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The Effect of Short-Term Hyperglycemia on the Innate Immune System

      Abstract

      Background

      Diabetes mellitus increases the susceptibility to infection by altering both the innate and the adaptive immune systems. Hyperglycemia has been associated with adverse outcomes in hospitalized patients, especially critically ill patients; these poor outcomes are explained in part by hospital-associated infections.

      Materials and Methods

      PubMed, EMBASE and Google Scholar were searched to identify studies published between 1970 and 2014 reporting short-term effects of hyperglycemia on the innate immune system. MeSH database search terms included hyperglycemia, immune system, inflammation, inflammation mediators, neutrophils, endothelial dysfunction, complement system proteins and diabetes. Pertinent articles reported studies in healthy volunteers and diabetic patients, using in vitro laboratory experiments, and with animal models.

      Results

      Hyperglycemia activates protein kinase C, and this inhibits neutrophil migration, phagocytosis, superoxide production and microbial killing. High glucose concentrations decrease the formation of neutrophil extracellular traps. Hyperglycemia can also induce Toll-like receptor expression and inhibit neutrophil function and apoptosis. High glucose concentrations decrease vascular dilation and increase permeability during the initial inflammatory responses, possibly through protein kinase C activation. Hyperglycemia can cause direct glycosylation of proteins and alter the tertiary structure of complement; these changes inhibit immunoglobulin-mediated opsonization of bacteria and complement fixation to bacteria and decreases phagocytosis. Hyperglycemia also stimulates the production and release of cytokines. Several trials have demonstrated that better glycemic control reduces nosocomial infections in critically ill patients and surgical site infections.

      Conclusions

      In summary, acute hyperglycemia can significantly alter innate immune responses to infection, and this potentially explains some of the poor outcomes in hospitalized patients who develop hyperglycemia.

      Key Indexing Terms

      Introduction

      Infections in hospitalized patients remain a challenging and costly problem, are a major factor in prolonged hospital stays, and increase morbidity and mortality rates.
      • Ken I.
      • Jayshree D.
      • Alison P.
      Nosocomial infections.
      The Centers for Disease Control and Prevention estimates that 1.7 million hospital-associated infections from all types of microorganisms cause or contribute to 99,000 deaths each year in the United States.
      National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1992 through June 2004, issued October 2004.
      Increased rates of infection in hospitalized patients, especially in intensive care units (ICUs), have been linked to invasive procedures, such as mechanical ventilation, urinary tract catheterization, and central venous catheters.
      • Emine A.
      • Andreas V.
      Ventilator associated pneumonia and infection control.
      • Vergidis P.
      • Patel R.
      Novel approaches to the diagnosis, prevention, and treatment of medical device-associated infections.
      Infection is particularly common in burn and trauma patients who develop acute reversible immunosuppression.
      • Wurtz R.
      • Karajovic M.
      • Dacumos E.
      • et al.
      Nosocomial infections in a burn intensive care unit.
      • Giamberardino H.I.
      • Cesário E.P.
      • Carmes E.R.
      • et al.
      Risk factors for nosocomial infection in trauma patients.
      Host responses to infection are essential for control and prevention of infection. Among the known factors that undermine host defenses, diabetes mellitus increases the susceptibility of patients to viral, bacterial and fungal infections mainly through modulation of the immune system.
      • Dana T.G.
      • Rayyan A.K.
      Diabetic complications and dysregulated innate immunity.
      • Juliana C.
      • Janine C.
      • Cresio A.
      Infections in patients with diabetes mellitus: a review of pathogenesis.
      Acute hyperglycemia has been associated with adverse outcomes in medical and surgical patients possibly by increasing the rate of infection in these patients.
      • Krinsley J.S.
      Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients.
      • Butler S.O.
      • Btaiche I.F.
      • Alaniz C.
      Relationship between hyperglycemia and infection in critically ill patients.
      This review examines studies on the association between hyperglycemia and alterations of the immune system to provide clinicians with an overview of these associations and the rationale for glucose control during hospitalization.

      Methods

      A literature search using PubMed, EMBASE and Google Scholar from 1970 to December 2014 was conducted. MeSH database search terms included hyperglycemia, immune system, inflammation, inflammation mediators, neutrophils, endothelial dysfunction, complement system proteins, surgical wound infections and diabetes. Each MeSH term was joined with hyperglycemia using the AND algorithm. Searches were restricted to English language articles and studies involving adult-aged patients and subjects. These searches were used to identify studies reporting short-term effects of hyperglycemia on the immune system. The focus was on the following types of studies: (1) studies in healthy volunteers and diabetic patients with controlled experimental increases in glucose levels, (2) in vitro laboratory experiments, and (3) studies involving animal models. For the purpose of this review, the duration of hyperglycemia in animal studies could not exceed 30 days, as the main interest was on the acute effects of hyperglycemia. Titles and abstracts were reviewed to identify relevant articles for more complete review. Reference lists from selected articles were carefully reviewed to identify additional articles; author names were used for additional searches in PubMed. Google Scholar was used to identify articles, which cited the articles selected for detailed review. The collected articles were used to write a narrative review.

      Discussion

      Hyperglycemia Effects on Host Defense Responses

      The host defense system includes both the innate and the adaptive immune systems. The innate immune system represents the dominant defense system against most organisms, has a fast response to infection, but has no immunological memory.
      • Litman G.W.
      • Cannon J.P.
      • Dishaw L.J.
      Reconstructing immune phylogeny: new perspectives.
      It includes surface barriers and their secretory exocrine glands, inflammation produced by cytokines and eicosanoids, the complement cascade system and cell barriers (neutrophils, monocytes, macrophages, mast cells, eosinophils, basophils and natural killer cells).
      • Hoffmann J.
      • Akira S.
      Innate immunity.
      The adaptive immune system has immunological memory that promotes quick elimination of pathogens when reinfection with the same pathogen occurs. It includes T and B lymphocytes and antibodies.
      • Janeway Jr, C.A.
      • Travers P.
      • Walport M.
      • et al.
      Immunobiology: The Immune System in Health and Disease: Principles of Innate and Adaptive Immunity.
      Hyperglycemia can affect several components of the immune system, but the primary focus in this review is on the innate immune system, which includes cellular defenses, the microcirculation, complement and cytokines. Acute hyperglycemia has direct effects on each of these components. Antimicrobial substances in airway surface liquids, innate lymphoid cells and the adaptive immune system were not considered in this review.

      Cellular Defenses

      Neutrophils are crucial phagocytes in the innate immune response. These cells are recruited first to inflammatory sites and are essential for eliminating pathogens. Any reduction in their function contributes to increased susceptibility to infection and increased severity of infections. Human studies and animal model studies using both in vitro and in vivo methods have demonstrated defective neutrophil function in hyperglycemic states (Figure) (Table 1).
      Figure thumbnail gr1
      FigureThe effect of hyperglycemia on neutrophil function at sites of infection.
      Table 1Effect of hyperglycemia on neutrophils.
      StudyStudy subjectsResultsConclusion
      Stegenga et al
      • Stegenga M.E.
      • van der Crabben S.N.
      • Blümer R.M.
      • et al.
      Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia.
      24 Healthy male volunteersHyperglycemia attenuated the LPS-induced increases in elastase (P < 0.001) and myeloperoxidase (P = 0.009) levels irrespective of insulin concentrationsHyperglycemia attenuates inflammation-induced neutrophil activation
      Wierusz-Wysocka et al
      • Wierusz-Wysocka B.
      • Wysocki H.
      • Wykretowicz A.
      • et al.
      The influence of increasing glucose concentrations on selected functions of polymorphonuclear neutrophils.
      20 healthy volunteer in vitro studyHigher than physiological concentrations diminish chemotaxis, phagocytosis and bactericidal capacity of neutrophil. PMNs adherence rose parallel with increasing glucose concentrationsAcute hyperglycemia decreased neutrophils chemotaxis, phagocytosis and bactericidal capacity
      Nielson and Hindson
      • Nielson C.P.
      • Hindson D.A.
      Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro.
      2 Healthy volunteersPMN had a significant reduction in the respiratory burst after 30 min of in vitro exposure to glucose concentrations greater than 200 mg/dLAcute hyperglycemia impairs neutrophil respiratory burst capacity
      Perner et al
      • Perner A.
      • Nielsen S.E.
      • Rask-Madsen J.
      High glucose impairs superoxide production from isolated blood neutrophils.
      In vitro studies of short-term cultures of neutrophil granulocytesIncubation of neutrophils with glucose dose-dependently reduced superoxide production, which was 50% decreased at 450 mg/dL glucoseHigh extracellular glucose concentrations acutely reduce superoxide production from activated neutrophils, possibly through inhibition of G6PD
      Van Oss (1978)
      • Van Oss C.J.
      • Border J.R.
      Influence of intermittent hyperglycemic glucose levels on the phagocytosis of microorganisms by human granulocytes in vitro.
      In vitro study of PMNsIntermittent exposure of normal PMNs in vitro to 800 mg/100 mL glucose once every 2 min for 2 h resulted in decrease in their phagocytic activityRepeated brief exposure to hyperglycemia decreased neutrophils phagocytosis activity in vitro
      Oldenborg et al
      • Oldenborg P.
      • Sehlin J.
      Hyperglycemia in vitro attenuates insulin-stimulated chemokinesis in normal human neutrophils: role of protein kinase C activation.
      In vitro experiment on venous blood samples from healthy volunteersActivation of CPK with PMA caused a dose-dependent inhibition of neutrophil random locomotionGlucose-induced PKC activation may mediate the inhibitory effects of high glucose on insulin-stimulated chemokinesis in normal human neutrophils
      Otto et al
      • Otto M.N.
      • Schindler R.
      • Lun A.
      • et al.
      Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro.
      In vitro study on human peripheral blood mononuclear cells taken from healthy volunteersWith increasing concentrations of glucose the LPS-stimulated production of IL-6 and IL-1β is significantly enhanced (P < 0.05). The addition of glucose (500 mg) and mannitol significantly reduced respiratory burst and phagocytosisHyperglycemia may lead to inflammation by enhancing cytokine production via the direct effects of hyperosmotic stress. Impaired phagocytosis and oxidative burst
      Joshi et al
      • Joshi M.B.
      • Lad A.
      • Prasad A.S.B.
      • et al.
      High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation.
      In vitro assayHigh concentrations of glucose (30 mM) inhibit the formation of neutrophil extracellular traps and increase bacterial survival in in vitro assaysIncreased concentrations of glucose reduce extracellular trap formation and in vitro bacterial killing
      The effect of established diabetes mellitus, especially poorly controlled diabetes, on the immune system and, in particular, on neutrophil function is well known.
      • Alba-Loureiro T.C.
      • Munhoz C.D.
      • Martins J.O.
      • et al.
      Neutrophil function and metabolism in individuals with diabetes mellitus.
      However, even transient changes in glucose levels can affect neutrophil function in diabetic patients.
      • Kjersem H.
      • Hilsted J.
      • Madsbad S.
      • et al.
      Polymorphonuclear leucocyte dysfunction during short term metabolic changes from normo- to hyperglycemia in type I (insulin dependent) diabetic patients.
      For example, Kjersem subjected 7 patients with insulin-dependent diabetes to controlled normoglycemia and hyperglycemia using insulin infusions and measured the function of harvested neutrophils in vitro. The phagocytosis of lipopolysaccharide-coated particles was decreased by hyperglycemia, but there was no change in neutrophil mobility or metabolism. Diabetes negatively affects neutrophil respiratory burst capacity and monocytes proliferation irrespective of the phenotype of diabetes, the duration of the disease or insulin use.
      • Daoud A.K.
      • Tayyar M.A.
      • Fouda I.M.
      • et al.
      Effect of diabetes mellitus vs in vitro hyperglycemia on selected immune cell functions.
      Insulin improves phagocytosis and increases the formation of reactive oxygen intermediates by neutrophils.
      • Inoue T.
      • Saito H.
      • Matsuda
      • et al.
      Growth hormone and insulin- like growth I augment bactericidal capacity of human polymorphonuclear neutrophils.
      • Jin G.
      • Guo Y.
      • Ball C.
      • Houston C.
      Insulin-like growth factor enhances phagocytosis by human neutrophils in vitro.
      Stegenga et al
      • Stegenga M.E.
      • van der Crabben S.N.
      • Blümer R.M.
      • et al.
      Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia.
      studied the effects of hyperglycemia or hyperinsulinemia or both on in vivo neutrophil responses during experimental inflammation induced in 24 healthy men volunteers with no history of diabetes by the injection of small doses of endotoxin. Under hyperglycemic conditions in vivo, neutrophils degranulation measured by elastase and myeloperoxidase (MPO) enzymes release was decreased. Insulin infusions did not reverse this effect. Clearly, in vivo studies on the effect of hyperglycemia on neutrophil function are difficult and likely complicated by unmeasured inflammatory response factors and interactions.
      In vitro studies allow more detailed examination of neutrophil function with better control of the multiple factors, which might alter cellular function. Wierusz-Wysocka et al
      • Wierusz-Wysocka B.
      • Wysocki H.
      • Wykretowicz A.
      • et al.
      The influence of increasing glucose concentrations on selected functions of polymorphonuclear neutrophils.
      isolated polymorphonuclear neutrophils (PMNs) from 20 healthy subjects and suspended them in isosmotic glucose solutions with concentrations ranging from 90-500 mg/dL to measure chemotaxis, adherence, phagocytosis, and bactericidal capacity. These experiments demonstrated that increasing glucose above physiological concentrations significantly reduced the chemotactic migration of neutrophil, phagocytosis, and bactericidal activity. However, the adherence of neutrophils increased in higher glucose concentrations reaching a maximum value at 300 mg/dL. This study clearly demonstrates that hyperglycemia reduces neutrophil microbiocidal activity and suggests that hyperglycemia might limit neutrophil migration out of vessels at sites of inflammation because of increased adherence. In a similar study, PMNs were isolated from fasting subjects and incubated in different glucose concentrations.
      • Nielson C.P.
      • Hindson D.A.
      Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro.
      The PMN incubated in high glucose concentrations (≥200 mg/dL) for 30 minutes had a marked reduction in the magnitude of respiratory burst. These authors suggested that this result might be explained by protein glycosylation. Van Oss and Border
      • Van Oss C.J.
      • Border J.R.
      Influence of intermittent hyperglycemic glucose levels on the phagocytosis of microorganisms by human granulocytes in vitro.
      showed that even very short-term hyperglycemia can have significant adverse effects on PMN phagocytosis and killing in vitro. In their study, intermittent exposure of normal neutrophils to 800 mg/100 mL glucose once every 2 minutes for 2 hours decreased phagocytosis of opsonized Gram-negative and Gram-positive bacteria by PMNs in vitro. These authors suggested that a possible explanation for increased susceptibility to infection in trauma and surgery patients is the multiple intermittent glucose infusions in those patients. Neutrophils can also kill extracellular microbes by the formation of neutrophil extracellular traps.
      • Brinkmann V.
      • Zychlinsky A.
      Neutrophil extracellular traps: is immunity the second function of chromatin?.
      These traps are smooth filaments that contain chromatin and granular and selected cytoplasmic proteins. Both granular elastase and MPO participate in the killing of microbes in these traps. High concentrations of glucose (30 mM) inhibit the formation of neutrophil extracellular traps and increase bacterial survival in in vitro assays.
      • Joshi M.B.
      • Lad A.
      • Prasad A.S.B.
      • et al.
      High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation.
      IL-6 is a potent inducer of neutrophil extracellular trap formation, and this effect is significantly reduced in in vitro by high concentrations of glucose.
      Neutrophils express multiple Toll-like receptors on their membranes.
      • Prince L.R.
      • Whyte M.K.
      • Sabroe I.
      • et al.
      The role of TLRs in neutrophil activation.
      These receptors identify invading microbes by detecting pathogen-associated molecular patterns. For example, Toll-like receptor 2 identifies Gram-positive bacteria by binding to triacylated bacterial peptides and Toll-like receptor 4 identifies Gram-negative bacteria binding to the lipid A component of lipopolysaccharide. Ligand binding to these receptors increases neutrophil cytokine production, reactive oxygen generation and phagocytosis through stimulation of NADPH oxidase. These receptors use a signal conduction pathway to increase the translocation of transcription factors into the nucleus and thereby increase the production of proteins, such as cytokines and chemokines, and other host defense factors. In addition, stimulation of these receptors can increase neutrophils survival by inhibiting apoptosis. High glucose levels (15 mM glucose) induce Toll-like receptor expression in monocytes in vitro.
      • Dasu M.R.
      • Devaraj S.
      • Zhao L.
      • et al.
      High glucose induces toll-like receptor expression in human monocytes.
      Very high glucose levels (30 mM glucose) downregulate these receptors on neutrophils and inhibit phagocytosis and killing of Staphylococcus aureus.
      • Jialal I.
      • Polage C.
      • Devaraj S.
      Severe hyperglycemia down regulates toll-like receptors on neutrophils: implications for propensity to infections in Diabetes.
      Therefore, the potential effects of glucose on neutrophils will depend on the glucose concentration. Increased antimicrobial activity in neutrophils should have beneficial effects in acute infections. However, prolonged neutrophil survival could increase the inflammatory process and have adverse consequences. Insulin binds to neutrophils and increases chemotaxis, phagocytosis and bactericidal activity and therefore lowers glucose levels and improves neutrophil function.
      • Xiu F.
      • Stanjcic M.
      • Diao L.
      • Jeschke M.G.
      Stress hyperglycemia, insulin treatment, and innate immune cells.
      The above studies demonstrate that hyperglycemia reduces the respiratory burst, migration, phagocytosis and killing by neutrophils, but the exact mechanisms explaining these effects are not clear. Perner incubated neutrophils with higher concentrations of glucose, and this caused a dose-dependent reduction in superoxide production with a 50% decrease in its level in solution with incubated neutrophils at 450 mg/dL glucose concentration for 1 hour.
      • Perner A.
      • Nielsen S.E.
      • Rask-Madsen J.
      High glucose impairs superoxide production from isolated blood neutrophils.
      Superoxide is an important antimicrobial activity in phagocytes produced by nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase, and in these experiments production was probably impaired by the inhibition of glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the formation of NADPH. Oldenborg reported that increased glucose concentrations inhibited extracellular superoxide production but not intracellular production. It also inhibited the release of MPO from activated PMNs.
      • Oldenborg P.A.
      • Sundqvist I.M.
      • Sehlin J.
      Different effects of glucose on extracellular and intracellular respiratory burst response in normal human neutrophils activated with the soluble agonist fMet-Leu-Phe.
      MPO is required for the formation of extracellular traps, and this requirement cannot be replaced by the addition of the extracellular products of MPO.
      • Metzler K.D.
      • Fuchs T.A.
      • Nauseef W.M.
      • et al.
      Myeloperoxidase is required for extracellular trap formation: implications for immunity.
      Oldenborg and Sehlin
      • Oldenborg P.
      • Sehlin J.
      Hyperglycemia in vitro attenuates insulin-stimulated chemokinesis in normal human neutrophils: role of protein kinase C activation.
      reported another possible mechanism underlying neutrophil dysfunction in acute hyperglycemia. In this in vitro study, activation of protein kinase C by phorbol-12-myristate 13-acetate (PMA) dose-dependently inhibited neutrophil random locomotion in the presence of insulin. Inhibition of protein kinase C reversed the effect (inhibition) of high concentrations of glucose on insulin induced neutrophil locomotion. Hence, the investigators concluded that hyperglycemia attenuated insulin-stimulated neutrophil chemokinesis, possibly mediated by hyperglycemia induced protein kinase C activation. Protein kinase C controls the function of other proteins through the phosphorylation of amino acids and is required for the assembly of NADPH oxidase and the initiation of the respiratory burst in neutrophils.
      In summary, hyperglycemia has effects on neutrophils in vivo and inhibits the essential steps (metabolism, phagocytosis and microbial killing) in the innate immune responses by neutrophils in in vitro studies. These effects on the neutrophil function should delay bacterial clearance at sites of infection and increase the severity of infection. In vitro studies also demonstrate that hyperglycemia increases neutrophil adherence, and this could limit neutrophil migration into extravascular sites of infection. These effects likely reflect changes in neutrophil metabolism through inhibition of G6PD or activation of protein kinase C and direct cellular effects through glycosylation of proteins and membrane perturbation by increased osmolality.

      Vascular Endothelial Function and Inflammation

      Tissue damage by trauma or microbial pathogens initiates a complex sequence termed inflammation, which includes both vasodilation and increased vascular permeability.
      • Ferrero-Miliani L.
      • Nielsen O.H.
      • Andersen P.S.
      • et al.
      Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation.
      Inhibition of the initial steps in tissue responses to microbial pathogens prevents the influx and sequestration of innate host defense cells in the infected area and increases the risk of adverse outcomes. Hyperglycemia can alter several events in the inflammatory responses to infection and tissue damage (Table 2).
      Table 2Hyperglycemia and endothelial function.
      StudyStudy modelResultConclusion
      Kim et al
      • Kim S.H.
      • Park K.W.
      • Kim Y.S.
      • et al.
      Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism.
      In vivo study on 8 patients with DM or impaired glucose metabolismEndothelial vasodilatation in response to acetylcholine infusion was significantly reduced after induction of hyperglycemiaHyperglycemia reduces endothelium-dependent vasodilatation
      Beckman et al
      • Beckman J.A.
      • Goldfine A.B.
      • Gordon M.B.
      • et al.
      Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans.
      In vivo study in 15 healthy volunteersWith protein kinase Cβ inhibition, there was no significant difference in the forearm blood flow response to methacholine chloride between euglycemia and hyperglycemiaProtein kinase Cβ activation by hyperglycemia inhibits endothelium-dependent nitric oxide induced vasodilatation
      Tesfamariam et al
      • Tesfamariam B.
      • Brown M.L.
      • Cohen R.A.
      Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C.
      In vitro animal model studyEndothelial relaxation induced by acetylcholine were significantly decreased in the aortic ring incubated in high glucose (700 mg/dL) compared to controls (200 mg/dL)Elevated glucose levels impair endothelium-depended relaxation by activation of protein kinase C
      Gomes et al
      • Gomes M.B.
      • Affonso F.S.
      • Cailleaux S.
      • et al.
      Glucose levels observed in daily clinical practice induce endothelial dysfunction in the rabbit macro- and microcirculation.
      In vitro animal model studyEndothelial-dependent relaxation in the thoracic aorta and renal vessels was significantly impaired in vitro by high glucose (270–450 mg/dL)Hyperglycemia induces endothelial dysfunction of conduit vessels and the renal circulation of nondiabetic rabbits
      Chakravarthy et al
      • Chakravarthy U.
      • Hayes R.G.
      • Stitt A.W.
      • et al.
      Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.
      In vitro study on cultured retinal microvascular endothelial cell (RMECS)A dose-dependent reduction of NO synthesis by RMECs occurred 5 d after exposure to 270 and 450 mg/dL of glucoseConstitutive nitric oxide synthase expression is diminished by high glucose and glycation end products, and this inhibits endothelial dilatation
      Cosentino et al
      • Cosentino F.
      • Eto M.
      • De Paolis P.
      • et al.
      High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species.
      In vitro study on human aortic endothelial cellsHyperglycemia in vitro (400 mg/dL) selectively increased mRNA and protein expression of cyclooxygenase, induced activation of PKC, and reduced nitric oxide productionHigh glucose, via PKC signaling, induces oxidative stress and up regulation of cyclooxygenase, resulting in reduced NO availability and an altered prostanoid profile
      Hempel et al
      • Hempel A.
      • Maasch C.
      • Heintze U.
      • et al.
      High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha.
      In vitro study on porcine aortic endothelial cellGlucose caused a rapid dose-dependent increase in endothelial cell permeability and this effect was reversed by using PKC inhibitors. Furthermore, PKC isoform alpha inhibitor abolished the observed effect of high glucoseIncrease in extracellular glucose in vitro (≥300 mg/dL) leads to a rapid dose-dependent increase in endothelial cell permeability by the activation of PKC alpha
      Tesfamariam et al
      • Tesfamariam B.
      • Cohen R.A.
      Free radicals mediate endothelial cell dysfunction caused by elevated glucose.
      In vitro study on rabbit aortaExposure of aortic segments to elevated glucose or to xanthine oxidase caused a significant increase in release of immunoreactive prostanoidsEndothelial cell dysfunction caused by elevated glucose is mediated by free radicals that are likely generated through the increased cyclooxygenase catalysis
      Endothelial-dependent vasodilation is an important initial step in inflammation. Kim et al
      • Kim S.H.
      • Park K.W.
      • Kim Y.S.
      • et al.
      Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism.
      studied the effect of induced hyperglycemia in 8 patients with diabetes or impaired glucose metabolism by infusing acetylcholine and measuring the vasodilatory response using the forearm blood flow ratio. The study showed that induction of hyperglycemia significantly reduced forearm blood flow ratio at all rates of acetylcholine infusion. Endothelium-dependent relaxation in the aortic rings and renal vessels in vitro is reduced by exposure to high glucose levels (270-450 mg/dL) for 3 hours.
      • Gomes M.B.
      • Affonso F.S.
      • Cailleaux S.
      • et al.
      Glucose levels observed in daily clinical practice induce endothelial dysfunction in the rabbit macro- and microcirculation.
      This change in endothelial function associated with hyperglycemia may be secondary to reduced nitric oxide production or decreased nitric oxide effect on vessels following exposure to bradykinin.
      • Santilli F.
      • Cipollone F.
      • Mezzetti A.
      • et al.
      The role of nitric oxide in the development of diabetic angiopathy.
      • Schiekofer S.
      • Balletshofer B.
      • Andrassy M.
      • et al.
      Endothelial dysfunction in diabetes mellitus.
      Bradykinin increases the synthesis of nitric oxide, and this promotes vasodilation and increased vascular permeability.
      • Bjørnstad-Ostensen A.
      • Berg T.
      The role of nitric oxide, adrenergic activation and kinin-degradation in blood pressure homeostasis following an acute kinin-induced hypotension.
      In in vitro studies, high concentrations of glucose and glycation end products decrease constitutive nitric oxide synthase expression in retinal vascular endothelial cells.
      • Chakravarthy U.
      • Hayes R.G.
      • Stitt A.W.
      • et al.
      Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.
      Protein kinase Cβ has been implicated in the reduced endothelium-dependent nitric oxide vasodilation responses. In a randomized, double blind, placebo-controlled crossover trial, 15 healthy volunteers were treated with selective protein kinase Cβ inhibitor (LY333531) or matching placebo for 7 days.
      • Beckman J.A.
      • Goldfine A.B.
      • Gordon M.B.
      • et al.
      Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans.
      The endothelial dilatation rate in response to methacholine chloride was measured during euglycemia and after 6 hours of a hyperglycemic clamp. In this experiment, hyperglycemia reduced blood flow in the placebo group but did not reduce blood flow in the volunteers treated with protein kinase Cβ inhibitor. This study suggests that protein kinase Cβ activation during hyperglycemia decreases endothelium-dependent nitric oxide induced vasodilation. Treatment with a Cβ protein kinase inhibitor decreases vascular dysfunction in diabetic rats.
      • Ishii H.
      • Jirousek M.R.
      • Koya D.
      • et al.
      Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.
      Protein kinase C (isoform alpha) activation during hyperglycemia is also associated with increased endothelial permeability in a dose-dependent manner.
      • Hempel A.
      • Maasch C.
      • Heintze U.
      • et al.
      High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha.
      This effect increases tissue edema. High glucose concentrations increase lipopolysaccharide stimulated changes in the permeability of pulmonary microvacular endothelial cells.
      • Liu X.J.
      • Zhang Z.D.
      • Ma X.C.
      High glucose enhances LPS-stimulated human PMVEC hyperpermeability via the NO pathway.
      The role of vasoconstrictive substances released in response to protein kinase activation during hyperglycemia has been investigated using the rabbit aorta in an in vitro model.
      • Tesfamariam B.
      • Brown M.L.
      • Cohen R.A.
      Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C.
      Aortas treated with PMA (a protein kinase activator) had decreased relaxation in the endothelium-dependent vasodilator in response to acetylcholine administration, and endothelium-dependent vasodilation was reduced in high glucose concentrations (400 and 700 mg/dL) for 6 hours. It was also noted that PMA caused a significant increase in basal and acetylcholine-stimulated release of vasoconstrictor prostanoids. Collectively these experiments suggest that hyperglycemia impairs endothelial-dependent relaxation by the release of prostanoids as a consequence of protein kinase C activation. In addition to altering the prostanoids profile, hyperglycemia also up-regulates cyclooxygenase-2, and this reduces nitric oxide availability, as cyclooxygenase-2 up-regulation leads to the production of free oxygen radicals that reduce endothelial relaxation.
      • Cosentino F.
      • Eto M.
      • De Paolis P.
      • et al.
      High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species.
      • Tesfamariam B.
      • Cohen R.A.
      Free radicals mediate endothelial cell dysfunction caused by elevated glucose.
      In summary, hyperglycemia decreases the initial vasodilatory response during acute inflammation and reduces blood flow to sites of infection. This reduces the initial neutrophil response to infection. Hyperglycemia also increases endothelial permeability and tissue edema, which can cause multisystem organ dysfunction and shock.
      • Steinbert B.E.
      • Goldenberg N.M.
      • Lee W.L.
      Do viral infections mimic bacterial sepsis? The role of microvascular permeability: a review of mechanisms and methods.

      Complement Cascade

      Complement system activation is an integral part of the early innate immune system response. This system consists of serum and surface proteins whose main functions are to promote the opsonization and phagocytosis of microorganisms by macrophages and neutrophils. Complement can also cause direct lysis of the pathogens and release mediators (eg, C3a and C5a), which direct neutrophil migration and chemotaxis. Several studies have shown that elevated glucose levels affect the complement cascade system (Table 3).
      Table 3The effect of acute hyperglycemia on the complement system.
      StudyStudy modelResultsConclusion
      Tang et al
      • Tang S.
      • Leung J.C.
      • Chan L.Y.
      • et al.
      Regulation of complement C3 and C4 synthesis in human peritoneal mesothelial cells by peritoneal dialysis fluid.
      In vitro study with cultured HPMCs obtained from human omentumConstitutive secretion and gene expression of C3 and C4 mRNA in HPMCs were up-regulated upon exposure to 75 mm glucoseThe use of hypertonic glucose solution induced chronic inflammation and fibrosis leading to PD failure
      Saiepouret al
      • Saiepour D.
      • Sehlin J.
      • Oldenborg P.A.
      Hyperglycemia-induced protein kinase C activation inhibits phagocytosis of C3b- and immunoglobulin g-opsonized yeast particles in normal human neutrophils.
      In vitro study with human neutrophils from the serum of healthy volunteers30-min preincubation with 270 or 450 mg/dL glucose, phagocytosis of C3bY was dose-dependently reduced to 73.2% ± 4.7% and 42.5% ± 2.7%Elevated glucose concentrations can inhibit complement receptor and Fc gamma receptor-mediated phagocytosis by normal human neutrophils by activating PKC alpha or PKC beta or both
      Hostetter
      • Hostetter M.K.
      Handicaps to host defense. Effects of hyperglycemia on C3 and Candida albicans.
      In vitro study with human serumC3 molecules was glycosylated after incubation with 50 mM glucose (P < 0.02). Glycosylation of C3 attributed to covalent attachment of glucose to the thiolester site.Binding of glucose to the biochemically active site of the third component of complement C3 inhibits the attachment of this protein to the microbial surface and impairs opsonization.
      Hennessey
      • Hennessey P.J.
      • Black C.T.
      • Andrassy R.J.
      Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation.
      In vitro study with human serumHigh glucose level (250 mg/dL) associated with significant glycation after 16 h. Complement fixation was significantly reduced after 48 hr of incubation (76 ± 5%)There is a significant reduction in complement fixation by immunoglobulin after transient hyperglycemia
      HPMCs, human peritoneal mesothelial cells; PD, Peritoneal dialysis.
      Tang et al
      • Tang S.
      • Leung J.C.
      • Chan L.Y.
      • et al.
      Regulation of complement C3 and C4 synthesis in human peritoneal mesothelial cells by peritoneal dialysis fluid.
      studied the mechanism underlying peritoneal membrane failure in patients on long-term peritoneal dialysis. As complement activation occurs in the peritoneal cavity in patients on chronic dialysis,
      • Young G.A.
      • Kendall S.
      • Brownjohn A.M.
      Complement activation during CAPD.
      • Reddingius R.E.
      • Schroder C.H.
      • Daha M.R.
      • et al.
      Complement in serum and dialysate in children on continuous ambulatory peritoneal dialysis.
      these investigators studied the effect of glucose on complement expression in cultured human peritoneal mesothelial cells and showed that high glucose concentrations up-regulated both C3 and C4 gene expression and secretion of C3 and C4 in human peritoneal mesothelial cells in a time dependent process. They concluded that hypertonic glucose use as an osmotic agent in peritoneal dialysis activated the complement system and that this leads to a chronic inflammatory state and eventually peritoneal fibrosis and peritoneal dialysis failure.
      In experiments more relevant to host defenses, hyperglycemia inhibited complement receptor and Fc gamma receptor-mediated phagocytosis of opsonized yeast particles by normal human neutrophils in vitro. Inhibitors of protein kinase C activation completely blocked this effect.
      • Saiepour D.
      • Sehlin J.
      • Oldenborg P.A.
      Hyperglycemia-induced protein kinase C activation inhibits phagocytosis of C3b- and immunoglobulin g-opsonized yeast particles in normal human neutrophils.
      Acute hyperglycemia also inhibits opsonization when glucose binds directly to the biochemically active site of the third component of complement C3 in a nonenzymatic reaction and blocks its attachment to the microbial surfaces.
      • Hostetter M.K.
      Handicaps to host defense. Effects of hyperglycemia on C3 and Candida albicans.
      Hyperglycemia can also cause nonenzymatic glycosylation of immunoglobulins.
      • Hennessey P.J.
      • Black C.T.
      • Andrassy R.J.
      Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation.
      This reduces complement fixation and potentially reduces opsonization of microbes. However, this effect requires elevated glucose levels in vitro for sustained periods (16 hours). Hai et al
      • Hair P.S.
      • Echague C.G.
      • Rohn R.D.
      • et al.
      Hyperglycemic conditions inhibit C3-mediated immunological control of Staphylococcus aureus.
      reported that increased glucose concentrations inhibited the activation of C3 by Staphylococcus aureus and the deposition of C3b and iC3b on the bacterial surface and reduced serum-mediated phagocytosis. These effects were not explained by glycation of lysine residues but by changes in the tertiary structure of the molecule. Mauriello et al
      • Mauriello C.T.
      • Hair P.S.
      • Rohn R.D.
      • et al.
      Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis.
      studied the effect of hyperglycemia on complement mediated clearance of S aureus in a rat model for peritonitis. Rats treated with a streptozocin developed acute hyperglycemia within 24 hours; staphylococcal clearance was measured at 2 and 24 hours following inoculation. At 2 hours IgG, total C4, total C3, C3a and C5a were reduced. C4 binding to the bacteria, C3 opsonization, phagocytosis and staphylococcal killing were also reduced. This study demonstrates that acute elevation glucose levels to approximately 500 mg/dL significantly reduces innate host defenses at a site of infection (peritoneum) against S aureus during a 2 hour exposure to hyperglycemia. Consequently, chronic exposure to glucose in the peritoneal cavity causes chronic inflammation, but acute exposure blocks complement fixation and reduces opsonization. This effect likely reflects acute changes in complement structure secondary to direct glucose effects. Whether or not short-term increases in glucose alter other aspects of complement, such as viral neutralization and the formation of membrane-attack complexes, has not been investigated.
      Changes in complement concentrations and complement function reduce the opsonization of microorganisms and reduce phagocytosis. This impairs the innate response to infection by neutrophils and delays bacterial clearance. In effect, hyperglycemia causes an acquired complement deficiency.

      Cytokines

      Cytokines are small proteins produced by a broad range of cells, including immune cells, such as mast cells, B lymphocytes, T lymphocytes and macrophages. They participate in cell signaling and modulate the balance between cellular and humoral immune responses.
      • Belardelli F.
      Role of interferons and other cytokines in the regulation of the immune response.
      Diabetes mellitus, hyperglycemia and impaired glucose tolerance are associated with increased levels of interleukin-6, tumor necrosis factor-α and C-reactive protein.
      • De Rekeneire N.
      • Peila R.
      • Ding J.
      • et al.
      Diabetes, hyperglycemia, and inflammation in older individuals, the health, aging and body composition study.
      Short-term hyperglycemia (3 hours of glucose clamp) increases oxidative stress and systemic inflammatory responses induced by endotoxin in rats.
      • Ling P.R.
      • Smith R.J.
      • Bistrian B.R.
      Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats.
      These animals have significantly higher levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, corticosterone and alpha-1 acid glycoprotein in the serum and higher levels of total glutathione and malondialdehyde in the liver. Similar results were seen in 2 studies with healthy volunteers in which hyperglycemia increased IL-6 and TNF synthesis by monocytes in vitro.
      • Morohoshi M.
      • Fujisawa K.
      • Uchimura I.
      • et al.
      Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro.
      • Morohoshi M.
      • Fujisawa K.
      • Uchimura I.
      • et al.
      The effect of glucose and advanced glycation end products on IL-6 production by human monocytes.
      Otto et al
      • Otto M.N.
      • Schindler R.
      • Lun A.
      • et al.
      Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro.
      studied the effect of hyperglycemia on cytokine levels and function of human peripheral blood mononuclear cells from healthy volunteers. The cells were incubated in media with different glucose concentrations (250, 500, and 1,000 mg/dL) for 3 hours and then stimulated by Escherichia coli lipopolysaccharide. Hyperglycemia increased the concentrations of IL-1β and IL-6 and reduced the respiratory burst rates and phagocytosis rates in PMNs. These authors suggested that the observed effects were due to the hyperosmolarity associated with high glucose levels.
      Krogh-Maden et al
      • Krogh-Madsen R.
      • Moller K.
      • Dela F.
      • et al.
      Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha, and FFAs to low-dose endotoxemia in humans.
      studied 3 healthy volunteers using glucose clamps and injecting low-doses of endotoxin. TNF alpha levels did not change during the hyperglycemic clamp, but IL-6 levels increased during the late phase of it. TNF, IL-6 and IL-18 levels were also increased after acute rises in glucose.
      • Esposito K.
      • Nappo F.
      • Marfella R.
      • et al.
      Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress.
      In another trial, the increased IL-6 level associated with hyperglycemia was reversed by adding a protein kinase C inhibitor in vitro.
      • Devaraj S.
      • Venugopal S.K.
      • Singh U.
      • Jialal I.
      Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and - {beta}.
      This suggests a role for protein kinase C activation by hyperglycemia in the induction of inflammation. Shanmugam et al
      • Shanmugam N.
      • Reddy M.A.
      • Guha M.
      • et al.
      High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells.
      have related the increase in TNF to oxidative stress and nuclear factor-kB transcription factor. Their experiments also demonstrated that high glucose levels could increase the expression of chemokine genes in the monocytes.
      These studies demonstrated that hyperglycemia triggers the synthesis and release of cytokines but also reduces phagocytosis. Therefore, hyperglycemia appears to have divergent effects on cytokine release and the innate immune cellular function. However, stress induced hyperglycemia in patients with sepsis is associated with increased cytokine production and increased mortality.
      • Leonidou L.
      • Mouzaki A.
      • Michalaki M.
      • et al.
      Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia.
      A critical issue in this complex host defense response is the balance between inflammatory and anti-inflammatory cytokines and the timing of their synthesis during the acute infection; hyperglycemia may alter this balance and increase adverse outcomes.

      Cell Signaling Pathways

      Both insulin and glucose have complex intracellular pathways, which potentially affect both neutrophil function and endothelial function in hyperglycemic conditions. Glucose moves into cells through glucose transporters and enters metabolic pathways resulting in either glucose storage as a glycogen or glucose utilization to produce energy. This metabolic pathway also results in the formation of diacetylglycerol that activates protein kinase C, which, in turn, controls multiple protein functions through the phosphorylation of hydroxyl groups on serine and threonine amino acid residues.
      • Haneda M.
      • Koya D.
      • Isono M.
      • Kikkawa R.
      Overview of glucose signaling in mesangial cells in diabetic nephropathy.
      High concentrations of glucose activate mitogen-activated protein kinases which influence transcription activity in the nucleus, upregulate TLR4 with increased NK-kappa B activation and IL-8 expression, and stimulate p62/PKC interaction which also results in NF-kappa B activation.
      • Haneda M.
      • Koya D.
      • Isono M.
      • Kikkawa R.
      Overview of glucose signaling in mesangial cells in diabetic nephropathy.
      • Xi G.
      • Shen X.
      • Wai C.
      • et al.
      Hyperglycemia stimulates p62/PKC interaction, which mediates NF-kB activation, increased Nox4 expression, and inflammatory cytokine activation in vascular smooth muscle.
      • Mudaliar H.
      • Pollock C.
      • Jin Ma
      • et al.
      The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose.
      These events regulate inflammatory responses and can alter both neutrophil and endothelial function. Insulin signaling pathways control the uptake and storage of glucose, protein synthesis, lipid synthesis and mitogenic responses through the mitogen-activated protein kinase cascades.
      • Siddle K.
      Signalling by insulin and IGJ receptors: supporting acts and new players.
      The most important short-term effect of insulin during periods of acute hyperglycemia likely involves the movement of intracellular glucose transporters to the cell membrane to increase glucose uptake. Clearly, these pathways have complex intracellular effects, which could rapidly alter neutrophil function and endothelial function during states of inflammation. In vitro studies with both neutrophils and endothelial cells suggest that the activation of protein kinase C by high glucose concentrations impairs host defense responses by the innate immune system.

      Clinical Studies on Glycemic Control in Critically Ill Patients

      Kosiborod et al
      • Kosiborod M.
      • Rathore S.S.
      • Inzucchi S.E.
      • et al.
      Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction.
      studied the relationship between admission glucose levels and outcomes in 141,680 older diabetic and nondiabetic patients admitted with acute myocardial infarctions. In a risk adjusted multivariable model, there was a clear association between the hazard ratio for mortality and admission glucose levels. These hazard ratios ranged from 1.13 (glucose > 110–140 mg/dL) to 1.77 (glucose > 240 mg/dL). This relationship was particularly true for patients with no known diabetes. This study and others have stimulated randomized controlled trials testing various glucose control strategies in critically ill patients.
      • Inzucchi S.E.
      • Siegel M.D.
      Glucose control in the ICU—how tight is too tight?.
      In the Leuven 1 trial study, 1,548 postcardiac surgery patients were randomized to either intensive glucose control (80–110 mg/dL) or conventional glucose control (180–200 mg/dL).
      • van den Berghe G.
      • Wouters P.
      • Weekers F.
      • et al.
      Intensive insulin therapy in critically ill patients.
      There was a statistically significant reduction in death in the ICU in the intensive control group (4.6% versus 8.0%, odds ratio = 0.58). In the Leuven 2 trial, 1200 critically ill patients in medical ICUs were randomized into intensive glucose control or conventional glucose control groups.
      • Van den Berghe G.
      • Wilmer A.
      • Hermans G.
      • et al.
      Intensive therapy in the medical ICU.
      There was no difference in survival between these 2 groups. The NICE-SUGAR trial included 6,104 patients in general ICUs who were randomized to either intensive glucose control (81–108 mg/dL) or conventional glucose control (144–180 mg/dL).
      Finfer S, Chittock DR, Su SY, et al. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients.
      There was a statistically significant increase in mortality at 90 days in the intensive glucose control group (27.5% versus 24.9%, odds ratio = 1.14). In this study, there was no difference in the number of positive blood cultures for pathogenic organisms in patients with intensive insulin control compared to conventional insulin control or in the outcome of the subgroup of patients with severe sepsis. Other trials have also demonstrated tight glucose control did not improve outcomes in critically ill patients.
      • Arabi Y.M.
      • Dabbagh O.C.
      • Tamim H.M.
      • et al.
      Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients.
      • Kalfon P.
      • Giraudeau B.
      • Ichai C.
      • et al.
      Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial.
      Brunkhorst et al
      • Brunkhorst F.M.
      • Engel C.
      • Gloos F.
      • et al.
      German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      reported a trial using intensive insulin therapy in patients with severe sepsis. At 28 days, there was no significant difference between the 2 groups in either death or the mean score for organ failure.
      Several meta-analyses of specialized patient groups have demonstrated that tight glycemic control has important beneficial effects. Qoi et al
      • Qoi Y.C.
      • Dagi T.F.
      • Maltenfort M.
      • et al.
      Tight glycemic control reduces infection and improves outcmoe in neurosurgical and neurological patients.
      reported that tight glycemic control reduced infection rates and improved neurological outcomes in both neurological and neurosurgical patients. The odds ratio for a lower infection rate was 0.59 (95% CI: 0.47–0.76). Murad summarized the results from 19 studies on noncritically ill hospitalized patients and found that patients managed with intensive glycemic control had a decreased risk of infection (odds ratio = 0.4; 95% CI: 0.21–0.77).
      • Murad M.H.
      • Coburn J.A.
      • Coto-Yglesias F.
      • et al.
      Glycemic control in con-critically ill hospitalized patients: a systematic review and meta-analysis.
      Sathya et al
      • Sathya B.
      • Davis R.
      • Taveira T.
      • et al.
      Intensity of peri-operative glycemic control and postoperative outcomes in patients with diabetes: a meta-analysis.
      concluded that moderate glycemic targets in patients with diabetes reduced postoperative mortality but did not change infection rates. Boreland et al
      • Boreland L.
      • Scott-Hudson M.
      • Hetherington K.
      • et al.
      The effectiveness of tight glycemic control on decreasing surgical site infections and readmission rates in adult patients with diabetes undergoing cardiac surgery: a systematic review.
      published a systematic review of surgical site infections and readmissions in adult patients with diabetes undergoing cardiac surgery. This study demonstrated that glycemic control with a continuous insulin infusion to achieve blood glucose levels below 200 mg/dL significantly reduced surgical site infection rates (odds ratio = 0.35; 95% CI: 0.25–0.49). Hemmila et al
      • Hemmila M.R.
      • Taddonio M.A.
      • Arbabi S.
      • et al.
      Intensive insulin therapy is associated with reduced infectious complications in burn patients.
      reported that intensive insulin therapy in burn patients with a target of 100–140 mg/dL decreased the rates of pneumonia, ventilator-associated pneumonia and urinary tract infection. Strict insulin therapy (target glucose range: 80–120 mg/dL) in patients in a surgical ICU reduced intravascular device infection, bloodstream infection, intravascular device–related bloodstream infection and surgical site infection, but this study included only 61 patients.
      • Grey N.J.
      • Pedrizet G.A.
      Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control.
      In summary, large multicentered trials do not demonstrate any overall survival benefit in critically ill patients admitted to either medical or surgical ICUs when treated with intensive glucose control protocols. However, meta-analyses of studies on specialized populations and smaller studies have demonstrated reduced rates of infection in certain ICU populations, including burn patients, postsurgical patients, neurological patients, and diabetics with tight glucose control. Insulin has effects on both glucose levels and innate immunity. Xiu et al
      • Xiu F.
      • Stanjcic M.
      • Diao L.
      • Jeschke M.G.
      Stress hyperglycemia, insulin treatment, and innate immune cells.
      summarized experimental studies relevant to insulin effects, including information on monocytes and macrophages, and these studies demonstrate that insulin increases chemotaxis, phagocytosis and bactericidal activity.

      Conclusions

      Hyperglycemia, whether induced by stress, medications like corticosteroids or parenteral nutrition, impairs nitric oxide related endothelium-dependent relaxation and increases vascular permeability. Short-term hyperglycemia alters host cellular defenses by affecting neutrophil chemotaxis, locomotion, phagocytosis, respiratory burst and antimicrobial activity. These effects are due mainly to changes in neutrophil metabolism through the inhibition of G6PD and activation of protein kinase C. The activation of protein kinase C also leads to defective complement system function, high glucose concentrations can glycosylate immunoglobulins and reduce their function and high concentrations of glucose can alter the tertiary structure of C3. Hyperglycemia increases inflammatory cytokine levels and potentially alters the balance between inflammatory and anti-inflammatory cytokines. These effects help explain the poor outcomes associated with hyperglycemia in patients admitted with different medical and surgical conditions.
      • Umpierrez G.E.
      • Isaacs S.D.
      • Bazargan H.
      • et al.
      Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes.
      • McAlister F.A.
      • Majumdar S.R.
      • Blitz S.
      • et al.
      The relation between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired pneumonia.
      • Capes S.E.
      • Hunt D.
      • Malmberg K.
      • et al.
      Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.
      Experimental studies indicate that glucose concentrations of 200 mg/dL for 30 minutes decrease the neutrophil respiratory burst in vitro and that concentrations of 500 mg/dL decrease innate defenses at sites of infection in vivo.
      • Nielson C.P.
      • Hindson D.A.
      Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro.
      • Mauriello C.T.
      • Hair P.S.
      • Rohn R.D.
      • et al.
      Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis.
      Glucose effects may depend on the glucose level, the duration of hyperglycemia, the rates of change in glucose concentrations, or the variability in glucose concentrations? This information will be difficult to obtain in clinical studies. The NICE-SUGAR trial demonstrates the complexity of glucose management in critically ill patients and reported that patients managed with conventional glucose control (target glucose < 180 mg/dL) had better outcomes (less mortality) than patients managed with intensive glucose control (target glucose levels of 81–108 mg/dL).
      Finfer S, Chittock DR, Su SY, et al. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients.
      However, there was significant overlap in the time-weighted mean glucose levels in the 2 cohorts, and it was not reported whether or not high glucose levels outside the target range in the conventional management group had adverse effects. Clinical trials studying the rates of infectious complications and recovery from presenting infections in critically ill patients are needed. These trials will need to consider both glucose levels and patterns and the use of insulin. Until more information is available, clinicians should remember that elevated glucose levels can have important effects on innate host defenses and that insulin has direct effects on neutrophil function. We suggest that glucose levels in the range of 140–180 mg/dL may provide optimal outcomes for hospitalized patients and represent reasonable therapeutic targets.
      Finfer S, Chittock DR, Su SY, et al. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients.
      • Minakata K.
      • Sakata R.
      Perioperative control of blood glucose level in cardiac surgery.

      Acknowledgments

      We thank Colleen Sims for supporting this review with the needed references.

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