CHAPTER 21

#### KEY POINTS

• The physiological regulation of blood glucose involves hormonal and neural mechanisms, resulting in a control of glucose flux across cell membranes.

• High glucose concentrations are associated with cellular toxicity.

• Stress hyperglycemia is a marker of severity of illness.

• Intensive insulin therapy used to tightly control blood sugar was found beneficial in one single-center study, but not in seven independent other prospective trials.

• Current recommendations advocate a moderate glucose control by insulin therapy.

#### INTRODUCTION

Critical illness is typically associated with a so-called stress-induced hyperglycemia, defined as a transient hyperglycemia during illness in patients without previous evidence of diabetes.1 The relationship between stress hyperglycemia and poor outcome is largely established. This association reflects the validity of blood glucose concentration as a marker of illness severity. However, the correction of a moderate stress hyperglycemia may improve the prognosis. Indeed, in 2001, a large randomized controlled trial in critically ill surgical patients demonstrated that tight glucose control (TGC) (defined as the restoration and maintenance of blood glucose between 80 and 110 mg/dL) by intensive insulin therapy (IIT) was associated with a decreased mortality and rate of complications.2 However, subsequent studies performed in other intensive care units (ICU)3-8 failed to reproduce the beneficial effects of IIT titrated to achieve TGC.

These conflicting results raise the clinically relevant question: How to control glycemia in ICUs? This chapter intends to summarize the current understanding of the physiological regulation of glycemia, the toxicity of hyperglycemia, the mechanisms and consequences of stress hyperglycemia, and the available clinical data from observational and interventional studies and to discuss the unsolved issues and the implications for the daily clinical practice. Updated formal recommendations will be suggested for glucose control in critically ill and postoperative patients.

#### PHYSIOLOGICAL REGULATION OF BLOOD GLUCOSE

Blood glucose concentration (BG) is tightly regulated by two types of mechanisms1:

• The hormonal system consists in a balance between insulin, which will induce the entrance and utilization of glucose into tissues, and the so-called “hyperglycemic” counterregulatory hormones (glucagon, epinephrine, cortisol).

• The neural mechanism consists in an activation of messages issued from glucose sensors of various organs.

These hormonal and neural signals modulate carbohydrate metabolism by controlling glucose fluxes, including endogenous production and the entrance of glucose into the cells. The translocation of glucose transporters (GLUT) is the prominent mechanism for the modulation of glucose transport across the cell membranes.9 Among those transporters, GLUT-1 is the predominant transporter for noninsulin-mediated glucose uptake (NIMGU) (Fig. 21-1).32 GLUT-2 regulates the flow of glucose across liver cell membranes. GLUT-4 is the main insulin-responsive glucose transporter and therefore modulates the insulin-mediated glucose uptake (IMGU) in adipose tissue, cardiac and skeletal muscles.

###### FIGURE 21-1

Insulin and glucose uptake by tissues in physiological conditions. Insulin promotes insulin-mediated glucose uptake (IMGU) in adipose tissues, skeletal ...

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