A B S T R A C T The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model.The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma.The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization. We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.

A B S T R A C T Analyses of the control of glucose metabolism by insulin have been hampered by changes in blood glucose concentration induced by insulin administration with resultant activation of hypoglycemic counterregulatory mechanisms. To eliminate such mechanisms, we have employed the glucose clamp technique which allows maintenance of fasting blood glucose concentration during and after the administration of insulin. Analyses of six studies performed in young healthy men in the postabsorptive state utilizing the concurrent administration of [1'C] During the glucose clamp experiments plasma insulin levels reached a plateau of 95±8 /U/ml. Over the entire range of insulin levels studied, glucose losses were best correlated with levels of insulin in a slowly equilibrating insulin compartment of a three-compartment insulin model. A proportional control by this compartment on glucose utilization was adequate to satisfy the observed data. Insulin also rapidly decreased the endogenous glucose production to 33% of its basal level (0.58 mg/ kg per min), this suppression being maintained for at least 40 min after exogenous insulin infusion was terminated and after plasma insulin concentrations had returned to basal levels.The change in glucose utilization per unit change in insulin in the slowly equilibrating insulin compartment is proposed as a new measure for insulin sensitivity. This defines insulin effects more precisely than previously used measures, such as plasma glucose/plasma insulin concentration ratios.Glucose clamp studies and the modeling of the coupled kinetics of glucose and insulin offers a new and potentially valuable tool to the study of altered states of carbohydrate metabolism.

A B S T R A C T The aim of the present experiments was to determine the role of insulin and glucagon in the regulation of basal glucose production in dogs fasted overnight. A deficiency of either or both pancreatic hormones was achieved by infusing somatostatin (1 ug/kg per min), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72+6 and 81±8%, respectively. Intraportal infusion of insulin and glucagon at rates of400 ,uU/kg per min and 1 ng/kg per min, respectively, resulted in the maintenance of the basal levels of each hormone. Glucose production was measured using tracer (primed constant infusion of [3-3H]glucose) and arteriovenous difference techniques.Isolated glucagon deficiency resulted in a 35+5% (P < 0.05) rapid and sustained decrease in glucose production which was abolished upon restoration ofthe plasma glucagon level. Isolated insulin deficiency resulted in a 52+16% (P < 0.01) increase in the rate of glucose production which was abolished when the insulin level was restored. Somatostatin had no effect on glucose production when the changes in the pancreatic hormone levels which it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon.In conclusion, in the anesthetized dog fasted overThis work was presented in part at

To investigate whether insulin exerts feedback regulation of its own secretion, paired studies were performed in normal men in two separate protocols. In the first protocol, four men were studied on two occasions. On one occasion, insulin was infused at 5 μU. per kilogram per minute for 120 minutes, achieving arterial insulin levels of 600 to 700 μU./ml. With use of a variable glucose infusion, the plasma glucose concentration was maintained at fasting levels for 60 minutes and then raised abruptly to 165 mg./dl. and was maintained at that level for the remaining 60 minutes. On a second occasion, the study was repeated except that saline was infused instead of insulin. The plasma glucose concentration remained at fasting levels until the last 60 minutes, when it was similarly raised to 165 mg./dl. and maintained at that level until the end of the study. Connecting peptide reactivity (CPR) was measured as an index of endogenous insulin secretion in the presence of exogenous insulin. During the initial 60 minutes of the study, with euglycemia maintained, there was a significant (46 per cent) decline (p &lt; 0.01) in the levels of CPR in the insulin-treated subjects. At 60 minutes, when hyperglycemia was induced, CPR rose in both groups. The rise of CPR in the insulin-treated group, however, was significantlyless (p &lt; 0.01) than in the saline control group. To investigate whether insulin inhibition of insulin secretion during hyperglycemia would occur without prolonged insulin pretreatment, paired studies were performed in three additional men. In this protocol, insulin (5 mU. per kilogram per minute) or saline was infused for 70 minutes. Euglycemia was maintained for just 10 minutes. Thereafter, the plasma glucose concentration was. raised to 170 mg./dl. in both groups. This acute induction of hyperglycemia without prolonged insulin pretreatment resulted in similar increases in CPR in both insulin- and saline-treated groups. From these data we conclude that (1) exogenous insulin administration, with maintenance of euglycemia, results in significant inhibition of basal insulin secretion; (2) the administration of exogenous insulin for 60 minutes before and for 60 minutes after the acute induction of hyperglycemia results in significant inhibition of glucose-stimulated insulin secretion; and (3) exogenous insulin administered for just 10 minutes before and during the acute induction of hyperglycemia, however, does not result in inhibition of the insulin response to the hyperglycemic stimulus.