There is at present general agreement, based upon abundant in vitro and in tvvo experimental evidence, that insulin exerts an immediate and profound effect on glucose utilization by muscle and adipose tissue (1-5). On the other hand, a direct hepatic action of insulin is disclaimed by most investigators since innumerable studies both in vitro and in vivo have failed to demonstrate clearly a consistent and reproducible effect of insulin upon hepatic glucose metabolism (5-12).Recent observations from this laboratory suggested that the site (13) and the rate (14) of insulin administration are important factors in eliciting a hepatic effect. However, in these as in all previous in vivo studies (11,(15)(16)(17)(18)(19), the conclusions regarding the hepatic action of insulin were inferential, since the net balance of glucose across the liver was not ascertained by direct measurement.Any experiments designed to elucidate the effect of insulin on hepatic carbohydrate metabolism should fulfill the following prerequisites:1. Hepatic, in contrast to splanchnic, glucose metabolism should be measured. In view of the marked sensitivity of the extrahepatic splanchnic tissues to insulin (1-5, 11, 12), separation of the effects of insulin on these tissues from its effects on the liver is mandatory. This, in turn, re-* This work was supported in part by a grant from the Upjohn Company and in part by the Dallas Heart Association. (23,24), and glucagon (25, 26), may obscure a hepatic effect of insulin by the marked increase in hepatic glucose release which characterizes the action of these counterregulatory hormones (27)(28)(29)(30).The present experiments were designed to meet these prerequisites in the following manner. First, dogs with complete end-to-side portacaval shunts were studied. This operation completely separates the liver from the remainder of the splanchnic tissues and thereby permits the measurement of hepatic rather than splanchnic glucose metabolism. Second, measures were taken to minimize or prevent the counter-regulatory mechanisms to hypoglycemia. In one group of experiments, insulin was administered by slow infusion which produced a very gradual modest decline in arterial glucose concentration. In another group, the hypoglycemic stimulus was further reduced in magnitude and duration by administering glucose after insulin infusion had been started. Finally hypoglycemia was prevented by using diabetic dogs with fasting hyperglycemia. 507

During the past few years, we have been impressed by the observation that our patients with pre-eclampsia and eclampsia usually demonstrate sulfobromophthalein sodium (BSP) retention in blood in the 45-minute BSP test. On the basis of these findings, we undertook a study of hepatic BSP-removal mechanisms during the course of normal pregnancy. Increased BSP retention in 45 minutes was not detected in normal pregnancy when compared to results obtained in a group of nonpregnant women of comparable age. When hepatic BSP-removal mechanisms were appraised quantitatively by a prolonged-infusion method (1, 2), however, significant changes in both hepatic uptake and excretion of BSP were observed. The following study presents in detail such data obtained from women in various stages of normal pregnancy and in the early postpartum period, and compares these findings with data obtained in a separate group of control nonpregnant women. METHODSThe method used in the present studies was devised by Wheeler and his associates (1,2) and is based on the observations that removal of BSP from plasma depends on the simultaneous operation of at least two separate hepatic mechanisms: 1) uptake of BSP into a hepatic * This work was supported by research grants from the U. S. Public Health Service (H-3439, A-6082), and frcm Parke, Davis & Co. Part of this work has appeared in abstract form (Clin. Res. 1962, 10, 189; 1963, 11, 58) and was presented at the Annual Meeting of the American Association for the Study of Liver Diseases, Chicago, Ill., November, 1962, and "storage compartment," and 2) active secretion into bile (1-8). The quantity of BSP taken up into the "storage compartment" appears to be directly proportional to plasma concentration (1). Thus, uptake into storage during a period of changing plasma concentration can be represented in symbols as S X AP/At, where the "relative storage capacity" S, a proportional factor, is defined as the number of milligrams of BSP stored in the liver per milligram per 100 ml of plasma concentration, and AP/At signifies the rate of change of plasma concentration in milligrams per 100 ml per minute. Secretion of BSP into bile is a rate-limited process characterized by a maximal excretory rate or Tm (1, 2, 8), defined in terms of milligrams per minute. The maximal rate of BSP secretion into bile is achieved when plasma BSP concentration is maintained in excess of 2 to 3 mg per 100 ml during prolonged infusions of BSP (1, 8). At these plasma concentrations, the general equation for the hepatic removal rate of BSP (1), RH, in milligrams per minute, is as follows: RH = S X (AP/At) + Tm.Values for RH and AP/At obtained during two or more different rates of BSP infusion are substituted in the formula, providing a set of simultaneous equations that can be solved for both S and Tm. In practice, values for RH and AP/At were obtained during three separate infusion rates of BSP, each given for an hour. As indicated by Wheeler, when the corresponding values for RH and AP/At are plotted on the ordinate an...

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Recent studies from this laboratory (1) have shown that insulin has an immediate and profound effect upon net hepatic glucose balance. When insulin was administered at a rate (2) estimated to minimize the counter-regulatory responses to hypoglycemia, the decline in blood glucose which ensued was largely the consequence of a diminished hepatic release of glucose (1).Since, under physiologic circumstances, endogenous insulin secretion is stimulated by the rising blood glucose concentration (3, 4) which follows a carbohydrate meal, the effect of insulin in regulating hepatic glucose metabolism is best assessed in the presence of a glucose load. Whether or not hyperglycemia, with its attendant release of endogenous insulin, results in a decrease or cessation of hepatic glucose output has been a controversial subject (5-13). However, in all but one of the previous studies (5), the conclusions were based upon inferential data, since net hepatic glucose balance was not measured.The present studies were undertaken to determine the effect of hyperglycemia and the concomitant release of endogenous insulin upon hepatic glucose metabolism. Hyperglycemia was produced by the intravenous infusion of glucose. The rate of glucose administration was varied in order to define better some of the factors that con-

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