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.

Stress Hyperglycemia as Predictive Factor of Recurrence in Children with Febrile Seizures

“…Multicentric and larger sample studies linking genetic pathology with febrile seizure prognosis would provide more insights into stress hyperglycemia as a predictor of seizure recurrence. fatty acids, and inflammation [1,[4][5][6][7][8][9][10][11]. During acute severe illness, the role of proinflammatory cytokines in inducing stress hyperglycemia is complex.…”

“…Interleukin-1 increases the secretion of corticosterone and glucagon associated with glucose production and by activating the inhibitor-kB kinase in the hepatocytes, it is correlated with the gene expression of inflammatory cytokines, finally suppressing GLUT4 translocation. Glucose transporter translocation is essential for cell glucose uptake [1,[4][5][6][7][8][9][10][11].…”

“…The proposed triggering mechanisms in febrile seizures are temperature-sensitive ion channels and increased neuronal excitability in the context of proinflammatory cytokines [3]. Both seizure activity and fever-illness context have common stress-related mechanisms with high metabolic states, hypoperfusion, relative hypoxic states due to rising oxygen demands needed for additional energy supply, and accelerated glycolysis [1,[4][5][6][7][8][9][10][11]. The oxidative stress is playing a key role as a common pathway for febrile seizures and stress hyperglycemia [8,12,13].…”

“…The oxidative stress is playing a key role as a common pathway for febrile seizures and stress hyperglycemia [8,12,13]. Moreover, in stress hyperglycemia, cytokines and hormones, interact in a complex manner supporting gluconeogenesis, glycogenolysis, and insulin resistance as pathogenic hallmarks [1,[4][5][6][7][8][9][10][11]. Further details on the endogenous mechanism of stress hyperglycemia are available in Figure A1 and the text in the Appendix A.…”

“…Further details on the mechanism of neuroendocrine responses, stress hyperglycemia, hyperlactatemia, and the immune system responses in febrile seizures are available in Appendix A. According to some other studies however, acute and long-term stress-induced hyperglycemia is currently believed to support a vicious cycle of self-promoting, exacerbating cytokine, inflammatory, and oxidative stress response [1,[4][5][6][7][8][9][10][11]. Moreover, during febrile seizures, hyperlactatemia with or without acidosis reflects a complex metabolic disturbance, an imbalance between anaerobic and aerobic lactate production and clearance between the glycolytic and Krebs cycle activity either from the overproduction of pyruvate by increased glycolysis or from the underutilization of pyruvate, or from both [22].…”