Effect of long chain triglyceride infusion on glucose metabolism in man

Thiébaud, D.; DeFronzo, Ralph A.; Jacot, E; Golay, Alain; Acheson, K. J.; Maeder, E.; Jéquier, E; Felber, J. P.

doi:10.1016/0026-0495(82)90163-9

Cited by 298 publications

(144 citation statements)

References 62 publications

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“…This suggests that, in contrast to normal peripheral tissues, glucose uptake and FFA metabolism are uncoupled in malignant lymphoma. At whole body level, FFAs inhibit glucose uptake, especially glucose oxidation (Thiebaund et al, 1982). The interaction between glucose and FFA metabolism was first demonstrated by Randle et al (1963) in a perfused rat heart.…”

Section: Discussionmentioning

confidence: 99%

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study

et al. 1999

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Increased use of glucose through glycolysis is characteristic for neoplastic growth while the significance of serum-free fatty acids for regulation of energy metabolism in cancer is poorly understood. We studied whether serum-free fatty acids (FFA) interfere with glycolytic metabolism of lymphoproliferative neoplasms as assessed with 2-F 18 -fluoro-2-deoxy-D-glucose ([F 18 ]FDG) and positron emission tomography (PET). Twelve patients with newly diagnosed non-Hodgkin's lymphoma ( n = 9) or Hodgkin's disease ( n = 3) participated in this study before start of oncologic treatment. Each patient underwent two [F 18 ]FDG PET studies within 1 week after overnight fast: once during high fasting serum FFA concentrations and once after reduction of serum FFA by administration of acipimox. Acipimox is a nicotinic acid derivative that inhibits lipolysis in peripheral tissues and induces a striking reduction in circulating FFA concentration. In all cases, dynamic PET imaging over the tumour area was performed for 60 min after injection of [F 18 ]FDG. Both graphical analysis (rMR FDG ) and single scan approach (SUV) were used to compare tumour uptake of [F 18 ]FDG under high fasting FFA concentrations and after pharmacologically decreased FFA concentrations. Serum FFA concentrations were reduced significantly from 0.92 ± 0.42 mmol l −1 at baseline to 0.26 ± 0.31 mmol l −1 after acipimox administration ( P = 0.0003). Plasma glucose, serum insulin and lactate concentrations were similar during both approaches. The retention of glucose analogue [F 18 ]FDG in tumour was similar between baseline and acipimox studies. Median rMR FDG of a total of 12 involved lymph nodes in 12 patients was 21.9 μmol 100 g −1 min −1 (range 8.7–82.5) at baseline and 20.1 μmol 100 g −1 min −1 (range 10.7–81.7) after acipimox. The respective values for median SUV were 7.8 (range 3.6–18.6) and 6.0 (range 4.1–20.2). As expected, [F 18 ]FDG uptake in myocardium was clearly enhanced by acipimox due to reduction of circulating FFAs. In conclusion, blood fatty acids appear to have minor significance for [F 18 ]FDG uptake in lymphoma. This suggests that glucose utilization is uncoupled of FFA metabolism and indicates that glucose-free fatty acid cycle does not operate in lymphomatous tissue. Glucose appears to be the preferred substrate for energy metabolism in tumours, in spite of the high supply of FFAs in the fasting state. Although acipimox and other anti-lipolytic drugs have potential for treatment of catabolic state induced by cancer, they are not likely to interfere with tumour energy metabolism which is fuelled by gluc...

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Section: Discussionmentioning

confidence: 99%

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study

et al. 1999

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mentioning

confidence: 99%

“…Although the cause and effect relationship between lipids and insulin resistance is complex, an experimental increase in plasma free fatty acid (FFA) 1 concentrations induces insulin resistance in skeletal muscle in healthy humans (2,3). Earlier studies explored the possibility that the Randle cycle could explain lipid-induced insulin resistance (2,3). Although the concept that FFA and glucose compete with one another as oxidative fuels in skeletal muscle has withstood the test of time, more recent studies have shown that FFA and FFA metabolites inhibit insulin signaling (4), glucose transport (4), and the activities of various enzymes involved in glucose metabolism (2).…”

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confidence: 99%

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

Richardson

Kashyap

Bajaj

et al. 2005

Journal of Biological Chemistry

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The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-␥ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ؎ 0.02 to 1.73 ؎ 0.43 mM and decreased insulin-stimulated glucose disposal from 8.82 ؎ 0.69 to 6.67 ؎ 0.66 mg/kg⅐min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.

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“…Increases in citrate and glucose 6-phosphate in human muscle biopsies have been observed immediately after exercise (Essen, 1977), suggesting activation of the cycle in this situation. Studies in humans by the insulin-glucose clamp technique have demonstrated that an micrease in plasma non-esterified fatty acids inhibits glucose utilization in peripheral tissues (Thiebaud et at, 1982;Ferrannini et al, 1983). Such inhibitory effects of non-esterified fatty acids were not observed in the presence of hypoinsulinaemia, when glycolysis-in skeletal muscle would presumably be minimal.…”

mentioning

confidence: 99%

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

Zorzano¹,

Balon²,

Brady³

et al. 1985

Biochemical Journal

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1. Concentrations of citrate, hexose phosphates and glycogen were measured in skeletal muscle and heart under conditions in which plasma non-esterified fatty acids and ketone bodies were physiologically increased. The aim was to determine under what conditions the glucose-fatty acid cycle might be operative in skeletal muscle in vivo. 2. In keeping with the findings of others, starvation increased the concentrations of glycogen, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in heart, indicating that the cycle was operative. In contrast, it decreased glycogen and had no effect on the concentration of citrate or the fructose 6-phosphate/fructose 1,6-bisphosphate ratio in the soleus, a slow-twitch red muscle in which the glucose-fatty acid cycle has been demonstrated in vitro. 3. In fed rats, exercise of moderate intensity caused glycogen depletion in the soleus and red portion of gastrocnemius muscle, but not in heart. In starved rats the same exercise had no effect on the already diminished glycogen contents in skeletal muscle, but it decreased cardiac glycogen by 2530% . 4. After exercise, citrate and the fructose 6-phosphate/fructose 1,6-bisphosphate ratio were increased in the soleus of the starved rat. Significant changes were not observed in fed rats. 5. The data suggest that in the resting state the glucose-fatty acid cycle operates in the heart, but not in the soleus muscle, of a starved rat. In contrast, the metabolite profile in the soleus was consistent with activation of the glucose-fatty acid cycle in the starved rat during the recovery period after exercise. Whether the cycle operates during exercise itself is unclear.

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Effect of long chain triglyceride infusion on glucose metabolism in man

Cited by 298 publications

References 62 publications

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

Effects of starvation and exercise on concentrations of citrate, hexose phosphates and glycogen in skeletal muscle and heart. Evidence for selective operation of the glucose-fatty acid cycle

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