Origin of glucose released in the regulatory response against hypoglycemia

When the rate of removal of glucose from the plasma is increased by the infusion of 50 μg/kg. min phlorizin (PHL) the rate of hepatic glucose release (Ra) increases, so that the concentration of glucose in plasma falls only marginally. The response is mediated by glucagon. The purpose of the experiments was to establish to what extent glycogenolysis and gluconeogenesis contribute to the increment in Ra mediated by glucagon which is released in response to a physiological stimulus: the increased rate of removal of glucose from the plasma. Two series of experiments were carried out on non-anaesthetized trained dogs. In the first, to dogs in the post-absorptive (p.a.) state ³H-3-glucose and ¹⁴C-U-alanine were infused in trace amounts. The Ra and the clearance of glucose from the plasma (CR) were calculated together with the irreversible rate of removal (Ri) of alanine and the rate of glucose formation from plasma alanine before, during and after the infusion of PHL. When Ra(glucose) was increased during the infusion of PHL, so was the synthesis of glucose from alanine. This was achieved by an increase in the fraction of utilized alanine which was converted to glucose, since Ri(alanine) remained unchanged. The experiment was repeated after 4 day fasting when the rate of gluconeogenesis was twice that in the p.a. state; the Ra(glucose) still increased during the infusion of PHL, but to a lesser degree and somewhat more slowly than in the p.a. state. The concentration of glucose in plasma fell by about 30 mg/dl. The Ri(alanine) was not changed. In the second series hepatic glycogen stores were pre-labelled with ³H-6-glucose three days before the experiment in which ¹⁴C-1-glucose was infused as the tracer. The appearance of ³H-atoms in plasma glucose was taken as a measure of glycogenolysis. During the infusion of PHL the rate of glucogenolysis was doubled. Conclusion: Glucagon released in response to an increased removal of glucose from plasma increases the rate of glucose production by stimulating both gluconeogenesis from alanine and breakdown of hepatic glycogen. In fasted dogs in which the basal rate of gluconeogenesis was twice as high than in the p.a. state, PHL infusion caused a further increase. The increase was achieved by a larger fraction of utilized alanine being converted to plasma glucose.