Abstract
BackgroundThis study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock.MethodsImmediately and 6 h after cecal ligation and puncture (CLP), mice randomly received either vehicle or the anti-diabetic drug EMD008 (100 μg · g-1). At 15 h post CLP, mice were anesthetized, mechanically ventilated, instrumented and rendered normo- or hyperglycemic (target glycemia 100 ± 20 and 180 ± 50 mg · dL-1, respectively) by infusing stable, non-radioactive isotope-labeled 13C6-glucose. Target hemodynamics was achieved by colloid fluid resuscitation and continuous i.v. noradrenaline, and mechanical ventilation was titrated according to blood gases and pulmonary compliance measurements. Gluconeogenesis and glucose oxidation were derived from blood and expiratory glucose and 13CO2 isotope enrichments, respectively; mathematical modeling allowed analyzing isotope data for glucose uptake as a function of glycemia. Postmortem liver tissue was analyzed for HO-1, AMPK, caspase-3, and Bax (western blotting) expression as well as for mitochondrial respiratory activity (high-resolution respirometry).ResultsHyperglycemia lowered mitochondrial respiratory capacity; EMD008 treatment was associated with increased mitochondrial respiration. Hyperglycemia decreased AMPK phosphorylation, and EMD008 attenuated both this effect as well as the expression of activated caspase-3 and Bax. During hyperglycemia EMD008 increased HO-1 expression. During hyperglycemia, maximal mitochondrial oxidative phosphorylation rate was directly related to HO-1 expression, while it was unrelated to AMPK activation. According to the mathematical modeling, EMD008 increased the slope of glucose uptake plotted as a function of glycemia.ConclusionsDuring resuscitated, polymicrobial, murine septic shock, glycemic control either by reducing glucose infusion rates or EMD008 improved glucose uptake and thereby liver tissue mitochondrial respiratory activity. EMD008 effects were more pronounced during hyperglycemia and coincided with attenuated markers of apoptosis. The effects of glucose control were at least in part due to the up-regulation of HO-1 and activation of AMPK.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-2-19) contains supplementary material, which is available to authorized users.
Highlights
This study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock
Since we recently demonstrated acute kidney injury during murine septic shock [27], we tested the hypothesis whether lowering glycemia using EMD008 would allow improving mitochondrial function and thereby attenuate apoptotic cell death
Blood glucose levels were higher in the hyperglycemia groups, which coincided with more pronounced hyperlactatemia
Summary
This study aims to test the hypothesis whether lowering glycemia improves mitochondrial function and thereby attenuates apoptotic cell death during resuscitated murine septic shock. A first line-defense drug for the treatment of type 2 diabetes may theoretically circumvent the undesired side effects of insulin [13] Metformin attenuated both the LPS-induced hyper-inflammatory response after partial hepatectomy [14] and oxidative stress due to mild inhibition of the mitochondrial complex I [15], decreases hepatic gluconeogenesis [16], and improves whole-body glucose oxidation during hyperglycemia [17]. Metformin stabilizes mitochondrial functioning by reducing the transition pore opening, which protects against ischemia- [18], oxidant[19,20], or hyperglycemia-induced [21] cell death It stimulates mitochondrial biogenesis via PG1α signaling [22], which in turn coincided with survival in patients with sepsis [23]. Hyperdynamic hemodynamics resulting from fluid resuscitation and continuous i.v. noradrenaline was investigated in order to exclude any systemic hemodynamic effect on metabolism: the above-mentioned data originate from long-term experiments in awake, spontaneous breathing animals presenting with lower-organ O2 supply than in healthy control animals [7,8]
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