Influence of thyroid state on the effects of glycerol on gluconeogenesis and energy metabolism in perfused rat liver.
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Biomedical subjects
Publications and source records attributed to L Sestoft.
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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. 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. The rate of uptake of the total measured gluconeogenic precursors was significantly higher in the diabetic group at a given load. 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. The observed antiketogenic effect of exercise was due to a decreased load of NEFA, mainly caused by a decrease in the hepatic blood flow.
Biopsies from skin of normal appearance from 18 patients treated with carbamazepine and diphenylhydantoin were investigated by a direct immunofluorescence technique. Seventeen had deposits of plasma proteins at the dermoepidermal junction, 16 had deposits in the vessel walls, and one had autofluorescence of the nuclei in the epidermis and vessel walls. These findings did not correlate with changes in serum IgG, IgA, IgM, IgD, IgE or alpha 2-macroglobulin. Eight patients had elevated alkaline phosphatase, 4 elevated IgG and one elevated IgA. Three had low values of IgA, and all had normal values of IgM, IgD and IgE, and blood cells. In three patients, carbamazepine was withdrawn, whereupon the deposits disappeared in two and decreased in the third, who changed to another drug. The changes were quantitatively and qualitatively similar to those seen in systemic lupud erythematosus induced by these drugs.
1 In a single-blind, cross-over study fenfluramine in a daily dose of 120 mg was found to reduce the daily blood glucose level moderately in hospitalized obese diabetics treated with a 1200 calorie diabetic diet. 2 After 7 days of treatment, fenfluramine was found not to influence the intravenous glucose tolerance, the insulin response to intravenously administered glucose, or the growth hormone response to arginine. 3 No changes in blood levels of lactate, beta hydroxybutyrate, triglycerides or cholesterol were seen during fenfluramine treatment.
1. The effects of ouabain on hepatic oxygen uptake, cell membrane potential, and Na-K transport were examined at 37 degrees C during non-recirculating perfusion of isolated livers from fasted normal rats and rats treated with triiodothyronine (T3). The perfusate was Krebs-Ringer bicarbonate buffer containing albumin and bovine erythrocytes. 2. Treatment with T3 increased the rate of hepatic oxygen uptake by 30% (i.e. by 0-83 (micromole/min) per gram liver). 3. After shifting to perfusate containing 2-5 mM ouabain, a 4-5 mV depolarization and maximal rates of net hepatic K release and Na uptake occurred within 2 min in both thyroid states. These changes were not accompanied by any significant change in the rates of hepatic oxygen uptake. 4. T3-treatment increased the maximal, post-ouabain net flux of K by 29% (i.e. by 0-52 (muequiv/min) per gram liver). The T3-indlced increase in the net flux of Na (19%) did not achieve statistical significance. 5. In either thyroid state, the observed passive fluxes of Na and K were calculated to be balanced by active vluxes at the expense of 5-6% of the observed rate of hepatic oxygen uptake. 6. The results indicate that hyperthyroidism may enhance the rate of hepatic Na-K transport, but the energy expenditure due to this process appears to be too small to make any important contribution to thyroid calorigenesis in perfused rat liver.
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The kinetics of glycerol uptake by the perfused rat liver were determined according to a model which includes membrane transport, intracellular phosphorylation and competitive inhibition of glycerol phosphorylation by L-glycerol 3-phosphate. The membrane transport obeys first-order kinetics at concentrations below 10 mM in the affluent medium. The K-m of the glycerol phosphorylation was 10 muM and the K-i of the L-glycerol 3-phosphate inhibition was 50 muM. The maximum activity (V) was 3.70 mumoles/min per g liver wet wt. These results are similar to in vitro kinetics of the glycerol kinase, except that K-i was found to be somewhat lower in the intact organ. At low glycerol concentrations, a steep concentration gradient exists across the liver cell membrane. The increase in the lactate to pyruvate concentration ratio during glycerol metabolism is related to the actual concentration of L-glycerol 3-phosphate, not to the rate of glycerol uptake.
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The uptake of acetate in the human forearm was studied in five fasting (14 h) subjects during 10-min periods of ergometer work at 7 and 10 kilopond-meters per minute (kpm/min). A constant arterial acetate concentration was established by administration of a small quantity of alcohol (25 g) to the subjects after a control work period. Blood flow was measured by an indicator dilution technique. Acetate uptake varied linearly with the product of arterial acetate concentration and blood flow. Acetate metabolism was calculated to account for about 6.5% of the energy metabolism, assuming complete combustion to carbon dioxide and water. Oxygen uptake and blood flow did not change in the presence of acetate and ethanol. After administration of ethanol the arterial concentrations of FFA and glycerol decreased to about half, whereas the lactate concentration increased to about twice the control values, confirming other reports. Glucose utilization was increased and lactate output decreased during the ethanol periods, presumably a consequence of the changing arterial concentrations and increased insulin level. Measurements of the arterial and venous lactate/pyruvate concentration ratios indicate that the NAD-mediated cytoplasmic redox state in the muscle is not changed in the presence of acetate and ethanol.
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