Stress hyperglycemia, cardiac glucotoxicity, and critically ill patient outcomes current clinical and pathophysiological evidence

Abstract

Stress hyperglycemia is a transient increase in blood glucose during acute physiological stress in the absence of glucose homeostasis dysfunction. Its's presence has been described in critically ill patients who are subject to many physiological insults. In this regard, hyperglycemia and impaired glucose tolerance are also frequent in patients who are admitted to the intensive care unit for heart failure and cardiogenic shock. The hyperglycemia observed at the beginning of these cardiac disorders appears to be related to a variety of stress mechanisms. The release of major stress and steroid hormones, catecholamine overload, and glucagon all participate in generating a state of insulin resistance with increased hepatic glucose output and glycogen breakdown. In fact, the observed pathophysiological response, which appears to regulate a stress situation, is harmful because it induces mitochondrial impairment, oxidative stress-related injury to cells, endothelial damage, and dysfunction of several cellular channels. Paradigms are now being challenged by growing evidence of a phenomenon called glucotoxicity, providing an explanation for the benefits of lowering glucose levels with insulin therapy in these patients. In the present review, the authors present the data published on cardiac glucotoxicity and discuss the benefits of lowering plasma glucose to improve heart function and to positively affect the course of critical illness.

Keywords: cardiogenic shock; glucotoxicity; heart; heart failure; insulin; stress hyperglycemia.

FIGURE 1

In states of acute physiological stress, glucose is shunted into cardiomyocytes via upregulated GLUT‐1. Glucose is metabolized via glycolytic and non‐glycolytic pathways, generating reactive oxygen species that target intracellular proteins that activate apoptotic pathways. The positive inotropic effects of insulin are mediated by the activation of the insulin receptor PI3 K/Akt pathway, leading to increased activity of NCX (a sodium‐calcium exchanger) and intracellular calcium accumulation. Insulin also counteracts the negative effects of peroxynitrite by inhibiting apoptotic pathways in cardiomyocytes. Part of this effect is mediated through the increased expression of HSP70 and its preferential localization to the plasma membrane with dystrophin. Insulin receptor activation also leads to the translocation of hexokinase (HK) to the mitochondrial membrane, where it exerts its cardioprotective effects via three mechanisms: (a) suppressing the generation of ROS, (b) inhibiting the release of cytochrome C (CyC) into the cytosol, and (c) inhibiting the formation of mitochondrial pores

FIGURE 2

Pathophysiology of stress hyperglycemia and cardiac glucotoxicity