One hundred and thirty brief infusions of unlabeled insulin were given to 75 unanesthetized nondiabetic human beings. The patients were examined (1) by different doses of insulin (5−50 mU/kg), (2) by intraportal and peripheral infusion, (3) in the morning and in the afternoon, and (4) during normoglycemia and moderate, steady hyperglycemia. After intraportal infusion of insulin, the non-steady state plasma clearance rate (ml min−1 kg−1) was lowerthe largerthe dose (decreased about 50% by a 10-fold increase in insulin dose) and lower at hyper- than at normoglycemia (decreased about 30% after small insulin doses). It was also lower the higher the relative body weight, but this correlation was weak. After peripheral insulin infusion, none of the above relationships was demonstrated. Regardless of the route of insulin infusion, plasma clearance rate did not vary with fasting plasma insulin concentration, time of day, insulin sensitivity, or glucose tolerance. We conclude that the liver modifies the distribution and removal of pancreatically released insulin in response to acute increases in insulin or glucose. Otherwise the plasma clearance rate of insulin showed a notable lack of relationships with common indexes of metabolism and with insulin action.

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