Regulation of Gluconeogenesis and Ketogenesis during Rest and Exercise in Diabetic Subjects and Normal Men

1977 ◽  
Vol 53 (5) ◽  
pp. 411-418 ◽  
Author(s):  
L. Sestoft ◽  
J. Trap-Jensen ◽  
J. Lyngsøe ◽  
J. P. Clausen ◽  
J. J. Holst ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Ketone Bodies ◽  
Venous Blood ◽  
Hepatic Metabolism ◽  
Hepatic Uptake ◽  
Diabetic Group ◽  
Hepatic Venous Blood ◽  
Juvenile Diabetic ◽  
Normal Men

1. The splanchnic—hepatic metabolism of glucose, lactate, pyruvate, alanine, glycerol, non-esterified fatty acids (NEFA), ketone bodies and oxygen were investigated in five normal men and six juvenile diabetic subjects at rest and during exercise after an overnight fast. 2. A linear relationship was found between load (arterial concentration multiplied by hepatic blood flow) and splanchnic—hepatic uptake of lactate, pyruvate, glycerol and NEFA. The uptake of alanine was highly sensitive to load, but was also regulated by the concentration of hepatic venous glucagon. The uptake of pyruvate was high in exercising diabetic subjects, who had a high lactate/pyruvate concentration ratio in hepatic venous blood. 3. The rate of uptake of the total measured gluconeogenic precursors was significantly higher in the diabetic group at a given load. 4. The rate of ketogenesis was linearly related to the NEFA load in both groups; however, the rate of ketogenesis was twofold at a given load in the diabetic group. The highest rates of ketogenesis were found coincident with the highest concentrations of glucagon in hepatic venous blood. 5. The observed antiketogenic effect of exercise was due to a decreased load of NEFA, mainly caused by a decrease in the hepatic blood flow.

Hepatic blood flow: accuracy of estimation from galactose clearances in cats

1986 ◽  
Vol 64 (10) ◽  
pp. 1310-1315 ◽  
Author(s):  
F. J. Burczynski ◽  
C. V. Greenway
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Infusion Rate ◽  
Venous Blood ◽  
The Other ◽  
Reliable Measure ◽  
Blood Samples ◽  
Blood Flows ◽  
Hepatic Venous Blood ◽  
Circuit Technique

Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from clearance data during infusions of galactose in anesthetized cats. Clearance calculations were compared directly with the measured hepatic blood flows using a hepatic venous long-circuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial and mixed hepatic venous blood samples without depletion of the animal's blood volume. It was found that infusions of galactose could not be used to estimate accurately hepatic blood flow. Infusion rate could not be used as an estimate of hepatic or splanchnic uptake owing to substantial and variable extrasplanchnic uptake. As a result, estimated hepatic flows allowing for incomplete extraction overestimated the true flow. On the other hand, extraction was less than 100%. This caused systemic galactose clearance to underestimate hepatic blood flow. These errors could cancel each other giving an apparently good estimate of hepatic flow from systemic galactose clearance. This agreement was fortuitous and occurred only at a specific dose and blood flow. We conclude that in the absence of independent measurements of both extrasplanchnic uptake and splanchnic extraction of galactose, systemic galactose clearance is not a reliable measure of hepatic blood flow in anesthetized cats. Until proved otherwise, it seems likely that this is also true in humans.

Hepatic plasma flow: accuracy of estimation from bolus injections of indocyanine green

1987 ◽  
Vol 252 (5) ◽  
pp. H953-H962 ◽  
Author(s):  
F. J. Burczynski ◽  
K. L. Pushka ◽  
D. S. Sitar ◽  
C. V. Greenway
Keyword(s):  
Blood Flow ◽  
Indocyanine Green ◽  
Hepatic Blood Flow ◽  
Plasma Flow ◽  
Venous Blood ◽  
Hepatic Venous Blood ◽  
Volume Measurements ◽  
Measured Flow ◽  
Icg Clearance ◽  
Extrahepatic Tissues

Experiments were performed to determine the validity of the indocyanine green (ICG) clearance technique, with and without allowances for incomplete hepatic extraction, as an estimate of hepatic plasma flow. This technique was compared with that of directly measured hepatic blood flow using a hepatic venous long-circuit preparation in the anesthetized cat. This preparation allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. Measurements of ICG by spectrophotometry and high-pressure liquid chromatography (HPLC) were equally accurate, but the HPLC was 100 times more sensitive and allowed smaller sample volumes. It was determined that systemic clearance of ICG after a bolus dose (1.3 mumol/kg) was much smaller than hepatic blood flow. Allowance must be made for the incomplete extraction. When the clearance was multiplied by extraction, mean estimated hepatic plasma flow exceeded the measured flow values by 20-30%, and this difference was attributed to temporary extrahepatic distribution. In all experiments estimated hepatic plasma flows were highly variable, and reasons for this are discussed. In hepatectomized cats ICG was found to be distributed into extrahepatic tissues.

Hepatic blood flow: estimation from clearances of very low dose infusions of ethanol in cats

1988 ◽  
Vol 66 (9) ◽  
pp. 1192-1197 ◽  
Author(s):  
C. V. Greenway ◽  
W. W. Lautt ◽  
D. S. Sitar
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Low Dose ◽  
Venous Blood ◽  
Control Level ◽  
Flow Estimation ◽  
Hepatic Venous Blood ◽  
Series Of Experiments ◽  
Flow Changes ◽  
Circuit Technique

Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from systemic clearances of ethanol during very low dose (8 μmol∙min−1∙kg−1) infusions of ethanol in anesthetized cats. Systemic clearances were compared with directly measured hepatic blood flow using a hepatic venous long-circuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. In 18 cats, Vmax for ethanol was 93 ± 7 μmol∙min−1 per 100 g liver or 21 ± 2 μmol∙min−1∙kg·body weight−1 and Km was 144 ± 19 μM in terms of logarithmic mean sinusoidal concentration. At the dose of 8 μmol∙min−1∙kg body weight−1 used for estimation of hepatic blood flow, extraction was 0.95 ± 0.07 (mean ± SD). Systemic clearance of ethanol overestimated directly measured hepatic blood flow by 15 ± 16%. Hepatic blood flow changes expressed as percentages of the control level were accurately estimated from systemic ethanol clearance (100 ± 10%). Since 73 ± 12% of the infused ethanol was eliminated by the liver and 83 ± 11% was eliminated by the splanchnic bed, an extrasplanchnic uptake of 17% accounted for the overestimation of hepatic blood flow. Estimation of hepatic blood flow from systemic clearances of ethanol during very low dose infusions may have advantages over other clearance methods. Its use in cats was illustrated in a separate series of experiments and it was shown that surgery significantly reduced hepatic blood flow. The method may merit trial for estimation of hepatic blood flow in humans.

Review of Cimetidine Drug Interactions

1983 ◽  
Vol 17 (2) ◽  
pp. 110-120 ◽  
Author(s):  
Eugene M. Sorkin ◽  
Diane L. Darvey
Keyword(s):  
Blood Flow ◽  
Drug Interactions ◽  
Hepatic Blood Flow ◽  
Hepatic Clearance ◽  
Hepatic Metabolism ◽  
Rapid Onset ◽  
Related Drug ◽  
Cytochrome P 450 ◽  
Acid Labile ◽  
Hepatic Cytochrome

The literature on cimetidine drug interactions has been thoroughly reviewed. Several different mechanisms have been proposed for cimetidine-related drug interactions. These mechanisms include: (1) impaired hepatic drug metabolism due to inhibition of hepatic microsomal enzymes, (2) reduced hepatic blood flow, resulting in decreased clearance of drugs that are highly extracted by the liver, (3) increased potential for myelosuppression when administered concurrently with other drugs capable of causing myelosuppression, and (4) altered bioavailability of acid-labile drugs. Cimetidine binds reversibly to the hepatic cytochrome P-450 and P-448 systems, resulting in decreased metabolism of drugs that undergo Phase I reactions (e.g., dealkylation and hydroxylation). In contrast, glucuronidation pathways are unaffected. The rapid onset and reversal of cimetidine's inhibition of hepatic metabolism indicates an effect on hepatic enzyme systems. Cimetidine also has been reported to decrease hepatic blood flow. Drugs that are highly extracted by the liver, such as propranolol, lidocaine, and morphine, may be postulated to have a decreased hepatic clearance. Cimetidine, through its effect on gastric pH, may increase the absorption of acid-labile drugs or may decrease the absorption of drugs. There have been reports of increased potential for myelosuppression when cimetidine is administered concurrently with drugs capable of causing bone marrow suppression. An understanding of the mechanisms involved in cimetidine drug interactions allows the clinician to prevent and predict these interactions.

EXTRAHEPATIC METABOLISM OF RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (tPA) IN DOGS

1987 ◽  
Author(s):  
K L L Fong ◽  
K E Boyle ◽  
C S Crysler ◽  
M S Landi ◽  
H E Griffin ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Hepatic Uptake ◽  
Tissue Type ◽  
Systemic Clearance ◽  
Artery Ligation ◽  
Β Phase

Hepatic uptake has been proposed as the major mechanism of tPA clearance from systemic circulation. However, our recent studies demonstrated that tPA was rapidly Inactivated through complexation with protease Inhibitors in dog plasma In vitro, and that tPA-inhibitor complexes were present in plasma of dogs receiving tPA. Therefore, the present work was undertaken to differentiate hepatic from extrahepatlc clearance of tPA. Pharmacokinetics of tPA were determined in anesthetized beagle dogs with either Intact hepatic circulation or with Interrupted hepatic blood flow achieved by hepatic artery ligation and portal caval shunt.Recombinant two-chain tPA was administered as an Intravenous bolus dose (80 μg/kg) and plasma active tPA concentrations were measured using a modified and validated S-2251 chromogenlc assay. Following tPA administration to Intact dogs, plasma active tPA concentration declined blexponentlally with time with 84% of the active tPA eliminated during the α-phase. The t1/2's of the a and β-phase were 1.76 ± 0.74 and 6.23 ± 1.56 min, respectively. The systemic clearance was 25.98 ± 1.13 ml/min/kg and the volume of distribution at steady state (VDss) was 73.9 ± 15.1 ml/kg. Upon the elimination of hepatic blood flow, the systemic clearance was reduced by 54% while VDss was unaffected. The contribution of plasma Inactivation of tPA to the systemic clearance was estimated from in vitro Inactivation studies In 37°C plasma. Based on the pseudo first order Inactivation rate constants of 0.184 min-1 and 0.095 min-1 at Initial tPA concentrations of 25 and 250 IU/ml respectively, clearance rates from 5.02 to 9.2 ml/min/kg were calculated. These data suggest that (1) in Intact dogs, 46% of the tPA clearance occurs extrahepatlcally and (2) Inactivation of tPA in plasma accounts for a major portion of the extrahepatlc clearance.

Derecruitment in cat liver: extension of undistributed parallel tube model to effects of low hepatic blood flow on ethanol uptake

1989 ◽  
Vol 67 (10) ◽  
pp. 1225-1231 ◽  
Author(s):  
C. V. Greenway ◽  
L. Bass
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Venous Pressure ◽  
Liver Blood Flow ◽  
Hepatic Uptake ◽  
Tube Model ◽  
Low Flows ◽  
Wide Range ◽  
Parallel Tube ◽  
Parallel Tube Model

Previous studies showed two deviations from the predictions of the undistributed parallel tube model for hepatic uptake of substrates: a small deviation at high flows and a large deviation at low flows. We have examined whether these deviations could be described by a single correction factor. In cats anesthetized with pentobarbital, a hepatic venous long-circuit technique with an extracorporeal reservoir was used to vary portal flow and hepatic venous pressure, and allow repeated sampling of arterial, portal, and hepatic venous blood without depletion of the cat's blood volume. Hepatic uptake of ethanol was measured over a wide range of blood flows and when intrahepatic pressure was increased at low flows. This uptake could be described by the parallel tube model with a correction for hepatic blood flow: [Formula: see text]. In 22 cats, [Formula: see text], k = 0.021 ± 0.0015 when flow (F) was in millilitres per minute per 100 g liver, and Km = 150 ± 20 μM when ĉ is the log mean sinusoidal concentration. (1 − e−kF) represents the proportion of sinusoids perfused and metabolically active. A dynamic interpretation of this proportion is related to intermittency (derecruitment) of sinusoidal flow. Half the sinusoids were perfused at a flow of 33 mL/(min∙100 g liver) and the liver was essentially completely perfused (> 95%) at the normal flow of 150 mL/(min∙100 g liver). Derecruitment was not changed by raising hepatic venous pressure, and it was not related to hepatic venous resistance.Key words: liver circulation, ethanol metabolism, liver blood flow, sinusoidal perfusion, portal pressure.

scholarly journals Blood flow and nutrient exchange across the liver and gut of the dairy cow

1983 ◽  
Vol 49 (3) ◽  
pp. 481-496 ◽  
Author(s):  
M. A. Lomax ◽  
G. D. Baird
Keyword(s):  
Fatty Acids ◽  
Blood Flow ◽  
Flow Rate ◽  
Ketone Bodies ◽  
Blood Flow Rate ◽  
Hepatic Uptake ◽  
Hepatic Glucose Output ◽  
Lactating Cows ◽  
Hepatic Glucose ◽  
Glucose Output

1. The rate of blood flow in the portal and hepatic veins, and the net exchange across the gut and liver of volatile fatty acids (VFA), glucose, lactate, pyruvate, amino acids, ketone bodies, glycerol, non-esterified fatty acids (NEFA) and oxygen, were measured in lactating and non-lactating cows (a) in the normal, fed state and (b) before, during and after 6 d of fasting.2. Blood flow rate through the liver was 52% higher in normal, fed, lactating cows as compared with non-lactating cows, and was decreased by fasting in both groups of cows. Portal blood flow rate increased with an increase in metabolizable energy (ME) intake.3. Lactating, as compared with non-lactating, cows exhibited lower arterial concentrations of glucose and lactate, higher net portal outputs of VFA and ketone bodies, a higher net hepatic output of glucose, and higher net hepatic uptakes of propionate and lactate. The splanchnic outputs of acetate, glucose and hydroxybutyrate were all apparently greater in the lactating cows.4. Fasting caused a rapid decrease in the blood concentrations of the VFA and an increase in those of glycerol and NEFA. The portal, i.e. gut, outputs of VFA, lactate, ketone bodies, alanine and (serine+threonine), and the portal uptake of O2, were all decreased by fasting. Fasting for 6 h also decreased the hepatic output of glucose and acetate by 77 and 95% respectively, increased the hepatic uptake of pyruvate, glycerol and NEFA, and doubled hepatic ketone-body output. The splanchnic output of acetate and glucose and the splanchnic uptake of O2 were also decreased by fasting.5. The net portal outputs of VFA, lactate and hydroxybutyrate, and the net hepatic output of glucose, were all correlated with ME intake in fed and fasted cows. Hepatic glucose output was also correlated with milk yield.6. The net hepatic uptake of gluconeogenic precursors measured in this study could account for net hepatic glucose output in the fasted cows, but not in the fed cows. The net hepatic uptake of the ketogenic precursors butyrate and NEFA was sufficient to account for the hepatic output of ketone bodies in both fed and fasted cows, but it is unlikely that the hepatic uptake of ketogenic precursors could also account for the observed hepatic output of acetate.

Effects of liver blood flow on hepatic uptake kinetics of galactose in anesthetized cats: parallel tube model

1987 ◽  
Vol 65 (6) ◽  
pp. 1193-1199 ◽  
Author(s):  
C. V. Greenway ◽  
F. J. Burczynski
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Hepatic Blood Flow ◽  
Venous Blood ◽  
Liver Blood Flow ◽  
Control Flow ◽  
Tube Model ◽  
Blood Flows ◽  
Parallel Tube ◽  
Parallel Tube Model

Hepatic galactose uptake in cats anesthetized with pentobarbital was determined during (i) steady-state infusions at several doses, (ii) rapidly increasing infusion rates at different blood flows, and (iii) prolonged infusion of a single dose at different blood flows. The hepatic venous long-circuit technique was used to allow frequent sampling of arterial, portal, and hepatic venous blood without depletion of the animal's blood volume and to allow measurement and alteration of total hepatic blood flow. Uptake was shown to follow Michaelis–Menten kinetics and was consistent with the "parallel tube model." The kinetic parameters Vmax and Kmax could be determined under steady-state and nonsteady-state conditions and were independent of hepatic blood flow over the range 60–150% of control flow. Mean Vmax was 80 μmol/(min∙100 g liver) and mean Km was 215 μM. Vmax declined by 50% when flow was reduced to half normal. It is concluded that the parallel tube model can be used to describe and predict hepatic galactose kinetics in anesthetized cats, although other models may fit the data equally well.

Effects of hepatic blood flow on hepatic ethanel kinetics measured in cats and predicted from the parallel tube model

1989 ◽  
Vol 67 (7) ◽  
pp. 728-733 ◽  
Author(s):  
C. V. Greenway
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Ethanol Concentration ◽  
Hepatic Uptake ◽  
Distributed Model ◽  
Tube Model ◽  
Logarithmic Mean ◽  
Parallel Tube ◽  
Predicted Values ◽  
Parallel Tube Model

In cats anesthetized with pentobarbital, a long-circuit technique was used to measure hepatic blood flow while portal flow was varied from 0 to 300% of normal in random steps. Arterial, portal, and hepatic venous blood samples were analyzed for ethanol concentrations during continuous infusion of ethanol (20 μmol/(min∙kg body weight)) into the reservoir. Measured values for logarithmic mean sinusoidal ethanol concentration, hepatic venous ethanol concentration, hepatic ethanol uptake, and ethanol extraction were compared with the values predicted by the parallel tube model for hepatic uptake of substrates using Vmax and Km determined in each cat at the start of the experiment. Measured and predicted values were very similar at all blood flows above 65% control, but statistical regression analysis indicated a small but highly significant deviation of the measured values from the predicted values. At low flows, measured values of logarithmic mean sinusoidal and hepatic venous concentrations markedly exceeded the predicted values in most cats. The results indicate that the parallel tube model, which assumes all sinusoids are identical and equally perfused, provides a useful approximation for the effects of hepatic blood flow on hepatic ethanol kinetics except at low flows. However, there appears to be a significant degree of sinusoidal heterogeneity that results in a better fit to the distributed model. Our previously reported data for hepatic galactose uptake followed a similar pattern when reanalyzed in this more rigorous way.Key words: liver circulation, ethanol metabolism, sinusoidal heterogeneity, distributed model for hepatic uptake.

Sign in / Sign up

Export Citation Format

Share Document