Bench-to-bedside review: Glucose and stress conditions in the intensive care unit

Abstract

The physiological response to blood glucose elevation is the pancreatic release of insulin, which blocks hepatic glucose production and release, and stimulates glucose uptake and storage in insulin-dependent tissues. When this first regulatory level is overwhelmed (that is, by exogenous glucose supplementation), persistent hyperglycaemia occurs with intricate consequences related to the glucose acting as a metabolic substrate and as an intracellular mediator. It is thus very important to unravel the glucose metabolic pathways that come into play during stress as well as the consequences of these on cellular functions. During acute injuries, activation of serial hormonal and humoral responses inducing hyperglycaemia is called the 'stress response'. Central activation of the nervous system and of the neuroendocrine axes is involved, releasing hormones that in most cases act to worsen the hyperglycaemia. These hormones in turn induce profound modifications of the inflammatory response, such as cytokine and mediator profiles. The hallmarks of stress-induced hyperglycaemia include 'insulin resistance' associated with an increase in hepatic glucose output and insufficient release of insulin with regard to glycaemia. Although both acute and chronic hyperglycaemia may induce deleterious effects on cells and organs, the initial acute endogenous hyperglycaemia appears to be adaptive. This acute hyperglycaemia participates in the maintenance of an adequate inflammatory response and consequently should not be treated aggressively. Hyperglycaemia induced by an exogenous glucose supply may, in turn, amplify the inflammatory response such that it becomes a disproportionate response. Since chronic exposure to glucose metabolites, as encountered in diabetes, induces adverse effects, the proper roles of these metabolites during acute conditions need further elucidation.

Figure 1

Overview of glucose metabolism in mammalian cells. Glucose is known to be oxidized through cytoplasmic glycolysis to produce pyruvate. Pyruvate may be reduced into lactate by lactate dehydrogenase or it may enter the mitochondria to participate in the citric acid cycle and the production of ATP by the mitochondrial respiratory chain and ATPase. However, glucose can be involved in other pathways. Glycogen synthesis is a major way to store glucose in muscle and liver. In the polyol pathway, aldose reductase reduces toxic aldehyde to inactive alcohol and glucose to sorbitol and fructose. In reducing NADPH to NADP⁺, this enzyme may be deleterious by consuming the essential cofactor needed to regenerate reduced glutathione, an essential antioxidant factor in cells. The hexosamine pathway originates from glycolysis at the fructose-6-phosphate level. In this pathway, glutamine fructose-6-phosphate amidotransferase is involved in the synthesis of glucosamine-6-phosphate, which is ultimately converted to uridine diphosphate (UDP)-N-acetyl-glucosamine. This glucosamine is able to activate transcription factors such as Sp-1 and to induce the production of pro-inflammatory cytokines. Diacylglycerol, which activates isoforms of protein kinase C (PKC), may be produced from dihydroxyacetone phosphate. The PKC activation can induce several pro-inflammatory patterns, such as activation of the transcription factor NF-κB, and the production of NADPH oxidase or pro-inflammatory cytokines. The pentose phosphate pathway may use glucose-6-phosphate to produce pentoses for nucleic acid production. This pathway is also able to produce NADPH for use in lipid, nitric oxide and reduced glutathione production, and also the synthesis of reactive oxygen species by NADPH oxidase. Advanced glycation end product (AGE) synthesis is linked to high intracellular glucose concentrations. AGEs can induce cell dysfunction by modifying cell proteins, and extracellular matrix proteins, which changes signalling between the matrix and the cell, or by activating receptors for advanced glycation end products (RAGEs), which induce the production of the transcription factors NF-κB and TNF-α or other pro-inflammatory molecules. GLUT, glucose transporter.

Figure 2

Integration of stress-signalling mechanisms. Damaged or dysfunctioning cells communicate with innate immune cells by releasing intracellular factors named damage-associated molecular pattern molecules (DAMPs). During cell death, these molecules, such as calgranulines from the protein S100 A superfamily or alarmines such as the nuclear protein high-mobility group box 1 (HMGB1), are released into the extracellular space to activate the immune system. These molecules associate with pathogen-associated molecular pattern molecules (PAMPs) from destroyed pathogens to activate cellular expression of Toll-like receptors (TLRs) of the pattern recognition receptor (PRR) superfamily. Some of these receptors, specifically TLR2, 4 and 9, recognize multiple DAMPS released during stress and cell death. Proteins with abnormal conformation are processed by the proteasome S26 system in the endoplasmic reticulum, where protein kinase R-like endoplasmic reticulum kinase (PERK)-type kinases are activated; these pathways depend on Ire1 (which requires inositol) and nuclear factors, such as NF-κB and Nrf2 (NF-E2 related factor). Nrf2 controls the expression of genes encoding enzymes that remove reactive oxygen species (ROS), including heme oxygenase 1 (HO-1) and glutathione S-transferase (GST). PERK-dependent phosphorylation of Nrf2 thus coordinates a transcriptional program connecting oxidative stress and endoplasmic reticulum stress. Activation of the transcription factor CREB-H can be achieved through this endoplasmic reticulum stress; CREB-H is responsible for the acute inflammatory response in the liver with acute phase protein synthesis. Adapted from [1]. GLUT, glucose transporter; HIF, hypoxia-inducible factor; HO, heme oxygenase; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; NOS, nitric oxide synthase; PKC, protein kinase C; RAGE, receptors for advanced glycation end products; ssRNA, single-stranded RNA.

Figure 3

Role of hypoxia in cell metabolic reprogramming. Hypoxia-inducible factors (HIFs), O₂-sensing transcription factors, regulate the transcription of genes encoding Heme-oxygenase-1 (HO-1), erythropoietin (EPO), and numerous molecules involved in vascular reactivity (such as nitric oxide synthase (NOS)), recruitment of endothelial progenitors, and cytoprotection through angiogenic growth factors such as vascular endothelial growth factor (VEGF). During hypoxia, glycogenolysis is stimulated, increasing glucose availability. An increase in glucose transporter (GLUT) expression enables augmented glucose uptake. This overexpression of GLUTs is mediated by the activation of AMP kinase (AMPK) and p38 mitogen-activated kinase. Stimulation of AMPK results from a decreased cytoplasmic ATP/AMP ratio together with altered cellular redox status. Phosphofructokinase-1 and lactate dehydrogenase activity is stimulated by increased lactate production. HIF decreases mitochondrial oxygen consumption and induces the expression of pyruvate dehydrogenase kinase, the main inhibitor of pyruvate dehydrogenase and of the entry of acetylCoA into mitochondria. Adapted from [36]. OXPHOS, oxidative phosphorylation; TGF, transforming growth factor.

Figure 4

Glucose and reactive oxygen species production during sepsis: hypothesis. In peripheral blood mononuclear cells harvested from healthy volunteers and septic patients, increasing extracellular glucose increased glucose uptake. Subsequent stimulation of these cells by various agonists, such as PMA (phorbol 12-myristate 13-acetate), a protein kinase C (PKC) activator, increased reactive oxygen species (ROS) production via NADPH oxidase in both the healthy volunteers and septic patients. The link between ROS and intracellular glucose levels could be increased production of NADPH via the pentose phosphate pathway.