immunoneuroendocrine axis and subsequent tion of phosphoenolpyruvate carboxykinase alteration in lipid and carbohydrate metabolisms (PEPCK) genes (the key enzyme for gluconeo- [1,22,23]. Disturbances in cross-taking between genesis) and induces gluconeogenesis, in which endocrine, immune and neural systems, which noncarbohydrates substrates, such as lactate, are highly interrelated with each other, and alter- alanine and glycine, are converted to glucose ation in their complex interactions during critical [34,35]. Elevated cortisol levels are observed in illnesses would finally result in metabolic insta- both acute and chronic phases of critically ill- bilities. Pre-existing conditions, such as diabetes nesses, and occur by different neurohormonal mellitus (DM), pancreatitis and cirrhosis, will mechanisms. It seems that there is a biphasic increase the risk of hyperglycemia in the intensive response to the HPA axis during the acute and care setting [1]. Iatrogenic causes of hyperglyc- protracted phases [36,37]. During the acute phase, emia, including administration of steroids, sym- both cortisol and corticotropin concentrations pathomimetics (e.g., catecholamines [ChAs]), are raised due to activation of the HPA axis and total parenteral nutrition (TPN) and in particu- steroidogenesis, which is more diverted toward lar, excess administration of dextrose must also be glucocorticoids synthesis [25,36]. In the chronic considered [1,24]. phase (>5-day stay in ICU), corticotropine levels decrease while cortisol levels remains high [29,37]. Immunoneuroendocrine alterations Stimulation of the sympathetic nervous sys- during acute illnesses tem enhances the level of counter regulatory Indeed, stress is a response to any situation that hormones, such as epinephrine, norepinephrine, threatens homeostasis, and usually results in the glucagon and growth hormone. ChAs increase activation of the hypothalamic–pituitary–adre- hepatic cAMP levels, which in turn, motivate nal (HPA) axis and sympathetic autonomic PEPCK gene transcription and increase hepatic nervous system [25–27]. gluconeogenesis [35]. Epinephrine promotes Neuroendocrine involvements and stimulation glycogenolysis in hepatocytes and skeletal mus- of the HPA axis, which is characterized by hyper- cle cells and, in combination with glucagon, has cortisolemia during critical illnesses, play a major an additive effect on both glycogenolysis and role in the occurrence of hyperglycemia [22,28]. gluconeogenesis [38]. In addition, inhibition of Activation of the HPA axis is associated with insulin receptor substrate (IRS)-1 activity and
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interruption of the insulin signaling pathway by It has been demonstrated that IL-6 increases epinephrine develop insulin resistance [39]. release of both CRH and ACTH, promoting Enhanced free fatty acid (FFA) levels secondary peripheral insulin resistance and hyper- to simulation of lipolysis by epinephrine inhib- glycemia [52]. Activation of IKK in hepatocytes its insulin signaling and, thus, glycogen synthe- by IL-1 results in gene expression of inflamma- sis [40]. ChAs also prevent insulin-mediated tory cytokines via NFκB. Serine phosphoryla- glucose uptake by inhibition of insulin binding tion of IRS-1 by IKK and decreased activation to the receptors and blocking tyrosine kinase of PI3K eventually suppress GLUT4 transloca- activity, which result in translocation failure of tion. IL-1 also increases secretion of glucagon glucose transporter (GLUT)-4 to the plasma cell and corticostrone, which have additive effects membrane [41]. Reduction of insulin-mediated on the production of glucose [53]. Traumatic glucose uptake can be prevented by blockade of events, such as acute brain injury, which cause β2 receptors, demonstrating the basic role of hyperglycemia are associated with increased ChAs during insulin resistance [42]. plasma levels of proinflammatory cytokines, Growth hormone reduces the number of insu- such as IL-8 and TGF-β1 [54]. Box 1 summa- lin receptors and impairs tyrosine kinase activity. rizes the major causes of hyperglycemia Glucagon also synergizes with epinephrine in the in CIPs. induction of glycogenolysis and, also activates gluconeogenesis [43]. Glucose toxicity in acute illnesses Association between hyperglycemia and poor Proinflammatory cytokines & hyperglycemia prognostic outcome following different types of Proinflammatory cytokines, such as TNFα, IL-1, acute illnesses (e.g., AMI, stroke, trauma and IL-6, and IL-8, as well as counter regulatory hor- complex surgery) has been well established. mones, have major roles in constitution of insulin Hyperglycemia may be associated with hypo- resistance and hyperglycemia during acute illnesses. volemia and trace element deficiencies, leading A stress response is associated with increased to serious complications [1]. secretion of proinflammatory cytokines from Hyperglycemia increases morbidity and mor- immune cells and other tissues, such as the gut tality rates in CIPs through numerous different and lung [44,45]. This immunological response mechanisms (Box 2). activates release of counter regulatory hor- mones, leading to increased hepatic glucose Hyperglycemia & its adverse effects production, decreased peripheral glucose Glucose has been recognized as a proinflamma- uptake and insulin resistance in skeletal muscle tory mediator. Glycemic control exerts an anti- and hepatocytes [2,46]. inflammatory effect. It has been demonstrated TNFα acts as an inhibitor of tyrosine kinases that glucose overfeed increases generation of of insulin receptors and diminishes IRS-1 tyro- reactive oxygen species (ROS) by immune sine phosphorylation in the liver and adipose tis- cells, which results in oxidative stress [55]. ROS sues. In addition, TNFα impairs activation of are involved in the pathophysiology of many phosphatidylinositol 3 kinase (PI3K), which has complicate specially diabetes [56,57]. a key role in insulin signaling [47]. Therefore, In addition, glucose increases intranuclear translocation of GLUT4 is affected and insulin NFκB and enhances the activator protein-1 and resistance occurs [48]. TNFα also activates the growth factor. These transcription factors regu- inhibitor κB kinase (IKK), a serine kinase that late the genes that encode proinflammatory controls activation of nuclear factor (NF)-κB, mediators [58]. Glucose also increases plasma which is a major proinflammatory transcription matrix metalloproteinase (MMP)-2 and -9, factor, and thus promotes inflammatory cascade which both have inflammatory properties [59]. [49,50]. TNFα also stimulates expression of hor- Enhanced production of proinflammatory mone-sensitive lipase, resulting in increased cytokines, such as TNFα, IL-1β and IL-6, has lipolysis. Furthermore, TNFα decreases the lipo- been observed during hyperglycemia [60–62]. protein lipase activity that results in mobilization Hyperglycemia, per se, promotes insulin of lipids from adipocytes, which appears to be resistance via overexpression of c-jun N-termi- another cause of insulin resistance [23]. Addition- nal kinase (JNK) and IKKβ. JNK and IKKβ, ally, TNFα stimulates secretion of counter regu- similar to mitogen-activated protein kinase latory hormones, which, in turn, facilitates and atypical protein kinase-C, are intracellular gluconeogenesis and glycogenolysis [51]. mediators of stress and inflammation and futurefuture sciencescience groupgroup www.futuremedicine.com 99 REVIEW – Kajbaf, Mojtahedzadeh & Abdollahi
Box 1. Causes of hyperglycemia during critical illness. Different theories regarding acute toxicity of hyperglycemia • Pre-existing conditions Some theories suggest that subtle molecular – Pre-existing diabetes mellitus – Obesity with metabolic syndrome differences, patients’ genetic background and – Pancreatitis differences between the acute and chronic sta- – Cirrhosis tus of hyperglycemia are interfering factors [23]. Others point out that intracellular glucose • Immunoneuroendocrine changes* overload during critically illnesses is involved – Increased level of counter regulatory hormones (e.g., epinephrine, in this scenario [6]. norepinephrine, growth hormone, glucagone and cortisol) – Increased level of proinflammatory cytokines (e.g., TNFα, IL-1 and IL-6) Glucose transporters & intracellular glucotoxicity • Iatrogenic It is known that glucose itself influences the – Catecholamines infusion regulation and expression of its cellular trans- – TPN (particularly excess amount of dextrose infusion) porters. Downregulation of GLUTs during – Drugs (e.g., corticosteroids, thiazide diuretics and phenytoin) moderate hyperglycemia in normal cells is a • Hypokalemia (impairs insulin secretion) protective mechanism against glucotoxicity [68]. *These metabolic alterations increase the rate of glycogenolysis and gluconeogenesis Glucose molecules are delivered across the cell and induce insulin resistance in skeletal muscles, adipose tissues and liver. membrane by several types of transporters. IL: Interleukin; TNF: Tumor necrosis factor; TPN: Total parental nutrition. GLUT1 is needed for basal glucose uptake, even under hypoglycemic situations. GLUT2 is could phosphorylate serine and threonine resi- responsible for hepatic glucose transport and dues (instead of tyrosine) suppressing insulin stimulates pancreas glucose-dependent insulin signaling and causing insulin resistance [23,63]. secretion. The GLUT4 isoform has been found Acute hyperglycemia reduces endothelial in skeletal and cardiac muscles and adipose tis- nitric oxide (NO) and promotes vascular con- sues, where insulin mediates glucose transport striction, which, in turn, causes abnormal per- by translocation of GLUT4 to the plasma cell fusion of organs. As mentioned earlier, membrane [69,70]. hyperglycemia generates ROS. However, NO Enhanced concentration of cytokines, such as that binds to superoxide radicals forms perox- TNFα, angiotensin II and endothelin-1, during ynitrite and promotes platelet proaggregatory the stress response stimulate the translocation and prothrombic events [63]. and upregulation of glucose transport in differ- An increased risk of infection is one of the ent cells [71–73]. Likewise, hypoxia has the same consequences of hyperglycemia, possibly via effect on GLUTs [74]. Therefore, upregulated disturbed immune system function [13]. Addi- glucose transporters that are working without tionally, hyperglycemia weakens neutrophil the influence of insulin cause extra influx of glu- function by decreasing their chemotactic and cose into the cell. This leads to enhanced inter- phagocytic capacity and it impairs the produc- cellular glucose levels in different cell tion of ROS and reduces the xidative burst of types,including endothelial and epithelial cells, leukocytes [13,64,65]. as well as immune cells.
Why is hyperglycemia profoundly fatal in Mitochondrial disturbances critical illnesses? & intracellular hyperglycemia General Impaired mitochondrial function of hepato- Insulin resistance is the main feature of Type 2 cytes has been reported during hyperglycemia diabetes and an inducer of the metabolic syn- [75]. This abnormality, which is not observed drome, in which normal circulatory insulin in skeletal muscles, reflects the direct effect of levels are insufficient to produce an expected intracellular glucose toxicity, as described biological effect [66]. Insulin resistance is associ- above. Hyperglycemia has been associated ated with chronic hyperglycemia, the major with enhanced mitochondrial superoxide pro- initiator of long-term complications and the duction. Mitochondrial dysfunction, with a major cause of morbidity and mortality in failure to produce energy for efficient metabo- diabetics [67]. lisms, is the major cause of cellular abnormali- Why is hyperglycemia during critical illnesses ties and organ dysfunction leading to multiple more toxic acutely than in diabetic patients? syndromes among CIPs who die [76].
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Box 2. Deleterious effects of stress- favorable metabolic and nonmetabolic effects induced hyperglycemia. that could reverse almost all undesirable adverse effects of stress response and prevent • Electrolyte disturbances glucotoxicity (Box 3). • Increase in the rate of oxidative stress • Procoagulative effects Insulin & its anti-inflammatory properties • Disturbances in the cardiovascular system Insulin has a potent anti inflammatory effect [63]. • Impairment in the immune system (which It has been demonstrated that insulin decreases increases the rate of infection and sepsis): κ κ – Decrease in the complement cascade intranuclear NF B and enhance I B levels in function mononuclear cells [78]. Additionally, insulin sup- – Decrease in the neutrophil phagocytic and press the actions of pro-inflammatory transcrip- chemotactic capacity tion factors early growth response-1 and activator • Hepatocyte mitochondrial dysfunction protein-1. It also reduces MMP-2 and -9, which • Increase in the rate of acute renal failure are important components of inflammation [79]. • Increase in the rate of polyneoropathy Insulin could reduce mannose-binding lectin and • Increase in the rate of insulin resistance C-reactive protein, which would result in anti-inflammatory effects [80]. Mitochondrial dysfunction is also attributed to insulin resistance. As a result of decreased oxida- Insulin & the cardiovascular system tion of mitochondrial fatty acids, intracellular Hyperglycemia promotes thrombosis by activa- fatty acyl coenzyme A and diacyl glycerol levels are tion of tissue factors, while insulin reverses that enhanced. Thus, atypical protein kinase C, JNK by suppressing tissue factor, plasminogen activa- and IKKβ are activated to block IRS-1 tyrosine tor inhibitor-1 and pro-MMP-1. MMP-1 moti- phosphorylation causing insulin resistance [77]. vates prothrombic process by activation of protease-activated receptor-1, which mediates Benefit of glycemic & nonglycemic the action of thrombin [81,82]. effects of intensive insulin therapy Insulin also increases the release of NO from Generally, intensive glycemic control improves the endothelium and increases the synthesis and the survival of CIPs and decreases morbidity expression of NO in endothelial cells and plate- and mortality rates. Insulin has a multitude of lets. Vasodilatation and inhibition of platelet aggregation are other non-metabolic benefits of Box 3. Beneficial effects of insulin therapy and insulin [23,83]. In oxidative stress, ROS increases glycemic control. and peroxynitrate is formed, which depresses • Anti-inflammatory effects mitochondrial function. Since insulin reduces – Decrease in proinflammatory cytokines (e.g., TNFa) the NO level and decreases inducible nitric oxide – Decrease in NFkB level synthase (iNOS) expression, it would protect – Increase in IkB level mitochondrial function and prevent systemic – Suppression of EGR-1 action inflammation [83]. It has been demonstrated that – Suppression of AP-1 action insulin has antiapoptotic and cardioprotective – Reduction in MBL and CRP level effects that are mediated by activation of the • Enhanced coagulation profile Akt–PI3K pathway and suppression of proin- – Suppression of tissue factor flammatory cytokines. In addition, insulin pro- – Suppression of plasminogen activator inhibitor motes the synthesis of endothelial NOS (eNOS) – Suppression of pro-MMP-1 and enhances anti-inflammatory process that • Enhanced cardiovascular profile eventually lead to preservation of myocardial – Increase NO formation and NO synthesis expression in endothelium integrities and protect on of infracted areas from – Cardio–protective effects ischemic reperfusion injuries [84,85]. – Decrease in iNOS expression
• Prevent mitochondrial dysfunction Insulin & lipid profile • Improvement in lipid profile Lipotoxicity in hepatocytes and skeletal muscles • Antiapoptotic effects is also involved in insulin resistance [66]. Insulin AP: Activator protein; CRP: C-reactive protein; EGR: Early growth response factor; therapy in CIPs decreases serum triglyceride iNOS: Inducible nitric oxide synthase; MBL: Mannose-binding lectin; MMP: Matrix and FFA levels, while it increases high-density metalloproteinase; NFκB: Nuclear factor κ B; NO: Nitric oxide; NOS: Nitric oxide lipoprotein level. Therefore, insulin therapy synthase; TNF: Tumor necrosis factor. improves the lipid profile [6,86,87].
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Figure 1. Interaction between immuno–neuroendocrine systems, skeletal muscle, adipose tissue and liver during stressful situations.
Neuroendocrine sytem Stress
counter-regulatory hormones
Skeletal muscle
AA Protein Immune system IKK NFκB
Glucose Alanine and lactate
Proinflammatory cytokines
PEPCK Glucose FFA and triglycerides
Liver
Adipose tissue
Insulin O2 ROS
Glucose Mitochondria
Insulin receptor Glucose transporter
Stress precipitates release of counter regulatory hormones by activation of the HPA axis and enhances the release of proinflammatory cytokines from immune cells. These proinflammatory cytokines activate the CRF–adrenocorticotropic hormone axis. In addition, stress increases extraction of alanine and lactate (two major gluconeogenesis substrates) from skeletal muscle. Conversely, counter regulatory hormones stimulate PEPCK (the key enzyme for gluconeogenesis) activity and expression, thus hepatic glucose output increases. Likewise, FFA and triglyceride levels increase by stimulation of counter regulatory hormones and the effect of glucose on adipose tissue. Glucose has deleterious effects on the immune system and skeletal muscle (e.g., hyperglycemia exacerbates muscle protein catabolism). Mitochondrial dysfunction and increased generation of ROS, which lead to oxidative stress, occur during hyperglycemia. Glucose promotes insulin resistance and has inflammatory properties and enhances proinflammatory cytokines secretion by promotion of transcriptional cofactors, such as NFκB, which regulate the proinflammatory mediators’ genes. FFA, triglyceride, counter regulatory hormones and proinflammatory cytokines induce insulin resistance by different mechanisms and prevent glucose uptake, which results in acute hyperglycemia. ACTH: Adrenocorticotropic hormone; CRF: Corticotropin-releasing factor; FFA: Free fatty acid; HPA: Hypothalamic–pituitary–adrenal axis; NF: Nuclear factor; PEPCK: Phosphoenolpyruvate carboxykinase; ROS: Reactive oxygen species.
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Discussion The safety and efficacy of metformin or thi- Insulin or glycemic control? azolidinediones have not been proven among Among all the clinical investigations, it is yet CIPs. Although it has been demonstrated that questionable whether it is insulin itself or glyc- metformin has a beneficial effect on the sur- emic control, or perhaps both, that influence the vival of burn patients by increasing the glucose positive fate of CIPs and their outcomes. clearance either due to enhanced insulin sensi- Although insulin has its unique therapeutic tivity or increasing insulin availability, more effects in CIPs, the mortality rate appears to be clinical trials must be designed [91]. An other higher among patients who receive higher doses valuable action of metformin is the improve- of insulin in order to reach euglycemia [88]. ment of muscle protein kinetics that occurs in As described previously, cytokine storms and combination with insulin in burn patients [92]. over-release of ChAs during the disturbed In addition, metformin activates AMP-acti- stressful condition in critical illnesses results in vated protein kinase [93,94], the major cellular insulin resistance. This occurs through regulatory factor in lipid and glucose metabo- destruction of subcellular insulin signaling lism and even has an indirect effect on insulin components or by affecting insulin receptor sensitivity in adipose and skeletal muscles [95,96]. sites [1,2,22,23]. Lactic acidosis is a matter of concern during metformin therapy in diabetic patients and it is Probable therapeutic targets & new controversial as to whether metformin causes therapeutic strategies lactic acidosis [97.98]. TNFα, among cytokines, and NFκB, among proinflammatory transcription factors, can be Outlook considered as therapeutic targets. The role of Generally, the stress response is recognized as a insulin-sensitizing agents, such as metformin programed and adaptive process for survival and thiazolididions, in the management of advantages in drastically disturbed physiologi- Type 2 diabetes is obviously clear. These drugs, cal situations, such as acute illness. Stress trig- besides their effects on the reduction of insulin gers systemic inflammatory processes that resistance, have the potential for anti-inflamma- accompany secondary complications, such as tory properties. For example, troglitazone acute hyperglycemia and insulin resistance. decreases the cellular level of NFκB and stimu- Stress-induced hyperglycemia has a direct pro- lates IκB with a beneficial effect on the suppres- portion to the morbidity and mortality rates in sion of inflammatory process [89]. Likewise, critical illnesses. metformin can exert a direct vascular anti- Intensive insulin therapy and glycemic control inflammatory effect by inhibiting NFκB have remarkable positive effects on the outcome through blockade of the PI3K–Akt pathway [90]. of CIPs. Downregulation of insulin receptor and
Highlights
• Insulin resistance and hyperglycemia occur in critical illnesses due to an alteration in the immunoneuroendocrine axis and subsequent alteration in the metabolism of lipid and carbohydrate. • Increased levels of counter regulatory hormone and proinflammatory cytokines cause insulin resistance and hyperglycemia. This happens by increasing the rate of glycogenolysis and gluconeogenesis, interrupting the components of the insulin-signaling pathway and impairing insulin-mediated glucose uptake. • Glucose has proinflammatory properties and glucose overfeed increases the generation of reactive oxygen species by immune cells, resulting in oxidative stress and promoting proinflammatory cytokine cascade. Likewise, hyperglycemia per se promotes insulin resistance. • During critical illnesses, extra influx of glucose into endothelial, epithelial, hepatocytes and immune cells leads to enhanced interacellular glucose levels, which intensify cellular inflammation and impair mitochondrial function. • Intensive glycemic control reduces morbidity and mortality rates. Insulin has a multitude of favorable metabolic and nonmetabolic effects that could reverse almost all undesirable events of stress response and prevent glucotoxicity. • Almost all components of the systemic inflammatory response could be considered as therapeutic targets since they are directly and indirectly involved in this event. • Every medication or intervention, such as insulin-sensitizing agents, which could prevent inflammatory process and insulin resistance might be considered as therapeutic strategies in improving critically ill patients.
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impaired insulin function deteriorate insulin necessary when insulin is used continuously. resistance via proinflammatory cytokines and Finally, the need for the development of new ChAs. Therefore, clinicians have to use increas- curative protocols to alleviate hyperglycemia and ingly more insulin to overcome the hyperglyc- to control systemic inflammatory response is emia. Cautious measurement of blood glucose is obviously required.
Bibliography 12. Butler SO, Btaiche IF, Alaniz C: Relationship 23. Andreelli F, Jacquier D, Troy S: Molecular 1. Mizock BA: Alterations in fuel metabolism between hyperglycemia and infection in aspects of insulin therapy in critically ill in critical illness: hyperglycaemia. Best critically ill patients. Pharmacotherapy 25(7), patients. Curr. Opin. Clin. Nutr. Metab. Pract. Res. Clin. Endocrinol. Metab. 15(4), 963–976 (2005). Care 9(2), 124–130 (2006). 533–551 (2001). 13. Turina M, Fry DE, Polk HC Jr: Acute 24. Rosmarin DK, Wardlaw GM, Mirtallo J: 2. Robinson LE, van Soeren MH: Insulin hyperglycemia and the innate immune system: Hyperglycemia associated with high, resistance and hyperglycemia in critical clinical, cellular, and molecular aspects. Crit. continuous infusion rates of total parenteral illness: role of insulin in glycemic control. Care Med. 33(7), 1624–1633 (2005). nutrition dextrose. Nutr. Clin. Pract. 11(4), AACN Clin. Iss. 15(1), 45–62 (2004). 14. Gore DC, Chinkes D, Heggers J, 151–156 (1996). 3. van den Berghe G, Wouters P, Weekers F: Herndon DN, Wolf SE, Desai M: Association 25. Mechanick JI: Metabolic mechanisms of Intensive insulin therapy in the critically ill of hyperglycemia with increased mortality after stress hyperglycemia. J. Parenter. Enteral. patients. N. Engl. J. Med. 345(19), severe burn injury. J. Trauma 51(3), 540–544 Nutr. 30(2), 157–163 (2006). 1359–1367 (2001). (2001). 26. Bateman A, Singh A, Kral T, Solomon S: 4. Krinsley JS: Effect of an intensive glucose 15. Mowlavi A, Andrews K, Milner S, The management protocol on the mortality of Herndon DN, Heggers JP: The effects of immune–hypothalamic–pituitary–adrenal critically ill adult patients. Mayo Clin. hyperglycemia on skin graft survival in the axis. Endocr. Rev. 10(1), 92–112 (1989). Proc. 79(8), 992–1000 (2004). burn patient. Ann. Plast. Surg. 45(6), 629–632 27. Blalock JE: Harnessing a neural immune 5. Van den Berghe G, Wilmer A, Hermans G (2000). circuit to control inflammation and shock. et al.: Intensive insulin therapy in the 16. Furnary AP, Zerr KJ, Grunkemeier GL, Starr J. Exp. Med. 195(6), F25–F28 (2002). medical ICU. N. Engl. J. Med. 354(5), A: Continuous intravenous insulin infusion 28. Imura H, Fukata J: Endocrine–paracrine 449–461 (2006). reduces the incidence of deep sternal wound interaction in communication between the 6. Vanhorebeek I, Langouche L, infection in diabetic patients after cardiac immune and endocrine systems. Activation Van den Berghe G: Glycemic and surgical procedures. Ann. Thorac. Surg. 67(2), of the hypothalamic-pituitary-adrenal axis nonglycemic effects of insulin: how do 352–360 (1999). in inflammation. Eur. J. Endocrinol. 130(1), they contribute to a better outcome of 17. Capes SE, Hunt D, Malmberg K, 32–37 (1994). critical illness? Curr. Opin. Crit. Care Gerstein HC: Stress hyperglycaemia and 29. Chrousos GP: The 11(4), 304–311 (2005). increased risk of death after myocardial hypothalamic–pituitary–adrenal axis and 7. Pittas AG, Siegel RD, Lau J: Insulin infarction in patients with and without immune-mediated inflammation. N. Engl. J. therapy and in-hospital mortality in diabetes: a systematic overview. Lancet Med. 332(20), 1351–1362 (1995). critically ill patients: systematic review and 355(9206), 773–778 (2000). 30. Frayn KN: Hormonal control of meta-analysis of randomized controlled 18. O’Neill PA, Davies I, Fullerton KJ, Bennett D: metabolism in trauma and sepsis. Clin. trials. JPEN J. Parenter. Enteral. Nutr. Stress hormone and blood glucose response Endocrinol. (Oxf.) 24(5), 577–599 (1986). 30(2), 164–172 (2006). following acute stroke in the elderly. Stroke 31. Miyoshi H, Shulman GI, Peters EJ, 8. Lazar HL, Chipkin S, Philippides G, Bao 22(7), 842–847 (1991). Wolfe MH, Elahi D, Wolfe RR: Hormonal Y, Apstein C: Glucose-insulin-potassium 19. Norhammar AM, Ryden L, Malmberg K: control of substrate cycling in humans. J. solutions improve outcomes in diabetics Admission plasma glucose. Independent risk Clin. Invest. 81(5), 1545–1555 (1988). who have coronary artery operations. Ann. factor for long-term prognosis after myocardial 32. Uyama N, Geerts A, Reynaert H: Neural Thorac. Surg. 70(1), 145–150 (2000). infarction even in nondiabetic patients. connections between the hypothalamus and 9. Brown G, Dodek P: Intravenous insulin Diabetes Care 22(11), 1827–1831 (1999). the liver. Anat. Rec. A. Discov. Mol. Cell Evol. nomogram improves blood glucose control 20. Laird AM, Miller PR, Kilgo PD, Meredith JW, Biol. 280(1), 808–820 (2004). in the critically ill. Crit. Care Med. 29(9), Chang MC: Relationship of early 33. Moore MC, Connolly CC, 1714–1719 (2001). hyperglycemia to mortality in trauma patients. Cherrington AD: Autoregulation of hepatic 10. Dilkhush D, Lannigan J, Pedroff T, J. Trauma 56(5), 1058–1062 (2004). glucose production. Eur. J. Endocrinol. Riddle A, Tittle M: Insulin infusion 21. Bochicchio GV, Sung J, Joshi M et al.: 138(3), 240–248 (1998). protocol for critical care units. Am. J. Persistent hyperglycemia is predictive of 34. Khani S, Tayek JA: Cortisol increases Health Syst. Pharm. 62(21), 2260–2264 outcome in critically ill trauma patients. gluconeogenesis in humans: its role in the (2005). J. Trauma 58(5), 921–924 (2005). metabolic syndrome. Clin. Sci. (Lond.) 11. Pozzilli P, Leslie RD: Infections and 22. Beishuizen A, Thijs LG: The 101(6), 739–747 (2001). diabetes: mechanisms and prospects for immunoneuroendocrine axis in critical illness: 35. Hanson RW, Reshef L: Regulation of prevention. Diabet. Med. 11(10), 935–941 beneficial adaptation or neuroendocrine phosphoenolpyruvate carboxykinase (GTP) (1994). exhaustion? Curr. Opin. Crit. Care 10(6), gene expression. Annu. Rev. Biochem. 66, 461–467 (2004). 581–611 (1997).
104 Therapy (2007) 4(1) futurefuture sciencescience ggrouproup Mechanisms underlying stress-induced hyperglycemia in critically ill patients – REVIEW
36. Vermes I, Beishuizen A: The receptor and impairs their ability to binding activities, in the expression of tissue hypothalamic–pituitary–adrenal response to undergo insulin-induced tyrosine factor and matrix metalloproteinase in critical illness. Best Pract. Res. Clin. phosphorylation. J. Biol. Chem. 272(47), mononuclear cells, and in plasma tissue Endocrinol. Metab. 15(4), 495–511 (2001). 29911–29918 (1997). factor and matrix metalloproteinase 37. Van den Berghe G, de Zegher F, Bouillon R: 49. Marik PE, Raghavan M: Stress- concentrations. Am. J. Clin. Nutr. 80(1), Clinical review 95: acute and prolonged hyperglycemia, insulin and 51–57 (2004). critical illness as different neuroendocrine immunomodulation in sepsis. Intensive Care 60. Esposito K, Nappo F, Marfella R et al.: paradigms. J. Clin. Endocrinol. Metab. Med. 30(5), 748–756 (2004). Inflammatory cytokine concentrations are 83(6), 1827–1834 (1998). 50. Barnes PJ, Karin M: Nuclear factor-κB: a acutely increased by hyperglycemia in 38. Gustavson SM, Chu CA, Nishizawa M pivotal transcription factor in chronic humans: role of oxidative stress. Circulation et al.: Interaction of glucagon and inflammatory diseases. N. Engl. J. Med. 106(16), 2067–2072 (2002). epinephrine in the control of hepatic 336(15), 1066–1071 (1997). 61. Morohoshi M, Fujisawa K, Uchimura I, glucose production in the conscious dog. 51. Flores EA, Istfan N, Pomposelli JJ, Numano F: The effect of glucose and Am. J. Physiol. Endocrinol. Metab. 284(4), Blackburn GL, Bistrian BR: Effect of advanced glycosylation end products on IL-6 E695–E707 (2003). interleukin-1 and tumor necrosis production by human monocytes. Ann. NY 39. Hunt DG, Ivy JL: Epinephrine inhibits factor/cachectin on glucose turnover in the Acad. Sci. 748, 562–570 (1995). insulin-stimulated muscle glucose transport. rat. Metabolism 39(7), 738–743 (1990). 62. Yu WK, Li WQ, Li N, Li JS: Influence of J. Appl. Physiol. 93(5), 1638–1643 (2002). 52. Mastorakos G, Chrousos GP, Weber JS: acute hyperglycemia in human sepsis on 40. Itani SI, Ruderman NB, Schmieder F, Recombinant interleukin-6 activates the inflammatory cytokine and counterregulatory Boden G: Lipid-induced insulin resistance hypothalamic–pituitary–adrenal axis in hormone concentrations. World J. in human muscle is associated with changes humans. J. Clin. Endocrinol. Metab. 77(6), Gastroenterol. 9(8), 1824–1827 (2003). in diacylglycerol, protein kinase C, and 1690–1694 (1993). 63. Dandona P, Mohanty P, Chaudhuri A, IκB-α. Diabetes 51(7), 2005–2011 (2002). 53. Devin A, Lin Y, Yamaoka S, Li Z, Karin M, Garg R, Aljada A: Insulin infusion in acute 41. Gearhart MM, Parbhoo SK: Hyperglycemia Liu Zg: The α and β subunits of IκB kinase illness. J. Clin. Invest. 115(8), 2069–2072 in the critically ill patient. AACN Clin. Iss. (IKK) mediate TRAF2-dependent IKK (2005). 17(1), 50–55 (2006). recruitment to tumor necrosis factor (TNF) 64. Weekers F, Giulietti AP, Michalaki M et al.: 42. Lang CH: Sepsis-induced insulin resistance receptor 1 in response to TNF. Mol. Cell Metabolic, endocrine, and immune effects of in rats is mediated by a β-adrenergic Biol. 21(12), 3986–3994 (2001). stress hyperglycemia in a rabbit model of mechanism. Am. J. Physiol. 263(4 Pt 1), 54. Hadidi E, Mojtahedzadeh M, Paknejad MH prolonged critical illness. Endocrinology E703–E711 (1992). et al.: Alterations of blood IL-8, TGF-β1 144(12), 5329–5338 (2003). 43. Smith TR, Elmendorf JS, David TS, and nitric oxide levels in relation to blood 65. Nielson CP, Hindson DA: Inhibition of Tu r i ns ky J : Growt h hormone-induced cells in patients with acute brain injury. polymorphonuclear leukocyte respiratory insulin resistance: role of the insulin Therapy 3(3), 399–405 (2006). burst by elevated glucose concentrations in receptor, IRS-1, GLUT-1, and GLUT-4. 55. Mohanty P, Hamouda W, Garg R, Aljada A, vitro. Diabetes 38(8), 1031–1035 (1989). Am. J. Physiol. 272(6 Pt 1), E1071–E1079 Ghanim H, Dandona P: Glucose challenge 66. Savage DB, Petersen KF, Shulman GI: (1997). stimulates reactive oxygen species (ROS) Mechanisms of insulin resistance in humans 44. Payen D, Faivre V, Lukaszewicz AC, generation by leucocytes. J. Clin. Endocrinol. and possible links with inflammation. Losser MR: Assessment of immunological Metab. 85(8), 2970–2973 (2000). Hypertension 45(5), 828–833 (2005). status in the critically ill. Minerva Anestesiol. 56. Astaneie F, Afshari M, Mojtahedi A et al.: 67. Sheetz MJ, King GL: Molecular 66(5), 351–357 (2000). Total antioxidant capacity and levels of understanding of hyperglycemia’s adverse 45. Menger MD, Vollmar B: Surgical trauma: epidermal growth factor and nitric oxide in effects for diabetic complications. JAMA hyperinflammation versus blood and saliva of insulin-dependent 288(20), 2579–2588 (2002). immunosuppression? Langenbecks Arch. diabetic patients. Arch. Med. Res. 36(4), 68. Klip A, Tsakiridis T, Marette A, Ortiz PA: Surg. 389(6), 475–484 (2004). 376–381 (2005). Regulation of expression of glucose 46. Hotamisligil GS: Inflammatory pathways 57. Rahimi R, Nikfar S, Larijani B, transporters by glucose: a review of studies in and insulin action. Int. J. Obes. Relat. Abdollahi M: A review on the role of vivo and in cell cultures. FASEB J. 8(1), 43–53 Metab. Disord. 27(Suppl. 3), S53–S55 antioxidants in the management of diabetes (1994). (2003). and its complications. Biomed. 69. Thong FS, Dugani CB, Klip A: Turning 47. Kanety H, Feinstein R, Papa MZ, Hemi R, Pharmacother. 59(7), 365–373 (2005). signals on and off: GLUT4 traffic in the Karasik A: Tumor necrosis factor α-induced 58. Guha M, Bai W, Nadler JL, Natarajan R: insulin-signaling highway. Physiology phosphorylation of insulin receptor Molecular mechanisms of tumor necrosis (Bethesda) 20, 271–284 (2005). substrate-1 (IRS-1). Possible mechanism for factor α gene expression in monocytic cells 70. Kono T, Nishida M, Nishiki Y, Seki Y, Sato K, suppression of insulin-stimulated tyrosine via hyperglycemia-induced oxidant stress- Akiba Y: Characterisation of glucose phosphorylation of IRS-1. J. Biol. Chem. dependent and -independent pathways. transporter (GLUT) gene expression in broiler 270(40), 23780–23784 (1995). J. Biol. Chem. 275(23), 17728–17739 chickens. Br. Poult. Sci. 46(4), 510–515 48. Paz K, Hemi R, LeRoith D et al.: A (2000). (2005). molecular basis for insulin resistance. 59. Aljada A, Ghanim H, Mohanty P, Syed T, 71. Shikhman AR, Brinson DC, Valbracht J, Lotz Elevated serine/threonine phosphorylation Bandyopadhyay A, Dandona P: Glucose MK: Cytokine regulation of facilitated glucose of IRS-1 and IRS-2 inhibits their binding to intake induces an increase in activator transport in human articular chondrocytes. J. the juxtamembrane region of the insulin protein 1 and early growth response 1 Immunol. 167(12), 7001–7008 (2001).
futurefuture sciencescience groupgroup www.futuremedicine.com 105 REVIEW – Kajbaf, Mojtahedzadeh & Abdollahi
72. Quinn LA, McCumbee WD: Regulation of 80. Hansen TK, Thiel S, Wouters PJ, 89. Ghanim H, Garg R, Aljada A et al.: glucose transport by angiotensin II and Christiansen JS, Van den Berghe G: Suppression of nuclear factor-κB and glucose in cultured vascular smooth muscle Intensive insulin therapy exerts stimulation of inhibitor κB by troglitazone: cells. J. Cell Physiol. 177(1), 94–102 (1998). antiinflammatory effects in critically ill evidence for an anti-inflammatory effect and 73. Sanchez-Alvarez R, Tabernero A, patients and counteracts the adverse effect of a potential antiatherosclerotic effect in the Medina JM: Endothelin-1 stimulates the low mannose-binding lectin levels. J. Clin. obese. J. Clin. Endocrinol. Metab. 86(3), translocation and upregulation of both Endocrinol. Metab. 88(3), 1082–1088 1306–1312 (2001). glucose transporter and hexokinase in (2003). 90. Isoda K, Young JL, Zirlik A et al.: astrocytes: relationship with gap junctional 81. Landin K, Tengborn L, Chmielewska J, Metformin inhibits proinflammatory communication. J. Neurochem. 89(3), von Schenck H, Smith U: The acute effect responses and nuclear factor-κB in human 703–714 (2004). of insulin on tissue plasminogen activator vascular wall cells. Arterioscler. Thromb. Vasc. 74. Clerici C, Matthay MA: Hypoxia regulates and plasminogen activator inhibitor in man. Biol. 26(3), 611–617 (2006). gene expression of alveolar epithelial Thromb. Haemost. 65(2), 130–133 (1991). 91. Gore DC, Wolf SE, Herndon DN, transport proteins. J. Appl. Physiol. 88(5), 82. Fendri S, Roussel B, Lormeau B, Tribout B, Wolfe RR: Metformin blunts stress-induced 1890–1896 (2000). Lalau JD: Insulin sensitivity, insulin action, hyperglycemia after thermal injury. 75. Vanhorebeek I, De Vos R, Mesotten D, and fibrinolysis activity in nondiabetic and J. Trauma 54(3), 555–561 (2003). Wouters PJ, De Wolf-Peeters C, diabetic obese subjects. Metabolism 47(11), 92. Gore DC, Herndon DN, Wolfe RR: Van den Berghe G: Protection of hepatocyte 1372–1375 (1998). Comparison of peripheral metabolic effects mitochondrial ultrastructure and function 83. Langouche L, Vanhorebeek I, Vlasselaers D of insulin and metformin following severe by strict blood glucose control with insulin et al.: Intensive insulin therapy protects the burn injury. J. Trauma 59(2), 316–322 in critically ill patients. Lancet 365(9453), endothelium of critically ill patients. J. Clin. (2005). 53–59 (2005). Invest. 115(8), 2277–2286 (2005). 93. Kirpichnikov D, McFarlane SI, Sowers JR: 76. West IC: Radicals and oxidative stress in 84. Gao F, Gao E, Yue TL et al.: Nitric oxide Metformin: an update. Ann. Intern. Med. Diabetes Diabet. Med. 17(3), 171–180 mediates the antiapoptotic effect of insulin 137(1), 25–33 (2002). (2000). in myocardial ischemia-reperfusion: the 94. Zhou G, Myers R, Li Y et al.: Role of 77. Brealey D, Brand M, Hargreaves I et al.: roles of PI3-kinase, Akt, and endothelial AMP-activated protein kinase in mechanism Association between mitochondrial nitric oxide synthase phosphorylation. of metformin action. J. Clin. Invest. 108(8), dysfunction and severity and outcome of Circulation 105(12), 1497–1502 (2002). 1167–1174 (2001). septic shock. Lancet 360(9328), 219–223 85. Das UN: Insulin: an endogenous 95. Musi N, Goodyear LJ: AMP-activated (2002). cardioprotector. Curr. Opin. Crit. Care 9(5), protein kinase and muscle glucose uptake. 78. Dandona P, Aljada A, Mohanty P et al.: 375–383 (2003). Acta Physiol. Scand. 178(4), 337–345 Insulin inhibits intranuclear nuclear factor 86. Mesotten D, Swinnen JV, Vanderhoydonc F, (2003). κB and stimulates IκB in mononuclear cells Wouters PJ, Van den Berghe G: 96. Hardie DG: Minireview: the AMP-activated in obese subjects: evidence for an anti- Contribution of circulating lipids to the protein kinase cascade: the key sensor of inflammatory effect? J. Clin. Endocrinol. improved outcome of critical illness by cellular energy status. Endocrinology Metab. 86(7), 3257–3265 (2001). glycemic control with intensive insulin 144(12), 5179–5183 (2003). 79. Aljada A, Ghanim H, Mohanty P, Kapur N, Therapy J. Clin. Endocrinol. Metab. 89(1), 97. Stades AM, Heikens JT, Erkelens DW, Dandona P: Insulin inhibits the pro- 219–226 (2004). Holleman F, Hoekstra JB: Metformin and inflammatory transcription factor early 87. Jabbar MA, Zuhri-Yafi MI, Larrea J: Insulin lactic acidosis: cause or coincidence? A growth response gene-1 (Egr)-1 expression therapy for a non-diabetic patient with review of case reports. J. Intern. Med. in mononuclear cells (MNC) and reduces severe hypertriglyceridemia. J. Am. Coll. 255(2), 179–187 (2004). plasma tissue factor (TF) and plasminogen Nutr. 17(5), 458–461 (1998). 98. Salpeter SR, Greyber E, Pasternak GA, activator inhibitor-1 (PAI-1) concentrations. 88. Finney SJ, Zekveld C, Elia A, Evans TW: Salpeter EE: Risk of fatal and nonfatal lactic J. Clin. Endocrinol. Metab. 87(3), Glucose control and mortality in critically ill acidosis with metformin use in Type 2 1419–1422 (2002). patients. JAMA 290(15), 2041–2047 diabetes mellitus: systematic review and (2003). meta-analysis. Arch. Intern. Med. 163(21), 2594–2602 (2003).
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