After severe
burn injury and other major
traumas,
glucose tolerance tests demonstrate delayed
glucose disposal. This 'diabetes of injury' could be explained by
insulin deficiency, and several studies have shown that soon after
trauma (ebb phase)
insulin concentrations are reduced in the face of
hyperglycemia. After
resuscitation of
trauma patients (flow phase), β-cell responsiveness normalizes and plasma
insulin levels are appropriate or even higher than expected, however,
glucose intolerance and
hyperglycemia persist. In the acute care setting, several approaches have been used for treating
insulin resistance, including
insulin infusion,
propranolol and glucagon-like-peptide-1 (GLP-1). Recently, it was demonstrated that a tetrapeptide with
antioxidant properties
D-Arg-Dmt-Lys-Phe-NH2 (SS31), but not its inactive analogue
Phe-D-Arg-Phe-Lys-NH2 (SS20) attenuates
insulin resistance in mice maintained on a high fat diet. In this report the effects of SS31 and SS20 on
burn-induced
insulin resistance was studied in mice. Oral
glucose tolerance tests (OGTT) were performed in 4 groups of 6 mice with thermal injury with or without pre-treatment with SS31 or SS20 and
sham controls. In addition, biodistribution of
18FDG was measured in burned mice with and without SS31 treatment and shams (subsets of these animals were also studied by µPET). For comparison purposes, groups of 6 cold-stressed mice with and without SS31 treatment were also studied. The results of these studies demonstrate that SS31 but not SS20 ameliorated
burn-induced
insulin resistance. In addition, SS31 treatment resulted in marked reduction in the increased
18FDG uptake by brown adipose tissue (BAT) in burned but not cold-stressed animals; suggesting that the stressors act by different mechanisms. Overall, these studies confirmed that SS31 can be used to reverse
burn-induced
insulin resistance and provide a firm pre-clinical basis for future clinical trials of SS31 for the treatment of
insulin resistance in patients with
burn injury.