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Stress hyperglycemia: an essential survival response!

Marik PE, Bellomo R - Crit Care (2013)

Bottom Line: Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control.However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes.Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Stress hyperglycemia is common in critically ill patients and appears to be a marker of disease severity. Furthermore, both the admission as well as the mean glucose level during the hospital stay is strongly associated with patient outcomes. Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control. However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes. We suggest that hyperglycemia and insulin resistance in the setting of acute illness is an evolutionarily preserved adaptive responsive that increases the host's chances of survival. Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful. This paper reviews the pathophysiology of stress hyperglycemia and insulin resistance and the protective role of stress hyperglycemia during acute illness.

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Postulated interaction between the insulin signaling pathway and activation of the pro-inflammatory cascade in the pathogenesis of insulin resistance in sepsis. GLUT, glucose transporter; IκB, inhibitor κB; IKK, inhibitor κB kinase; IRS-1, insulin receptor substrate-1; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-kappa B; NO, nitric oxide; TLR4, Toll-like receptor-4.
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Figure 2: Postulated interaction between the insulin signaling pathway and activation of the pro-inflammatory cascade in the pathogenesis of insulin resistance in sepsis. GLUT, glucose transporter; IκB, inhibitor κB; IKK, inhibitor κB kinase; IRS-1, insulin receptor substrate-1; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-kappa B; NO, nitric oxide; TLR4, Toll-like receptor-4.

Mentions: The neuroendocrine response to stress is characterized by excessive gluconeogenesis, glycogenolysis and insulin resistance (Figure 1) [5]. Stress hyperglycemia, however, appears to be caused predominantly by increased hepatic output of glucose rather than impaired tissue glucose extraction. The metabolic effects of cortisol include an increase in blood glucose concentration through the activation of key enzymes involved in hepatic gluconeogenesis and inhibition of glucose uptake in peripheral tissues such as the skeletal muscles [5]. Both epinephrine and norepinephrine stimulate hepatic gluconeogenesis and glycogenolysis; norepinephrine has the added effect of increasing the supply of glycerol to the liver via lipolysis. Inflammatory mediators, specifically the cytokines TNF-α, IL-1, IL-6, and C-reactive protein, also induce peripheral insulin resistance (Figure 2) [5]. In addition, the altered release of adipokines (increased zinc-alpha2 glycoprotein and decreased adiponectin) from adipose tissue during acute illness is thought to play a key role in the development of insulin resistance [14]. The degree of activation of the stress response and the severity of hyperglycemia are related to the intensity of the stressor and the species involved. Hart and colleagues [15] demonstrated that hemorrhage, hypoxia and sepsis were amongst those stressors that resulted in the highest epinephrine and norepinephrine levels. In reviewing the literature, we have demonstrated large interspecies differences in the degree of activation of the HPA axis with stress, with humans having the greatest increase in serum cortisol level (Figure 3) [16].


Stress hyperglycemia: an essential survival response!

Marik PE, Bellomo R - Crit Care (2013)

Postulated interaction between the insulin signaling pathway and activation of the pro-inflammatory cascade in the pathogenesis of insulin resistance in sepsis. GLUT, glucose transporter; IκB, inhibitor κB; IKK, inhibitor κB kinase; IRS-1, insulin receptor substrate-1; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-kappa B; NO, nitric oxide; TLR4, Toll-like receptor-4.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672537&req=5

Figure 2: Postulated interaction between the insulin signaling pathway and activation of the pro-inflammatory cascade in the pathogenesis of insulin resistance in sepsis. GLUT, glucose transporter; IκB, inhibitor κB; IKK, inhibitor κB kinase; IRS-1, insulin receptor substrate-1; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-kappa B; NO, nitric oxide; TLR4, Toll-like receptor-4.
Mentions: The neuroendocrine response to stress is characterized by excessive gluconeogenesis, glycogenolysis and insulin resistance (Figure 1) [5]. Stress hyperglycemia, however, appears to be caused predominantly by increased hepatic output of glucose rather than impaired tissue glucose extraction. The metabolic effects of cortisol include an increase in blood glucose concentration through the activation of key enzymes involved in hepatic gluconeogenesis and inhibition of glucose uptake in peripheral tissues such as the skeletal muscles [5]. Both epinephrine and norepinephrine stimulate hepatic gluconeogenesis and glycogenolysis; norepinephrine has the added effect of increasing the supply of glycerol to the liver via lipolysis. Inflammatory mediators, specifically the cytokines TNF-α, IL-1, IL-6, and C-reactive protein, also induce peripheral insulin resistance (Figure 2) [5]. In addition, the altered release of adipokines (increased zinc-alpha2 glycoprotein and decreased adiponectin) from adipose tissue during acute illness is thought to play a key role in the development of insulin resistance [14]. The degree of activation of the stress response and the severity of hyperglycemia are related to the intensity of the stressor and the species involved. Hart and colleagues [15] demonstrated that hemorrhage, hypoxia and sepsis were amongst those stressors that resulted in the highest epinephrine and norepinephrine levels. In reviewing the literature, we have demonstrated large interspecies differences in the degree of activation of the HPA axis with stress, with humans having the greatest increase in serum cortisol level (Figure 3) [16].

Bottom Line: Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control.However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes.Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Stress hyperglycemia is common in critically ill patients and appears to be a marker of disease severity. Furthermore, both the admission as well as the mean glucose level during the hospital stay is strongly associated with patient outcomes. Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control. However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes. We suggest that hyperglycemia and insulin resistance in the setting of acute illness is an evolutionarily preserved adaptive responsive that increases the host's chances of survival. Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful. This paper reviews the pathophysiology of stress hyperglycemia and insulin resistance and the protective role of stress hyperglycemia during acute illness.

Show MeSH
Related in: MedlinePlus