[relations between free fatty acids and protein metabolism in vivo].
Explore the source record for details and available documents.
Fatty Acids, Nonesterified↗
Biomedical subjects
M Beylot
Publications and source records attributed to M Beylot.
Mechanisms of the glucose lowering effect of a carnitine palmitoyl transferase inhibitor in normal and diabetic rats.
To determine the respective part of modifications of glucose appearance and disappearance rates in the hypoglycemic action of a compound (B 827-33) inhibiting carnitine palmitoyl transferase (CPT I), we measured glucose kinetics ([6,6(2)H2]glucose) in normal and diabetic (streptozocin) rats before and after injection of either saline or B 827-33. Studies were initiated 4 hours (postabsorptive groups) and 24 hours (fasted groups) after food withdrawal. In all groups, there was evidence of inhibition of fatty acids oxidation (sharp decrease of ketone bodies [KB] and increase of plasma nonesterified fatty acids [NEFA]) after B 827-33 injection. Glucose levels decreased also in all groups after B 827-33 administration, the decrease being more important in starved than in postabsorptive groups and, whatever the nutritional status, in diabetic than in normal rats. In all groups, the evolution of plasma insulin was comparable after saline or B 827-33 injection. The mechanisms responsible for the decrease in glucose levels appeared dependent on the nutritional status. In postabsorptive normal and diabetic rats, compared with saline-injected rats, we observed a moderate inhibitory action (P less than .05) of B 827-33 on glucose production without stimulation of glucose utilization rate. After 24 hours of starvation, the decrease in glucose levels of normal rats was entirely due to a stimulation of glucose utilization (P less than .05), whereas glucose production was unexpectedly increased (P less than .05) above values of saline-injected rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans.
To determine the effect of insulin and glucagon on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB), we measured simultaneously in normal subjects NEFA and KB kinetics at different NEFA levels in the presence of basal (control test) or increasing insulin concentrations with glucagopenia (somatostatin + insulin infusion, insulin test) and without glucagopenia (somatostatin + insulin + glucagon infusion, glucagon test). NEFA levels were controlled during these tests by an intravenous (IV) infusion of a triglyceride emulsion. During the control test, a moderate increase of NEFA (464 +/- 30 to 715 +/- 56 mumol/L) increased the percentage of NEFA converted into KB (13.3% +/- 1.4% to 26.4% +/- 2.1%, P less than .05), and there was a linear relationship between this percentage and NEFA levels (r = .788, P less than .01). During the insulin and glucagon tests, the progressive increase in NEFA induced by the triglyceride emulsion infusion was associated, despite the increase of insulinemia, with an increase in KB production rate (P less than .05) and in the proportion of NEFA used for ketogenesis in the presence (8.1% +/- 1.2% to 14.2% +/- 6.3%, P less than .05) and absence (15.7% +/- 2.8% to 25.2% +/- 3.99%, P less than 0.05) of glucagopenia. In both tests, this percentage was always linearly related with NEFA levels (P less than .05) and the slopes of these relationships were comparable to that observed in the control test. However, the fraction of NEFA used for ketogenesis was always higher (P less than .05) during glucagon substitution than in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption↗
Lipolytic and ketogenic fluxes in human hyperthyroidism.
The effect of hyperthyroidism on lipolytic and ketogenic fluxes was determined by measuring simultaneously (stable isotope methodology) glycerol, nonesterified fatty acids (NEFA), and ketone body (KB) kinetics in euthyroid and hyperthyroid subjects. In the postabsorptive state hyperthyroid patients had normal concentrations of insulin and glucagon, but increased concentrations (P less than 0.01) and turnover rates (P less than 0.01) of glycerol, NEFA, and KB. The ratio of NEFA appearance rate to glycerol appearance rate was decreased in hyperthyroid subjects (2.34 +/- 0.23 vs. 3.15 +/- 0.22; P less than 0.05), indicating that intracellular cycling between triglycerides and fatty acids was increased. The percentage of NEFA flux used for KB production, calculated from NEFA disappearance rates and KB appearance rates, was increased in hyperthyroid patients (21.20 +/- 2.75% vs. 13.37 +/- 0.63%; P less than 0.05), suggesting a diversion during hyperthyroidism of hepatic fatty acid metabolism toward ketogenesis. However, when the plasma NEFA levels of control subjects were raised by the infusion of a triglyceride emulsion to levels comparable to those observed in hyperthyroid patients their percentage of NEFA flux used for ketogenesis rose to values slightly higher (26.30%) than those of hyperthyroid subjects. In conclusion, 1) hyperthyroidism results not only in increased lipolysis, but also in enhanced triglyceride-fatty acid cycling, which could contribute to the excessive energy expenditure; and 2) the increased KB production of hyperthyroid patients results more from an increase in NEFA availability than from a direct stimulation of hepatic ketogenesis.
Adult↗
[New techniques for investigation of human nutrition].
Accurate determination of energy requirement and nutrients metabolism is essential to improve physiological knowledge and for physiopathological purpose in human nutrition. This evaluation is an absolute necessity for food industry. Energy expenditure could be precisely determined by indirect calorimetry or doubly labeled water technic. Nutrients metabolism (kinetics?) and substrates turn-over studies are now accessible without health hazard using tracers labelled with stable isotopes. These three methods are the basic tools for the new Research Nutrition Center which are now in progress.
Calorimetry, Indirect↗
[Hyperthyroidism and glucose metabolism].
Explore the source record for details and available documents.
Blood Glucose↗
[Increase of energy expenditure in Parkinson's disease].
Energy expenditure was determined in 18 patients with Parkinson's disease, 6 healthy volunteers and 6 patients with essential tremor, age-matched, using the indirect calorimetric method which measures the gas exchange rate. The results showed a significant increase in the relative energy expenditure, i.e. the difference between absolute and predictable values from the Harris and Benedict equation, among the parkinsonian patients (+21 +/- 4.1 p. 100; mean +/- S.E.M.) as compared to the 2 control groups (-8.6 +/- 7 p. 100 and -2.1 +/- 4.1 p. 100 respectively; p less than 0.001). There was no correlation between the rate of energy expenditure and the duration or degree of severity of the disease, and particularly the occurrence and magnitude of weight loss, which is frequently observed during the course of the disease. The relative energy expenditure was not significantly different between untreated and treated parkinsonian patients (18.8 +/- 3 p. 100 and 24.5 +/- 6.2 p. 100 respectively). Further investigations were designed to determine whether the increased energy expenditure could reflect a functional impairment of the automatic nervous system. The integrity of the vagus nerve was tested by plotting vs time the plasma Pancreatic Polypeptide levels in response to insulin-induced hypoglycaemia. A physiological stimulation was obtained in the 8 parkinsonian patients studied. This is not the case in chronic autonomic failure. On the contrary, the relative energy expenditure was significantly decreased in the 6 patients that were given a beta-blocking drug, pindolol, 15 mg daily for 3 weeks (+30.7 +/- 4.3 p. 100 before and +21 +/- 4.2 p. 100 after treatment; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Reappraisal of the effect of Ca2+ on the activity of liver microsomal glucose-6-phosphatase.
It has recently been reported that free Ca2+, a second hormonal messenger in the liver, can modulate the activity of liver glucose-6-phosphatase by inhibition (van de Werve, G. (1989) J. Biol. Chem. 264, 6033-6036) or activation (Yamagushi, M., Mori, S., and Suketa, Y. (1989) Chem. Pharm. Bull. (Tokyo) 37, 388-390). Such a controversial role for Ca2+ is reinvestigated by comparing the effect of the addition of free Ca2+ (10(-10) to 20.10(-3) M) under the form of CaCl2 or of Ca-EGTA buffers. We show that the glucose-6-phosphatase activity is: 1) increased in the presence of CaCl2 at concentrations higher than 10(-4) M and unaffected in the presence of CaCl2 at lower concentrations; 2) decreased in the presence of Ca-EGTA buffers yielding free Ca2+ concentrations higher than 10(-8) M; 3) the latter effect is not depending on free Ca2+ or free EGTA concentrations, but on Ca.EGTA complex concentration. In addition, these effects can be reproduced in the same concentration ranges by MgCl2 and Mg-EDTA buffers, respectively. It is concluded that a physiological role for free Ca2+ on the activity of liver glucose-6-phosphatase remains to be established.
Animals↗
Use of a new gas chromatograph isotope ratio mass spectrometer to trace exogenous 13C labelled glucose at a very low level of enrichment in man.
The use of 13C labelled glucose in human metabolic studies has been limited by the high cost of the tracer and the problems of measuring low 13C isotopic abundance in plasma glucose. In the present work we describe a new gas chromatograph-isotope ratio mass spectrometer allowing the measurement of a 0.001 atom % increase in 13C abundance over baseline, on a nanomole glucose sample. Studies were performed in rats and in human subjects. The rate of glucose appearance in 24 h fasted rats using D-[1-13C] glucose as tracer and analysed by this new method was found to be 10.4 +/- 0.7 mg.kg-1.min-1, a value 21% lower than that found using D-[6,6-2H2] glucose as tracer (13.1 +/- 1.1 mg.kg-1.min-1) analysed by classic gas chromatography-mass spectrometry. The new method was also used to trace, in combination with D-[6,6 2H2] glucose, the metabolic fate in human subjects of two oral glucose loads (0.5 g.kg.-1,1 g.kg.-1) labelled with 0.1% D-[U-13C] glucose. During the six hours following the glucose load, it was found that total glucose appearance was 0.97 +/- 0.04 g.kg.-1 and 1.2 +/- 0.04 g.kg.-1, exogenous glucose appearance was 0.51 +/- 0.02 g.kg.-1 and 0.84 +/- 0.04 g.kg.-1, endogenous glucose production was 0.44 +/- 0.04 g.kg.-1 and 0.35 +/- 0.06 g.kg.-1 after the 0.5 and 1 g.kg.-1 load respectively. These values are similar to those reported using glucose labelled with radioactive isotopes.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Interactions of glucagon and free fatty acids with insulin in control of glucose metabolism.
To study the interactions of physiological glucagon and free fatty acids (FFA) concentrations with insulin in the control of glucose metabolism, we determined in normal subjects the response of endogenous glucose production (EGP) and glucose utilization (Rd) to a progressive and moderate increase of insulinemia in the presence of glucagon and FFA levels either decreased (somatostatin [SRIF] and insulin infusion, C test) or maintained to normal postabsorptive values isolated (SRIF + insulin + glucagon infusion, G test; SRIF + insulin + Intralipid infusion, IL test) or in association (SRIF + insulin + glucagon + Intralipid infusion, IL + G test). Compared with the C test, maintenance of glucagon level had only small and inconsistent effects on glucose Rd, but induced a shift to the right of the dose-response curve to insulin of EGP (apparent ED50: C test, 10.9 mU.L-1; G test, 15.2 mU.L-1). Intralipid infusion resulted, whether glucagon was substituted or not, in a near total suppression of the insulin-induced increase of glucose Rd (Rd at the end of the tests: C test, 6.13 +/- 0.85 mg.kg-1.min-1; G test, 7.29 +/- 0.87 mg.kg-1.min-1; IL test, 3.30 +/- 0.65 mg.kg-1.min-1; IL + G test, 3.57 +/- 0.42 mg.kg-1.min-1). In the absence of glucagon, substitution Intralipid infusion also antagonized the action of insulin on EGP. However, this effect was no longer apparent when glucagon was replaced (dose-response curve to insulin of EGP during the G and the IL + G test were comparable).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Hormonal and metabolic effects of chronic interleukin-2 infusion in cancer patients.
Interleukin-2 (IL-2) is secreted during the immune response to trauma, sepsis, and transplant rejection. Its role in the development of the metabolic abnormalities observed in these circumstances is not well defined. We studied the clinical, hormonal, and metabolic response to a 5-day IL-2 infusion (3 x 10(6) U/m2/day) of nine patients with metastatic renal carcinoma. IL-2 induced systemic manifestations after a latent period of 4 h (fever, tachycardia) or 8 h (hypotension). These manifestations persisted until the end of the infusion. Insulin levels were not modified. Among the stress hormones, cortisol increased at the onset of fever and tachycardia, whereas the rise in catecholamines occurred later (24 h) and appeared more as a response to the development of hypotension. The only metabolic effects observed were a late (third day) rise of lactate and a late and transient (third to fourth day) decrease of glycerol and nonesterified fatty acids. These metabolic modifications were temporally related to the development of hypotension and result more likely from low tissue perfusion rather than from a direct or hormone-mediated effect of IL-2.
Adult↗
Vasoactive intestinal peptide stimulates long-chain fatty acid oxidation and inhibits acetyl-coenzyme A carboxylase activity in isolated rat enterocytes.
The effects of vasoactive intestinal peptide (VIP) on fatty acid oxidation in isolated rat enterocytes were investigated. VIP (10(-7) M) increased more than 2-fold the production of 14CO2 from [U-14C]palmitate. This effect was dose-dependent (K0.5 = 5.10(-11) M) and appeared to be related to the stimulation of cAMP production since it was mimicked by forskolin (10(-4) M). VIP also stimulated oxygen consumption of the cells, an effect accounted for by the stimulation of the oxidation of both exogenous added palmitate (0.12 mM) and endogenous fatty acids produced by lipolysis. VIP appeared to specifically enhance the oxidation of long-chain fatty acids since its effects were counteracted by 5.10(-5) M sodium 2-[6-(chlorophenoxy)hexyl]oxirane-2-carboxylate, a potent inhibitor of carnitine palmitoyltransferase 1, and since VIP did not affect cell respiration in the presence of octanoate. These results suggested that VIP stimulated long-chain fatty acid oxidation by increasing their translocation into the mitochondria. Therefore, we examined the effect of VIP on the activity of acetyl-coenzyme A carboxylase, the enzyme responsible for the biosynthesis of malonyl-CoA, a physiological inhibitor of carnitine acyltransferase 1. VIP produced an acute, dose-dependent (Ki = 3.10(-11) M), 90% inhibition of acetyl-coenzyme A carboxylase activity. These results allow us to elucidate the mechanism of the recently reported inhibitory effect of VIP on glucose oxidation (Vidal, H., Comte, B., Beylot, M., and Riou, J. P. (1988) J. Biol. Chem. 263, 9206-9211) and demonstrate for the first time that balance between fatty acids and glucose as energetic fuels is under neurohormonal control in isolated rat enterocytes.
Acetyl-CoA Carboxylase↗
Positional isotopic analysis of 13C-labelled glucose by mass spectrometry: applications to the study of gluconeogenesis in liver cells.
The aim of the present investigation was to ascertain whether mass spectrometric analysis of glucose allows determination in small samples (0.01 nmol) of the sites and the extent of labelling of glucose produced by isolated liver cells from various gluconeogenic labelled precursors. The electron impact spectrum of the methyloxime pentatrimethylsilyl derivative of natural glucose affords fragment ions retaining specific carbon atoms, i.e. 1-2 (m/z 160), 1-2-3 (m/z 262), 3-4-5-6 (m/z 319), 4-5-6 (m/z 217), 5-6 (m/z 205), 6 (m/z 103). The mass fragmentography analysis of the same derivative of commercially available labelled glucose molecules (1-13C, 6-13C, 2-2H, 3-2H, 6,6-2H2) permitted evaluation of the degree of specificity of these fragment ions, and development of a calculation method for isotope incorporation. Using this methodology we found that incubation of hepatocytes with (2-13C)glycerol, (1,3-13C)glycerol or NaH13CO3 plus pyruvate or lactate produced (2,5-13C)glucose, (1,3,4,6-13C) glucose or (3,4-13C)glucose, respectively. The extent of labelling was measurable on individual carbon of the glucose molecule except for carbon 1. The lowest enrichment detectable on carbon 1-3 or 3 was found to be 0.5%. In conclusion, gas chromatography mass spectrometry is a reliable method for positional isotopic analysis of 13C-labelled glucose, and appears useful in the study of the gluconeogenic pathway.
Animals↗
Regulation of ketone body flux in septic patients.
To assess the effect of sepsis on ketone body (KB) kinetics in humans, we measured in normal and septic subjects KB appearance rate (Ra) before (initial state) and during a rise of free fatty acids (FFA) level (intravenous infusion of a triglycerides emulsion). We studied normal subjects in postabsorptive state and septic patients when receiving an hypocaloric intravenous infusion of glucose and amino acids or 12 h after its interruption. When receiving glucose and amino acids infusion, septic patients had higher glucose and insulin levels than normal subjects, and despite lower FFA concentrations (255 +/- 44 vs. 480 +/- 51 mumol/l, P less than 0.05) comparable initial KB Ra (2.50 +/- 0.10 vs. 2.48 +/- 0.30 mumol.kg-1.min-1). Triglyceride infusion increased FFA to comparable values (septic 780 +/- 130, normal 730 +/- 45 mumol/l), but KB Ra rose in septic patients only to 3.7 +/- 1.1 instead of 7.7 +/- 1.1 mumol.kg-1.min-1 as in normal subjects (P less than 0.05). Somatostatin infusion decreased the hyperinsulinemia of septic patients but did not restore a normal ketogenesis. After interruption of nutriment infusion, septic patients had normal FFA levels and only mild hyperglycemia and hyperinsulinemia. Their initial KB Ra was not modified. However, their response of KB Ra (increase to 6.27 +/- 2.0 mumol.kg-1.min-1) to raised FFA levels (842 +/- 170 mumol/l) was comparable to the response of normal subjects. In conclusion, although septic patients receiving an hypocaloric parenteral nutrition had a depressed ketogenesis they were able to restore a normal ketogenic capacity after a short-time caloric deprivation. Glucose and/or insulin appears to have a major role in this modulation of hepatic ketogenesis.
Adult↗
Inhibition of glucose oxidation by vasoactive intestinal peptide in isolated rat enterocytes.
Glucose metabolism and its hormonal regulation have been investigated in isolated enterocytes from rat small intestine. About 70% of the glucose consumed by the cells was transformed into lactate, 5% into pyruvate, and 4% into alanine. The remaining 20% was oxidized. Among several tested gastrointestinal peptides and hormones, only vasoactive intestinal peptide (VIP) was found to affect the metabolic fate of glucose. VIP (10(-7) M) induced a 40% inhibition of glucose oxidation without significant modification of either glucose uptake or production of lactate, pyruvate, and alanine. This acute inhibition was dose-dependent (Ki = 3.10(-11) M) and appeared to be dependent on the stimulation of cAMP production (K0.5 = 3.10(-9) M) since dibutyryl-cAMP and forskolin reproduced all the effects of VIP. Similar inhibition of cell respiration by VIP was observed when pyruvate, fructose, and dihydroxyacetone were used as substrates, while the oxidation of glutamine, ketone bodies, and octanoate was unaffected, suggesting that the peptide acts on pyruvate metabolism. The suppression of VIP effects by dichloroacetate (5 mM) and pyruvate (10 mM) and the significant decrease (18%) of the activity of the pyruvate dehydrogenase complex after incubation of the cells with the neuropeptide, support the hypothesis that the effects of VIP on glucose oxidation may occur through an inhibition of the pyruvate dehydrogenase complex. The total suppression of the inhibitory effects of VIP by sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, a potent inhibitor of long-chain fatty acid oxidation, suggests that VIP did not affect the pyruvate dehydrogenase directly, but more probably acted through modifications of fatty acid oxidation.
Animals↗
Dawn phenomenon in type 1 (insulin-dependent) diabetic adolescents: influence of nocturnal growth hormone secretion.
In order to reassess the role of growth hormone in the dawn phenomenon, we studied eight C-peptide negative diabetic adolescents, who are likely to exhibit important nocturnal growth hormone surges. The insulin infusion rate necessary to maintain euglycaemia was predetermined in each patient from 22.00 hours to 01.00 hours, and then kept constant until 08.00 hours resulting in stable free insulin levels. Blood glucose rose from 4.3 +/- 0.7 mmol/l at 01.00 hours to 7.1 +/- 1.1 mmol/l at 08.00 hours (p less than 0.01) secondary to an increased hepatic glucose production. All the subjects presented an important growth hormone secretion, ranging from 20 to 66 ng/ml (peak values) and from 3619 to 8621 ng.min.ml-1 (areas under the curve). The insulin infusion rate selected for each patient was positively correlated with the nocturnal growth hormone secretion (area under the curve) (r = 0.87, p less than 0.01). On the other hand, there was no relationship between the nocturnal growth hormone secretion and the magnitude of the early morning blood glucose rise (r = -0.48, p greater than 0.2). We conclude that, in Type 1 (insulin-dependent) diabetic adolescents, the dawn phenomenon exists but is moderate despite important growth hormone surges; the nocturnal growth hormone secretion influences the nocturnal insulin requirements but not the dawn phenomenon itself, if insulinisation is adequate.
Adolescent↗
Hormonal control of glucose production and pyruvate kinase activity in isolated rat liver cells: influence of hypothyroidism.
Hormonal control of glucose production and of L-pyruvate kinase activity has been measured in isolated liver cells from fed control and thyroidectomized rats. In hypothyroid rats, sensitivity to isoproterenol as measured by these parameters was increased: the apparent K0.5 for isoproterenol-induced stimulation of glucose production decreased from 8.0 +/- 3 X 10(-6) M in control rats to 2.0 +/- 0.2 X 10(-8) M in hypothyroid rats (P less than 0.001) and the apparent K0.5 for inhibition of L-pyruvate kinase was 5 +/- 2 X 10(-7) M vs. 7 +/- 2 X 10(-9) M (P less than 0.001) in control and thyroidectomized rats, respectively. Utilisation of specific adrenergic antagonists confirmed increased beta-adrenergic responsiveness in hypothyroid rats. This phenomenon was not reversed by 3 days of T3 treatment (10 micrograms/100 g body weight). Sensitivity to the alpha-agonist was unchanged by thyroid status. Stimulation of glucose production and inhibition of L-pyruvate kinase activity by glucagon and their reversal by insulin were not affected by hypothyroidism. The dose-response curve to vasopressin and its maximal effect measured on stimulation of glucose production were unchanged in thyroidectomized rats. Thus, hypothyroidism produces a specific enhancement of liver beta-adrenergic responsiveness without affecting sensitivity to glucagon, insulin and vasopressin.
Animals↗
Effect of epinephrine on the relationship between nonesterified fatty acid availability and ketone body production in postabsorptive man: evidence for a hepatic antiketogenic effect of epinephrine.
The effect of epinephrine (EPI) on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB) in normal subjects was determined by measuring simultaneously NEFA ([1-13C]palmitic acid) and KB ([3-13C]- or [3,4-13C2]acetoacetate) kinetics at different NEFA levels in the presence of basal (control test) or increased (EPI infusion test) EPI concentrations. During the control test the initial (postabsorptive state) concentrations and turnover rates of NEFA and KB were 476 +/- 47 (+/- SEM) and 4.30 +/- 0.17 mumol kg-1 min-1 (NEFA) and 126 +/- 17 and 2.49 +/- 0.07 mumol kg-1 min-1 (KB). The fraction of NEFA converted into KB was between 11.5-14.6%. Raising NEFA levels to about 650 mumol L-1 (iv infusion of a triglyceride emulsion) resulted in an increase in this fraction to between 26-30.3% (P less than 0.01). When NEFA concentrations were next abruptly raised to high levels (near 3 mmol L-1) by heparin injection this fraction returned to near the initial values (15-19.2%). During the EPI infusion test the initial (postabsorptive) concentrations and turnover rates of NEFA and KB as well as the fraction of NEFA converted into KB (10.5-11.5%) were comparable to the initial values of the control test. Intravenous infusion of EPI (10 ng kg-1 min-1) raised NEFA between 600 and 750 mumol L-1, comparable to values during the triglyceride test, but the fraction of NEFA converted into KB remained between 8.2-12% (P less than 0.05 vs. control test); when NEFA then were raised to even higher values (near 2.5 mmol L-1) by the infusion of a triglyceride emulsion and the injection of heparin, this fraction decreased to between 4-8% (P less than 0.05 vs. initial values of the EPI test and P less than 0.05 vs. the control test). In conclusion, 1) the fraction of NEFA converted into KB appears to depend in part on the NEFA concentration; and 2) the net effect of EPI infusion was to decrease the fraction of NEFA converted into KB.
Absorption↗