Insulin resistance postburn: underlying mechanisms and current therapeutic strategies

Abstract

The profound hypermetabolic response to burn injury is associated with insulin resistance and hyperglycemia, significantly contributing to the incidence of morbidity and mortality in this patient population. These responses are present in all trauma, surgical, or critically ill patients, but the severity, length, and magnitude is unique for burn patients. Although advances in therapeutic strategies to attenuate the postburn hypermetabolic response have significantly improved the clinical outcome of these patients during the past years, therapeutic approaches to overcome stress-induced hyperglycemia have remained challenging. Intensive insulin therapy has been shown to significantly reduce morbidity and mortality in critically ill patients. High incidence of hypoglycemic events and difficult blood glucose titrations have led to investigation of alternative strategies, including the use of metformin, a biguanide, or fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist. Nevertheless, weaknesses and potential side affects of these drugs reinforces the need for better understanding of the molecular mechanisms underlying insulin resistance postburn that may lead to novel therapeutic strategies further improving the prognosis of these patients. This review aims to discuss the mechanisms underlying insulin resistance induced hyperglycemia postburn and outlines current therapeutic strategies that are being used to modulate hyperglycemia after thermal trauma.

Figure 1. Metabolic changes underlying insulin resistance post-burn

Marked and sustained increases in catecholamine, glucocorticoid, glucagon and cytokine secretion are thought to initiate the cascade of events leading to the acute hypermetabolic response to severe burn injury and oppose the anabolic effects of insulin. By enhancing adipose tissue lipolysis and skeletal muscle proteolysis, they increase gluconeogenic substrates, including glycerol, alanine and lactate, thus augmenting hepatic glucose production in burned patients. Catecholamine-mediated augmentation of hepatic glycogenolysis, as well as direct sympathetic stimulation of glycogen breakdown, further aggravates the hyperglycemia in response to stress. Catecholamines and cytokines, such as IL-1, IL-6, MCP-1 and TNF, have also been shown to impair glucose disposal via alterations of the insulin signaling pathway and GLUT-4 translocation, resulting in peripheral insulin resistance.

Figure 2. Molecular mechanisms underlying insulin resistance following thermal injury

Activation of JNK or IKK by cytokine signaling or lipid products during ER stress may lead to phosphorylation of IRS-1 at serine residues which may preclude its tyrosine phosphorylation by the insulin receptor tyrosine kinase, thus resulting in impaired PI3K/Akt signaling and insulin resistance with its associated consequences.