Previous studies have examined the effect of burn injury on glucose utilization in patients and animal models. Wilmore found that leg glucose turnover rates were increased in patients with burns greater than 50% BSA. Health showed that hepatic glyogenolysis was elevated after scald injury in rats. Wilmore made a similar observation in patients. Wilmore also found that glucose uptake was markedly elevated in burned extremities and normal kidney. Numerous studies by Burke, Wolfe, and Wilmore have demonstrated that burn injury increases hepatic glucose production, while increasing the rate of disappearance of glucose from the blood by 2- to 3-fold. Burn injury has been shown to reduce the amount of glycogen which is the storage form of glucose in both liver and skeletal muscle. These latter changes where associated with changes in the glycogen synthetase activity.

Hyperglycemia and glucose intolerance are frequently associated with the metabolic response to major trauma. Following injury, burn shock or systemic infection, oral and intravenous glucose tolerance tests have demonstrated delayed disposal of glucose from plasma into tissues. This diabetes of injury could be explained if there were an insulin deficiency, and several studies have shown that early after trauma (ebb phase) insulin concentrations are reduced even in the face of hyperglycemia. After resuscitation of trauma patients (flow phase), beta cell responsiveness to glucose administration normalizes and plasma insulin levels are appropriate or even higher than expected. However, despite this appropriate acute insulin response to glucose administration, glucose intolerance and hyperglycemia continue. This suggests that some of the tissues in trauma patients are relatively insensitive to the effects of insulin.

Although the number of investigations addressing the mechanism of this insulin resistance in trauma patients has been limited, one important study using the euglycemic insulin clamp technique demonstrated: (i) The maximal rate of glucose disposal is reduced in trauma patients. (ii) The metabolic clearance rate of insulin is almost twice normal in these patients. (iii) Post-trauma insulin resistance appears to occur in peripheral tissues, probably skeletal muscle, and is consistent with a post-receptor effect. Unfortunately, the procedures used in this study were not capable of independently accessing the contributions of glucose transport, phosphorylation, and subsequent intracellular metabolism of glucose. However, since the insulin resistance in trauma patients has many similarities to the insulin resistance that occurs in obesity and in patients with non-insulin dependent diabetes mellitus (NIDDM), information gained from studies of these conditions could potentially provide important mechanistic similarities described below.

Defects of glucose transport and phosphorylation may underlie insulin resistance in burn patients. To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into thigh muscle will be performed using positron emission tomography during basal and insulin-stimulated conditions. Initially, these studies will be performed in groups of rabbits with 25% TBSA burns at 3 times after injury (48-72 hrs, 2-3 weeks and 6-8 weeks). This will be followed by studies in healthy volunteers. Finally patients with 30-50% TBSA burns will be studied after the acute phase of injury, at 2-3 week after injury and just prior to discharge. In addition, muscle will be obtained by biopsy during basal and insulin-stimulated conditions for assay of mRNA and protein content of GLUT 4 and the translocation of insulin across the plasma membrane by immunohistochemical labeling.

Alterations in the phosphorylation and/or degradation of insulin receptor substrate 1 (IRS-1) produced by burn injury may be responsible, in part, for burn-induced insulin resistance. Specifically, the reduction in glucose transport in skeletal muscle following burn injury may be secondary to altered abundance and/or phosphorylation of IRS-1. We propose that altered serine phosphorylation of IRS-1 following burn injury, mediated by the activation of the stress kinases (p38, MAPK, or SAPK intermediate pathways) by cytokines, such as interleukin-6 (IL-6) or Tumor Necrosis Factor [TNF], down-regulates IRS-1 functions through several mechanisms. Phosphorylation can alter IR/IRS1 interaction as well as IRS1/PI 3-kinase interaction. Moreover, the abundance of IRS-1 is a major determinant of insulin signaling, and the degradation of IRS-1 is controlled, in part, through altered IRS-1 ser/thr phosphorylation, e.g., by an mTOR-dependent pathway. Therefore, we propose that burn injury may increase the turnover of IRS-1. We believe that the best way to further characterize and explore the metabolic etiology of impaired glucose tolerance and the “insulin-resistance” associated with severe burn injury is to compliment the integrated set of studies in human subjects described above with more invasive and mechanistically-focused investigations using murine burn models. The latter will be exploited to define possible cellular loci of insulin function and action that might be causally responsible for the metabolic alterations and abnormalities observed in the clinical setting and would serve as a basis for the rational design of interventions aimed at minimizing the untoward consequences of impaired glucose metabolism and homeostasis. Specific aspects of these studies will include: determinations of stress kinase activities after injury and characterization of the phosphorylation sites on IRS-1.

References:

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