The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6,9,16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 μU/ml., respectively. Since the portal vein insulin concentration in the intact rat averaged 48 μU/ml. after a twenty-six-hour fast and 125 μU/ml. two hours after removal of food, the studies were conducted at insulin levels within the physiological range. The effect of each insulin concentration on the net accumulation of K+, amino acid nitrogen, urea nitrogen and glucose in the perfusing medium was assessed against the net accumulation of perfusate constituents during perfusion of control livers and livers perfused with perfusate insulin levels greater than 500 μU/ml. The results indicate that essentially maximal suppression of amino acid nitrogen outflow and retention of K+ occurred at insulin concentrations of 72 μU/ml., with lesser effects being noted at 41 μU/ml. Inhibition of ureogenesis was demonstrated at insulin levels above 120 μU/ml. However, significant effects of insulin on suppressing net glucose outflow was not observed until insulin levels had reached 500 μU/ml. due presumably to the absence of a sustained rate of glycogenolysis by control livers. The observation that perfused livers from normal rats are extremely sensitive to several metabolic effects of insulin at physiological concentrations suggests that this experimental approach can provide useful information as to the role of the liver in the pathogenesis of various insulin resistant states.

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