Contribution of the Liver and Extrasplanchnic Tissues to the Hypoglycemic Action of Dichloroacetate in the Conscious Dog

In a previous study, administration of sodium dichloroacetate (DCA) to 48-h fasted dogs had no effect on glucose production (Ra), utilization (Rd), or clearance, possibly because the direct effects of DCA were offset by the consequences of the fall in plasma insulin that it caused. To examine this possibility, dichloroacetate was infused (0.4 mg/kg min) for 5 h into 48-h fasted conscious dogs whose insulin and glucagon levels were “clamped” at basal values using a technique that involved the peripheral infusion of somatostatin to inhibit the endocrine pancreas and intraportal replacement of insulin (273 μ U/kg·min) and glucagon (1 ng/kg·min). Metabolite balances across the liver were measured using an A-V difference technique, glucose turnover was determined using a tracer technique, and gluconeogenesis was assessed by measuring the conversion of alanine and lactate into glucose. In the presence of fixed concentrations of insulin (14 μU/ml) and glucagon (162 pg/ml), DCA caused the conversion of alanine and lactate to glucose to fall by 73 ± 10﹪ (P < 0.01), glucose production to fall by 19 ± 9﹪ (NS), glucose utilization to fall by 17 ± 8﹪ (NS), glucose clearance to increase by 55 ± 16﹪ (P < 0.05), and the plasma glucose level to fall from 107 ± 10 to 56 ± 6 mg/dl (P < 0.001) after 300 minutes. Thus, with the plasma insulin level fixed, DCA induced hypoglycemia through an effect on both glucose production and clearance. Since the effects of DCA in the above experiment were undoubtedly attenuated by the hypoglycemia that occurred, the experiment was repeated with the exception that glucose was infused to maintain euglycemia (113 ± 11 mg/dl). In this case, the conversion of alanine and lactate to glucose fell by 76 ± 1﹪ (P