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 μU/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 < 0.01), endogenous glucose production fell 46 ± 11﹪ (P < 0.01), glucose utilization rose 39 ± 14﹪ (P < 0.05) and glucose clearance increased 40 ± 18﹪ (P < 0.05). Normalization of the alanine and lactate levels during the last 90 min of the latter experiment failed to significantly change glucose production and enhanced gluconeogenic conversion only slightly. Thus, in the conscious 48-h-fasted dog, we conclude that: (1) DCA acts to reduce the insulin/glucagon molar ratio such that the production of hypoglycemia is prevented, (2) when the effect of the compound on the pancreas is prevented, DCA causes hypoglycemia by a reduction in hepatic glucose production and a stimulation of peripheral glucose uptake, and (3) the effect of DCA on glucose production is in part due to reduced gluconeogenic substrate supply, but is principally related to the action of DCA on intrahepatic enzymatic processes.