The net hepatic metabolism of amino glycerol, lactate, and pyruvate was determined in conscious fed sheep by multiplying the venoarterial concentration differences by the hepatic blood or plasma flow. In each experiment several sets of control blood samples were taken; glucagon or insulin then was infused intraportally for 2 h during which additional samples were taken. Four types of experiments were performed: 1) glucagon infusion (150 mug/h) into normal sheep, 2) glucagon infusion (100 mug/h) into insulin-treated alloxanized sheep, 3) insulin infusion (1.17 U/h) into normal sheep, and 4) insulin plus glucose infusion (12.3 mmol/h) into normal sheep. The second group of experiments was performed to prevent reflex hyperinsulinemia, and the fourth was performed to prevent reflex hyperglucagonemia. Glucagon directly stimulated the net hepatic uptake of alanine, glycine, glutamine, arginine, asparagine, threonine, serine, and lactate. Glucagon also stimulated lipolysis in adipose tissue. Insulin, on the other hand, appeared to have a lipogenic effect on adipose tissue and to stimulate directly the uptake of valine, isoleucine, leucine, tyrosine, lysine, and alanine only at extrahepatic sites. The study showed that, in sheep, the effects of glucagon primarily are on liver, and insulin's effects primarily are on skeletal muscle and adipose tissue where it promotes protein and lipid synthesis.
Glucose-glucagon relationships were examined in adult sheep. Hyperglycemia was induced by infusing glucose at 120 mg/hr/kg body weight. Hypoglycemia was obtained by infusing insulin at 1.2 U/hr. In several experiments glucose at 40 mg/hr/kg was infused with insulin to obtain hyperinsulinemia without hypoglycemia to distinguish glucose-insulin effects. Glucagon concentrations decreased during hyperglycemia and increased during hypoglycemia. This study indicates that glucose-glucagon interactions may be important in regulation of glucagon secretion in sheep.
Ketonemia can be a physiological response to a reduction in dietary intake. It also may occur when energy demands exceed the energy intake. Normally, alimentary ketogenesis is the major source of ketone bodies in ruminants. During ketonemia there is increased hepatic ketone body production. During physiological ketosis, the mobilization of free fatty acids is inadequate to support a high rate of hepatic ketogenesis. However, during clinical ketosis, the hormonal status (low insulin, high glucagon/insulin ratio) in combination with hypoglycemia promotes excessive lipid mobilization and a greater hepatic removal of fatty acids and switches the liver to a higher rate of ketogenesis. The low insulin, furthermore, can impair maximal ketone body utilization, thus exacerbating the hyperketonemia.
The hepatic and portal productions of acetoacetate and beta-hydroxybutyrate and lipolysis were studied in normal and insulin-controlled alloxan-diabetic sheep. Since hyperinsulinemia is associated with glucagon administration, the latter group of sheep were used to maintain constant plasma insulin levels. After control values were obtained glucagon was infused intraportally at 90 mug/hr for two hours. The ketone body production by portal drained viscera was not significantly affected by glucagon. In alloxanized sheep, glucagon significantly (P less than 0.01) increased net hepatic production of acetoacetate (from -0.54 +/- 0.08 to 0.46 +/- 0.07 g/hr). Lipolysis also increased. However, in the normal sheep, hyperinsulinemia prevented any stimulatory effect of glucagon on hepatic ketogenesis and lipolysis. Therefore, while glucagon appears capable of stimulating ketogenesis andlipolysis, these effects are readily suppressed by insulin.
The insulin and glucose responses to glucagon infusions (27 microgram/hr) were determined in sheep before and after parenteral lead treatment (6 mg/kg intravenously). Glucose production was measured by primed continuous infusion of [6-3H]glucose. Glucagon and insulin concentrations before and during glucagon infusions were not significantly different between lead treatment and control experiments. Lead administration did not affect the concentration or production of glucose in the preinfusion period. However, depressed hyperglycemia during glucagon infusion in lead treated experiments tended to be associated with decreased glucose production. The reduced glucogenic response to glucagon may be the result of reduced function of pyruvate carboxylase, a key hepatic gluconeogenic enzyme in sheep, from lead induced impairment of mitochondrial function.
The secretion of insulin into the portal blood and its removal by the liver and kidneys in conscious fed sheep were determined by simultaneously measuring venoarterial plasma concentration differences and portal, hepatic, and renal plasma flows. The basal secretory rate of insulin was 0.43 +/- 0.03 U/h or 7.8 mU/kg-h. The secretory rate of insulin and the amount of insulin presented to the liver also were altered by 2-h intraportal infusions of glucagon (150 mug/h), insulin (1.17 U/h), and insulin (1.17 U/h) lus glucose (2.2 g/h). Hepatic removal under all conditions was about 50% of the insulin secretory rate, although the extraction ratio was only 0.08. Renal removal was 35% of the insulin secretory rate. The renal extraction ratio was 0.35. During insulin-induced hypoglycemia and also during starvation, the hepatic extraction ratio of insulin increased significantly, but the removal as a percentage of insulin secretion did not change. It appears that in sheep on a maintenance diet the basal secretory rate of insulin is less than that of nonruminant species and that, within physiological limits, the liver disposes of about one-half and the kidney about one-third of the insulin. Other tissues, presumably, remove the remaining 10--20%.
