Targeting Warburg Effect to Reverse Stress-Induced Insulin Resistance in Burns

Massachusetts General Hospital, Boston MA

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Abstract

Metabolic derangements are a major complication of burn injury and adversely affect the clinical outcome of burn patients. Severe metabolic derangement (aka burn cachexia) is recognized by concomitant hyperlactatemia, hypermetabolism, insulin resistance, and muscle wasting. For years, the predominant assumption has been that insulin resistance drives the development of these metabolic derangements, although the underlying mechanism has never been identified. The currently prescribed insulin-sensitizers (i.e., metformin, thiazolidinediones) produce adverse side effects (e.g., lactic acidosis, edema) in burn patients and therefore new insulin-sensitizers have been awaited. Despite decades of research, however, no new treatments that target stress-induced insulin resistance have emerged. Hence, new strategies need to be developed. A recent study points to 'protein farnesylation' as a promising new target, but further study is required to clarify the underlying molecular mechanism(s). The study showed that burn increases protein farnesylation and that farnesyltransfrase (FTase) inhibitor (FTI) reverses burn-induced muscle insulin resistance. The explanation for this new concept of burn insulin resistance is the Warburg effect (aka cytopathic hypoxia). The Warburg effect was originally described as the metabolic reprogramming of cancer cells in favor of glycolytic ATP synthesis as opposed to mitochondrial oxidative phosphorylation, even under normoxia. Recently, the Warburg effect has been linked to the inflammatory response, and it has been widely observed in various inflammatory diseases, including critical illness. Preliminary studies showed that burn causes the Warburg effect in mouse muscle as indicated by the induction of hypoxia-inducible factor-1? (HIF-1?) and pyruvate kinase isoform M2 (PKM2) and by increased aerobic glycolysis under normoxia, all of which can be reversed by FTI. The data in cultured muscle cells also indicated that: (1) HIF-1? expression is sufficient and required for cytokine-induced insulin resistance; and (2) farnesylation of LKB1 (a master kinase in the regulation of metabolism) mediates cytokine-induced HIF-1? expression. Based on these recent studies and preliminary data it is hypothesized that the Warburg effect causes and/or exacerbates insulin resistance in skeletal muscle, which challenges the existing paradigm. Aim 1 will test the hypothesis that the burn-induced Warburg effect causes and/or exacerbates insulin resistance in mice. Aim 2 will determine whether inhibition of farnesylation by FTI prevents the Warburg effect and insulin resistance after burn. Aim 3 will test the hypothesis that farnesylation of LKB1 mediates the burn-induced Warburg effect and muscle insulin resistance in mice. This project is designed to determine whether the Warburg effect is an appropriate target for reversing burn-induced insulin resistance and metabolic disturbance. This research is expected to provide the scientific basis for a clinical trial of tipifarnib, clinically applicable FTI, in burn patients.