Glucose kinetics and pyruvate dehydrogenase activity in septic rats treated with dichloroacetate

Decreased pyruvate dehydrogenase (PDH) activity in skeletal muscle has been observed during sepsis and may contribute to the altered glucose kinetics seen in this condition. The purpose of the present study was to determine if dichloroacetate (DCA), a known stimulator of PDH activity, could reverse the sepsis-induced increase in glucose metabolism. Hypermetabolic sepsis was produced in chronically catheterized rats by repeated subcutaneous injections of live Escherichia coli. Whole body glucose kinetics, assessed by a constant iv infusion of [6-3H and U-14C]-glucose, were determined in fasted septic and nonseptic rats before and for 4 hr after an injection of DCA (30 mg/100 g BW, iv). Sepsis produced hyperthermia (+1.6 degrees C) and increased the rates of glucose appearance (Ra; 95%), recycling (318%), metabolic clearance (MCR; 114%), and elevated plasma lactate levels (295%) compared to nonseptic controls. After injection of DCA into septic rats, glucose levels gradually fell, and the sepsis-induced hyperlactacidemia was completely reversed. Treatment of septic rats with DCA reversed the elevated glucose Ra; recycling, although reduced, was still elevated by 50% compared to control animals. DCA did not alter the hyperglucagonemia seen in septic animals, but it did reduce the plasma insulin levels by 60%. Hepatic and muscle PDH activities were not different in saline-treated septic and nonseptic animals. DCA elevated PDH activity in muscle from septic rats, but the increase was smaller than that seen in control animals. This may explain the smaller decline in glucose recycling and plasma lactate in septic animals. These results are consistent with DCA reducing the elevated glucose Ra in sepsis by partial activation of PDH, which reduces the elevated precursor (lactate) supply for gluconeogenesis. However, alterations in PDH activity did not appear to contribute to the underlying increase in glucose Ra and recycling observed in sepsis.