Acute critical conditions cause cellular injuries that are known to initiate repair or cell death pathways (Figure 2). These integrative mechanisms tend to either contain the response at the local level or, on the contrary, spread it by recruiting circulating cells and factors for repair.

Damaged cells communicate with innate immune cells by releasing intracellular factors named damage-associated molecular pattern molecules (DAMPs), such as calgranulines [²⁵] and alarmines [²⁶,²⁷] (Figure 2). Together with pathogen-associated molecular pattern molecules (PAMPs), they activate the cellular expression of Toll-like receptors (TLRs) [²⁸]. Accumulation of abnormal proteins, which are processed by the proteasome S26 system in the endoplasmic reticulum [²⁹], as well as fluctuations of nutrients or energy availability, hypoxia, viruses and toxins activate a complex transcriptional response called the endoplasmic reticulum stress response (Figure 2), or the unfolded protein response [³⁰].

Receptors for recognition of inflammation appear on both target cells and inflammatory cells. The alteration of the extracellular milieu is transmitted into the cell, modifying its functions. In peripheral blood mononuclear cells, for instance [³¹], an increased energy demand associated with a simultaneous metabolic failure can occur [³²,³³]. The increased permeability of the injured mitochondria leads to energy loss and cell death, which by itself fuels the inflammatory process through the release of the cell contents.

Sepsis corresponds to a systemic inflammation related to the abnormal presence of bacterial antigens and involves different mechanisms such as hypoxia and oxidative stress. At the early phase, inhibition of glycogen synthesis results in increased global glucose availability and increased cellular uptake [^52-54]. Glucose uptake appears to be most increased in organs containing a vast population of phagocytic cells (liver, spleen, gut, lung) [^55-57]. In rats injected with endotoxin or TNF-α, insulin-independent glucose uptake is increased in liver non-parenchymal cells (Küpffer cells, endothelial cells) [⁵⁸], as observed in circulating immune cells, including polymorphonuclear leukocytes [⁵⁹,⁶⁰], lymphocytes, monocytes and macrophages [^61-63]. Skeletal muscle displays only a limited increase in glucose uptake, probably because of the development of insulin resistance.

Sepsis also modifies cytoplasmic glycolysis at the transcriptional level. In healthy volunteers receiving intra-venous endotoxin, there was an early under-expression of genes encoding metabolic enzymes [⁶⁴]. In particular, the key enzymes of glycolysis and those of the mitochondrial respiratory chain (MRC) were transiently under-expressed. In the diaphragm of septic rats, transcription, synthesis and activity of the constituents of the MRC, as well as of phosphofructokinase-1, a key-enzyme of glycolysis, are reduced [⁶⁵]. In muscle of septic rats, the activity of pyruvate dehydrogenase is reduced, with a simultaneous increase in the activity of its inhibitor, pyruvate dehydrogenase kinase. The net result of these modifications is a reduction in pyruvate entering the mitochondria while the conversion of pyruvate to lactate is promoted [⁶⁶].

In septic shock patients, increased use of glucose and increased lactate production was observed under aerobic conditions [⁶⁷]. A microdialysis study of quadriceps muscles showed lactate overproduction during septic shock resulting form exaggerated aerobic glycolysis through Na/K-ATPase stimulation. To maintain cell functions, stimulation of glycolysis was shown to adaptively compensate for the metabolic rate increase [⁶⁸]. Elevated circulating epinephrine stimulates Na/K-ATPase, which promotes lactate hyperproduction without any oxygen debt [⁶⁹].

Mitochondrial dysfunction during sepsis [⁷⁰] involves alterations in the structure [⁷¹] and function of the MRC, including impairment of key enzymes of electron transport and ATP synthesis [⁷²,⁷³] and mitochondrial biogenesis [⁷⁴]. These results were also found with monocytes [⁷⁵] and skeletal muscle [⁷⁶] harvested from septic shock patients. ATP levels in skeletal muscle cells were maintained despite mitochondrial ultrastructural alterations [⁷⁶]. This mitochondrial dysfunction results from plasmatic factors that promote uncoupled MRC oxygen consumption [⁷⁷] that correlates with sepsis-induced modifications of the immune phenotype and is associated with increased mitochondrial permeability [⁷⁸].

In summary, glucose metabolism alterations in acute critical conditions can be viewed as a 'redistribution of glucose consumption away from mitochondrial oxidative phosphorylation' towards other metabolic pathways, such as lactate production. This re-channelling does not seem to affect energy supply to the cells. This may result from decreased ATP consumption by the cells, which in turn lose some of their characteristics, indicating metabolic failure [⁷⁹].

Insulin resistance (IR) is a reduction in the direct effect of insulin on its signalling process leading to metabolic consequences [⁸¹], very similar to type 2 diabetes, and is commonly observed during sepsis [⁸²].

Insulin acts mainly on the liver, muscle and fat (metabolic effects), but it also targets many cellular subtypes to stimulate essentially protein and DNA synthesis as well as apoptosis (mitogenic effects). Hepatic IR involves increased hepatic glucose production (gluconeogenesis) together with decreased glycogen synthesis. During sepsis, however, gluconeogenesis can be limited by inhibition of important enzymes [⁸³,⁸⁴]. Muscle IR corresponds to decreased glycogen deposition and glucose uptake linked to decreased expression of GLUT4, while a transient defect in insulin signalling has also been described [⁸⁵]. IR in adipocytes leads to inhibition of lipogenesis and activation of lipolysis.

In fasted animals, increased circulating glucagon induces a gluconeogenic program by activating the nuclear transription factor CREB through a molecule named Crtc2 (CREB regulated transcription coactivator 2) or TORC 2 (Transducer of regulated CREB activity 2) [¹⁰³,¹⁰⁴]. The expression rate of gluconeogenic enzymes is thus increased, especially for glucose-6-phosphatase.

Re-feeding in turn increases insulin levels, which inhibits hepatic glucose production partly by ubiquitin-dependent destruction of Crtc2 [¹⁰⁵]. During sustained hyperglycaemia, the hexosamine pathway can be activated [¹⁰⁶]. In hepatocytes, Crtc2 is then O-glycosylated on a serine residue instead of being phosphorylated. It can thus migrate into the nucleus to activate CREB and the gluconeogenic program, contributing to maintain hyperglycaemia [¹⁰⁷]. This has been described as the 'sweet conundrum' [¹⁰⁵]. Regulation of this pathway during acute injury remains to be proven.

In diabetics, glucose channelling through alternative glycolytic pathways seems to depend on MRC activity [¹⁰⁶,¹⁰⁸]. The accumulation of energy substrates induced by isolated hyperglycaemia without a concomitant increase in energy demand may enhance the flux of carbon hydrates to the mitochondria with increased activity of the MRC and proton driving force. Once the activity of ATPase is saturated, intermediate radicals from the MRC will accumulate and may react with the surrounding available O₂ to produce ROS [¹⁰⁹], as shown in bovine endothelial cells. When inhibiting this radical production, the activity of alternative glycolytic pathways is decreased as well as the expression of transcription factor NF-κB [¹¹⁰]. Inhibition of glyceraldehyde-3-phosphate dehydrogenase, an enzyme involved in cytoplasmic glycolysis, has also been observed. Metabolites accumulate upstream of this enzyme and are funnelled towards alternative pathways (Figure 1). Polymers of ADP-ribose, produced by nuclear PARP to repair DNA altered by mitochondrial ROS, may be involved in this inhibition. PARP, by migrating into the cytosol, may be a key to glucose toxicity [¹¹¹]. There is still a lack of evidence to fully extrapolate these theories to explain mitochondrial dysfunction and organ failure observed during stress-induced hyperglycaemia.

Glucose also acts as a pro-inflammatory molecule [⁸¹,¹¹²]. Glucose ingestion in healthy volunteers rapidly increases the activity of NF-κB [¹¹³] and the production of mRNA for TNF-α [¹¹⁴]. Under the same conditions, acute hyperglycaemia increased the activity of the transcription factors AP-1 (Activator protein-1) and EGR-1 (Early growth response-1), which in turn activate the production of matrix metalloproteinase-2 (MMP-2) by monocytes, an enzyme that facilitates the diffusion of inflammation by hydrolysing extracellular matrix. Production of tissue factor, a prothrombotic and proaggregant molecule [¹¹⁵], is increased, as is production of cellular adhesion molecules [¹¹⁶]. Acute hyperglycaemia induced in healthy volunteers by octreotid, an inhibitor of insulin release, leads to a rapid and transient secretion of proinflammatory cytokines (IL-6, TNFα, IL-8). This effect is amplified in insulin-resistant subjects and blunted with antiradical treatment [¹¹⁷].

Many questions regarding glycaemia remain to be solved for daily critical care practice. How should we achieve glycaemic control: should we take into account nutritional support, especially parenteral nutrition [⁹]? Should we control the physiological response to an induced hyperglycaemia or should we control the endogenous stress-induced hyperglycaemia that may be adaptive in the absence of exogenous glucose intake? Is there a place for new therapeutics such as incretins [¹²⁸]? Does endogenous hyperglycaemia have a similar impact as hyperglycaemia induced by nutritional support? These questions in turn prompt investigation of the role of glucose deprivation induced by fasting with regard to normoglycemia achieved by insulin therapy. Similarly, the consequences of spontaneous versus insulin-induced hypoglycaemia remain to be investigated. Answers to these questions will probably help to solve the conflict between supporters and opponents of tight glycaemia control in the ICU. This discussion is in accordance with the concerns raised by several authors about early initiation of parenteral nutrition in acute critical patients [¹²⁹,¹³⁰], as supported by the results of two large multicentre studies, Nice-Sugar [¹⁴] and Glucontrol [¹⁵].