Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways

Abstract

Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation.

Keywords: Warburg effect; dipeptidyl peptidase IV; glycolysis; hyperglycemia; oxidative phosphorylation; sepsis.

Figure 1

The Warburg Effect in sepsis. During septic shock, a build-up in mitochondrial succinate levels due to anaplerosis (glutamine transformation to α-ketoglutarate, a succinate precursor) is observed resulting in release into the cytoplasm. Prolyl hydroxylase (PHD) hydroxylates HIF-1α leading to its degradation. If PHD is inhibited by succinate release, then HIF-1α can inhibit the TCA cycle thereby favoring oxidative glycolysis (i.e., Warburg Effect) even when oxygen levels are sufficient.

Figure 2

Importance of DPP4 in hyperglycemia. Dipeptidyl peptidase IV (DPP4), or CD26, is a cell surface and soluble peptidase that can cleave the first two N-terminal amino acids from specific proteins and peptides. DPP4 is up-regulated in immune and endothelial cells as a result of inflammation seen in critically ill patients. Of specific importance to hyperglycemia, DPP4 cleaves the N-terminus of glucagon-like peptide 1 (GLP-1). GLP-1 is important in the storage and regulation of blood glucose by promoting insulin and limiting glucagon release. This cleavage of GLP-1 causes the inactivation of GLP-1 contributing to hyperglycemia. Inhibitors of DPP4 could be important in glucose control in critically ill patients with hyperglycemia.