A B ST R A CT The effect of equal (1.1±0.1 g/kg body wt) amounts of glucose administered orally, or by peripheral intravenous or intraportal infusion on hepatic glucose uptake and fractional hepatic extraction of insulin and glucagon was studied in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery and catheters in the portal vein, hepatic vein, carotid artery, and superior mesenteric vein. Portal vein and hepatic vein plasma flow increased only after oral glucose administration. Arterial plasma glucose increased equally to 150-160 mg/100 ml after all three routes of glucose administration. Portal vein glucose was similar after oral (195±15 mg/100 ml) and intraportal glucose infusion (215±11 mg/100 ml) and significantly higher than after peripheral intravenous glucose. Hepatic glucose uptake after oral (68±4%) and intraportal glucose administration (65±7%) significantly exceeded that after peripheral intravenous glucose infusion (23±5%). The amount of insulin above basal presented to the liver during the 180 min after oral glucose was 7.6±1.3 U, 4.3±0.6 U after intraportal glucose, and 4.1±0.6 U after peripheral intravenous glucose. Hepatic extraction of insulin increased significantly after oral glucose (42±3 to 61±4%), but was unchanged after intraportal and peripheral intravenous glucose administration. When the portal vein glucose levels achieved during peripheral intravenous glucose infusion for 90 min were maintained by a subsequent 90-min intraportal glucose infusion, hepatic glucose uptake was significantly greater during the intraportal glucose infusion.Received for publication 7 December 1982 and in revised form 3 March 1983.Glucagon secretion was suppressed equally after oral glucose, intraportal glucose, and peripheral intravenous glucose administration; fractional hepatic extraction of that hormone, which was significantly less than that of insulin, was unchanged.These results indicate that hepatic glucose uptake is significantly greater after oral and intraportal glucose administration than after peripheral intravenous glucose infusion. This difference is not simply related to the amount of glucose or insulin presented to the liver and the increased hepatic glucose uptake did not depend solely upon the augmented fractional hepatic extraction of insulin. Hepatic extraction of insulin and hepatic glucose uptake appear to be regulated independently. INTRODUCTIONThe liver is important in glucose homeostasis. Splanchnic removal of glucose was greater after oral glucose compared with peripheral intravenous administration of glucose (1-6), but the mechanism of this effect is not clearly understood. DeFronzo et al. (5,6) implicated gut factors released after ingestion of glucose but Bergman et al. (7) reported similar hepatic uptake of glucose after intraportal glucose infusion and oral glucose administration. Abumrad et al. (8) also excluded a significant role for gut factors and concluded that both hyperglycemia and hyperinsulinemia were major factors in m...

First-pass hepatic extraction of insulin and hepatic and peripheral contributions to hypoglycemia were compared in conscious dogs during portal infusion of insulin A1, B29 diacetyl insulin, or A1-B29 dodecoyl insulin at 7 and 14 pmol X kg-1 X min-1. The liver removed 43 +/- 2% of insulin, 12 +/- 1% of dodecoyl, and 8 +/- 1% of diacetyl insulin, in a single transhepatic circulation. The hypoglycemia induced by insulin and diacetyl insulin and the ensuing glucagon response were greater than that produced by the dodecoyl analogue. Diacetyl insulin primarily increased glucose utilization, dodecoyl insulin solely inhibited hepatic production, and insulin affected both. The lack of hepatic effect of diacetyl insulin during hypoglycemia can be ascribed to greater counterregulation, because under euglycemic clamp conditions, this analogue caused suppression of glucose production. The different patterns of hypoglycemia exhibited can be explained by the combined effects of altered distribution between the liver and peripheral tissues caused by differences in hepatic extraction, the effect of this phenomenon on the counterregulatory response, and the intrinsic biological potency of the analogues.

Previous studies comparing the effects of oral, intraportal, and peripheral venous administration of glucose in conscious dogs demonstrated a significant increase in hepatic extraction of insulin only after oral glucose, but similar hepatic uptake of glucose after oral and intraportal glucose, which was greater than that after peripheral intravenous glucose infusion. This study evaluated the effect of atropine blockade of the parasympathetic nervous system on the increased fractional hepatic extraction of insulin and the role of gastric inhibitory polypeptide (GIP) on augmented hepatic uptake of oral glucose in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery, and catheters in the portal and hepatic veins and carotid artery. Since atropine infusion decreased absorption of glucose, and in order to achieve comparable portal vein levels of glucose and insulin, the dogs receiving atropine were given 1.9±0.1 g/kg glucose, compared with the control dogs who received 1.1±0.1 g/kg. The percentage of the glucose load that was absorbed was greater in the dogs not given atropine (80±4 vs. 44±7%), but because of the different loads, the absolute amount of glucose absorbed was similar in both groups (20.2±1.6 vs. 21.7±4.1 g). Although delayed by atropine, the peak portal vein glucose and insulin concentrations and the amounts presented to the liver were similar in both groups. However, the increased portal vein plasma flow and fractional hepatic extraction of insulin observed after oral glucose was not observed in the dogs infused with atropine. The net hepatic glucose uptake after oral glucose was significantly less at 10, 20, and 45 min in the atropine-treated dogs, and the area under the curve over the 180-min period was 44% less. However, the latter was not statistically significant. Infusion of GIP with peripheral intravenous glucose did not increase hepatic uptake ofglucose or the fractional hepatic extraction of insulin compared with peripheral intravenous glucose alone. These results indicate an important role for parasympathetic innervation in the augmented fractional hepatic extraction of insulin, and increased portal vein plasma flow after oral glucose. Although a relationship between the augmented fractional extraction of insulin and the net hepatic glucose uptake may exist, it does not necessarily indicate that the former is required for the latter. Such parasympathetic innervation may Dr. Ishida's current address is First

The effect of thyroid hormone excess on hepatic glucose balances and fractional hepatic extraction of insulin and glucagon was examined in six conscious dogs with catheters in the portal vein, hepatic vein, and femoral artery and Doppler flow probes on the portal vein and hepatic artery. An oral glucose tolerance test was performed before and after the animals were made hyperthyroid by intramuscular thyroxine administration (100 micrograms.kg-1.day-1) for 10 days. In the basal state and after oral glucose, insulin and glucagon levels in the three vessels and the basal fractional hepatic extraction of insulin and glucagon were not significantly modified by thyroid hormone. These results suggest that in short-term thyrotoxicosis insulin secretion is not impaired, and the rise in fasting plasma glucose and increased hepatic glucose production could reflect hepatic insulin resistance, increased availability of precursors for gluconeogenesis, or increased glycogenolysis. Hyperthyroidism significantly increased basal flows in the portal vein (14.7 +/- 0.6 vs. 12.9 +/- 0.5 ml.kg-1.min-1), the hepatic artery (4.8 +/- 0.3 vs. 3.9 +/- 0.2 ml.kg-1.min-1) and vein (19.6 +/- 0.7 vs. 16.9 +/- 0.4 ml.kg-1.min-1), the fasting plasma glucose concentration (104 +/- 3 vs. 92 +/- 2 mg/dl), and basal hepatic glucose output (2.1 +/- 0.2 vs. 1.5 +/- 0.2 mg.kg-1.min-1). It did not alter the nonhepatic splanchnic uptake of glucose, the percent of orally administered glucose that appeared in the portal vein (47 +/- 2 vs. 45 +/- 11%), the percent of hepatic uptake of glucose (59 +/- 11 vs. 74 +/- 22%), or the shape of the glucose tolerance test.

Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27±4 uU/ml to a maximum of 84±22 ,U, ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132±25 pg/ml to 251±39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCO acidosis. Evaluation of the arteriovenous potassium difference across the hindleg during ketoacid infusion demonstrates that peripheral uptake of potassium is unlikely to be responsible for the observed hypokalemia. Although the tissue responsible for the different kalemic responses could not be defined with certainty, the data are compatible with an hepatic role in response to alterations in the portal vein insulin and/or glucagon levels in both acid infusion studies. We propose that cellular uptake of potassium is enhanced by hyperinsulinemia Correspondence and reprint requests should be addressed to Dr.

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ABSTRACT. --Continuous exposure of male rats to an elevated environmental temperature (33-35 ° C) for 3 weeks led to heat-acclimatized (HA) rats whose serum testosterone concentratrion was significantly lower (P < 0.01) than that of control (C) rats (20-22 ° C). The decrease in the androgen level was independent of major changes in serum FSH and LH concentrations, as well as hypothalamic content of thyrotropinreleasing hormone (TH R), gonadotropin-releasing hormone (GnRH) and prostaglandin E 2 (PGE2). However, the prostaglandin F2~(PGF2~) content of the hypothalamus of HA rats was significantly lower (P < 0.05) than that of C. The number of receptors for human chorionic gonadotropin (hCG) was significantly lower in testicular tissue of HA rats as compared to C males. Histological examination of t he testis disclosed t hat exposure to heat adversely affected the sperm production and integrity of the Sertoli cells. Activity of enzymes associated with testosterone biosynthesis in testicular tissue of rats incubated at temperatures similar to those prevailing in the scrotum of HA rats resembled the activity of these enzymes observed in HA animals. Catabolism of testosterone was enhanced when kidney and liver of C rats were incubated at temperatures similar to the deep-body temperatures of HA rats, supporting the thesis that acclimatization to heat is coupled, interalia, with increased androgen catabolism and excretion. It is suggested that the lower reproductive performance of H A rats is associated wit.h several phenomena: a low number of receptors for hCG in the testes, decreased testosterone production rate by the Leydig cells, increased catabolism and excretion of androgen, and partial atrophy of seminiferous tubules and Sertoli cells. These changes appear to be independent of either alteration in serum gonadotropin concentration or hypothalamic contents ofTRH, GnR H and PGE2. The physiological significance in the response of PGF:~ awaits further clarification.

The relation between portal vein insulin concentrations and suppression of hepatic glucose production, as well as peripheral venous insulin level and increase of peripheral glucose utilization, was compared in conscious, depancreatized, diabetic dogs after infusion of insulin at 0.25 and 0.5 mU/kg/min into either the portal system or the peripheral circulation. Glucose appearance and clearance was measured using [3-3H]-glucose. Before infusion of insulin, portal vein insulin concentrations were undetectable. The intraportal infusion of insulin at 0.25 mU/kg/min increased portal vein insulin to 16 +/- 1 microU/ml, significantly higher than the arterial concentration (9 +/- 1 microU/ml). Infusion of the same amount of insulin into a peripheral vein raised peripheral insulin levels to 14 +/- 1 microU/ml and portal vein concentrations to 12 +/- 1 microU/ml. When 0.5 mU/kg/min of insulin was infused into the portal system, the portal vein insulin level was 28 +/- 2 microU/ml and significantly greater than the arterial concentration (16 +/- 1 microU/ml). After the same amount of insulin was infused into a peripheral vein, the arterial insulin level was higher than that of the portal vein (25 +/- 1 microU/ml versus 20 +/- 1 microU/ml, respectively). The ensuing hypoglycemia was greater after the 0.5 mU/kg/min infusion compared with the 0.25 mU/kg/min infusion. At each dose there was no significant difference between the peripheral venous or the portal route.(ABSTRACT TRUNCATED AT 250 WORDS)