REVIEW

Mechanisms underlying -induced hyperglycemia in critically ill patients

Farshad Kajbaf1, Critical illnesses associate with alteration in metabolic status. Insulin resistance and Mojtaba Mojtahedzadeh1 enhanced blood 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 and among those with . These tums.ac.ir complications occur in patients with or without a history of . 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 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 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 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 (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 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.

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