[Atherosclerosis and diabetes. Hepatic synthesis of lipids].
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Animals↗
Biomedical subjects
G Mingrone
Publications and source records attributed to G Mingrone.
[Budd-Chiari syndrome in the course of polycythemia rubra vera. Presentation of a clinical case].
An unusual case of Budd-Chiari syndrome during erythraemia is presented. Acute thrombosis of the suprahepatic veins became chronic with progressive improvement, shown clinically and radiologically in the form of partial recanalisation of thromboses of these veins and the porta. The pathogenetic relationship between polycythaemia and the Budd-Chiari syndrome is also discussed.
Budd-Chiari Syndrome↗
Delay in diagnosis of colorectal cancer.
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Colonic Neoplasms↗
Effects of insulin on hepatic lipid synthesis in alloxan diabetic rats.
In vitro hepatic synthesis of lipids starting from 1-(14)C-acetate was studied in rats made diabetic by subcutaneous alloxan administration (175 mg/kg b.w.). A second group of diabetic rats was treated with lente insulin. In the alloxan-treated rats, a decrese was observed in hepatic incorporation of 1-(14)C-acetate into phospholipids, triglycerides and esterified cholesterol; there was an increased incorporation into nonesterified fatty acids (NEFA) and free cholesterol. Insulin administration restored lipid synthesis values to normal. On histologic examination, an intranuclear glycogenesis was observed in the hepatocytes of the alloxan-treated rats, along with severe hepatic necrosis; the latter however, only in rats sacrified on the 3rd day. Hepatic steatosis with small, medium and large droplets was present in the insulin-treated rats; signs of cellular degeneration were less evident.
Animals↗
Endocrinology. Fat busters fail.
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Anti-Obesity Agents↗
Clinical nutrition practice in Italian Gastroenterology Units.
BACKGROUND: Nutritional status affects the course, ensuing complications and prognosis of virtually all diseases. AIMS: To define the role of nutrition in Gastroenterology Units by means of two investigations that analyse: a) availability of devices for assessing nutritional status; b) nutritional treatment in clinical practice: incidence and frequency of indications for its use, together with type of treatment adopted. PATIENTS AND METHODS: Two questionnaires were sent to Italian Academic and Hospital Gastroenterology Units, all with clinical wards. RESULTS: Results refer to 27 Units, 22 of which took part in both parts of the analysis, enrolling 547 patients during the two-week study The first analysis shows that scales and the altimeter are not available everywhere, while more specific tools, such as skinfold calipers are available in 54% of the Units, and caloric intake can be assessed in 22-41%. The second analysis reveals that nutritional treatment was necessary in 50% of patients in the series examined, and that this was taken into account and prescribed in almost all cases (91%). Of the patients treated, 69% received dietetic supplementation and 31% artificial nutrition [12% enteral, 88% parenteral), although supportive parenteral nutrition is often contraindicated in conditions where good bowel function provides the conditions for enteral nutrition. CONCLUSION: Data emerging from the investigation showed that i) artificial nutrition is commonly used in gastroenterology Units in Italy although 23% of them never consider either enteral or parenteral nutrition as medical treatment of gastrointestinal disease; ii) malnutrition is a very frequent complication (mean 27%; range 4-55%0) in Gastroenterology Unit patients albeit only 42% of malnourished patients received artificial nutrition; iii) indications for enteral and parenteral nutrition are not always respected, as there is an excessive use of parenteral nutrition and an unjustified resistance to the use of enteral nutrition; iv] nutritional treatment is often administered without adequate nutritional assessment and without a complete adherence to the standards recommended for preparation of parenteral bags, supported by suitable technology; v) only two Gastroenterology Units report admitting and following patients in a home parenteral nutrition programme; vi) this investigation probably reflects the response of those Gastroenterology Units most aware of the importance of nutritional problems. Better awareness of correct practices for nutritional support should be promoted, encouraging greater use of diagnostic and monitoring techniques and a more discerning choice of the most suitable type of artificial nutrition to be administered in gastroenterology
Delivery of Health Care↗
Preliminary studies of a dicarboxylic acid as an energy substrate in man.
Azelaic acid (Az), a straight saturated chain nine carbon dicarboxylic acid, was administered in saline form to six healthy male volunteers by iv route. Serum levels of Az and urinary amounts of both azelaic and pimelic (C7) acids were measured by an improved gas liquid chromatographic method. Stoichiometric analysis of Az metabolism was compared with that of glucose and palmitic acid. The respiratory quotient (RQ) as well as the ATP/CO2 ratio of Az were quite similar to that of palmitic acid. Therefore, Az oxidation is associated with a low cost of ATP synthesis in terms of carbon dioxide production. At the infusion rate used (7.5 g/hr) more than 50% of the administered dose was excreted in the urine. However, the remaining portion was cleared from the plasma in 200 min suggesting an uptake by body tissues which was also confirmed by indirect calorimetric analysis.
Adenosine Triphosphate↗
Short-term infusion of azelaic acid vs intralipid in healthy subjects evaluated by indirect calorimetry.
Medium-chain dicarboxylic acids (MCDA) are usually considered byproducts of beta-oxidation when omega-oxidizable medium-chain monocarboxylic acids are accumulated, as in beta-oxidation impairment. However, evidence exists of a mitochondrial and cytoplasmatic peroxisomal carnitine independent beta-oxidation of these diacids. Our purpose was to evaluate whether MCDA could be used as source of calories. The metabolic response to intravenous administration of azelaic acid (AA) vs Intralipid (IL) was evaluated in six healthy overnight fasting male volunteers who received an infusion of 10 g of AA over 80 min and as a control 10 g of IL. AA reached a peak concentration at 80 min, (589 +/- 61 micrograms/ml) and was rapidly cleared from plasma (82 +/- 5 micrograms/ml at 240 min). Respiratory and metabolic parameters were evaluated by indirect calorimetry from the beginning of the infusion for 240 min. In both groups the CO2 production (VCO2) remained unchanged with no significant change from basal values. The O2 consumption (VO2 ml/min/m2) increased over basal values reaching a peak at the end of the infusion in both groups (AA from 119.4 +/- 16.9 to 143.0 +/- 27.6; IL from 124.7 +/- 16.8 to 152.3 +/- 29.5). Respiratory quotient (RQ) consequently decreased significantly (AA from 0.85 +/- 0.06 to 0.76 +/- 0.06; IL from 0.89 +/- 0.06 to 0.78 +/- 0.03) and calories derived from lipids increased. Metabolic rate (MR kcal/hr/m2) showed a slight increase (AA from 34.0 +/- 4.4 to 40.3 +/- 6.8; IL from 35.9 +/- 5.1 to 41.3 +/- 10.5). There was no significant difference between AA and IL treatment in all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Tissue uptake and oxidation of disodium sebacate in man.
In order to better ascertain its possible use as an alternative fuel substrate in total parenteral nutrition, sebacate (Sb) metabolism was studied in seven overnight-fasting healthy male volunteers, who received a constant iv infusion (99 mmoles over 8 hours) of disodium sebacate. Sb oxidation rate was determined using an isotopic sebacate (disodic salt of (1-10)14C-sebacic acid) infusion (100 mu Ci from the fourth to the eighth hour of the cold sebacate infusion). Blood samples were collected during and after sebacate infusion at intervals of 30 minutes and Sb serum concentrations were determined by high performance liquid chromatography. Excreted radioactivity (mu Ci/min) was measured by bubbling the expired air into an apparatus containing 3 mEq hyamine to trap CO2 from a 20-L Douglas-bag. CO2 production and O2 consumption were measured before and at 4 and 8 hours after starting the infusion. Twenty-four hour nitrogen excretion with urine was obtained. The RQ and the percent of calories derived from lipid oxidation were calculated by indirect calorimetry. The Sb serum level at the plateau phase was (mean +/- SD) 4.54 +/- 0.71 mumole/mL, the overall rate of tissue uptake was 180.89 +/- 4.50 mumole/min, and the percent oxidation was 6.14 +/- 0.44%. At the end of Sb infusion the RQ dropped to 0.839 +/- 0.043, the percent of calories due to sebacate oxidation was 1.59 +/- 0.52%, and the calories derived from lipids increased to 37.77 +/- 12.90%. These data show that a definite amount of the sebacate infused is oxidized in human tissues.
Adipates↗
Use of even-numbered carbon atom dicarboxylic salts in parenteral nutrition as fuel substrate.
Sebacic acid (C10), a saturated, straight-chain dicarboxylic acid with 10 carbon atoms in disodic salt form, was given intravenously to two groups of healthy male volunteers in order to evaluate its possible use in total parenteral nutrition. The first group, composed of six subjects, received 1000 mg of sebacate as a bolus; six other subjects (second group) received 10 g of sebacate dissolved in 500 mL of double-distilled water at an infusion rate of 3.33 g/h over 3 hours. The serum sebacate data for each subject were analyzed by computer, using biexponential fit corresponding to a 2-compartment open model. The distribution half-life (t1/2) was 0.34 +/- 0.06 hour and the elimination phase was rather rapid (Ke = 2.10 +/- 0.38/h); the volume of the central compartment was 2.79 +/- 0.54 L and the volume of tissue compartment 3.72 +/- 0.14 L. These data showed a good tissue fixation of sebacate. The plasma clearance was evaluated to be 5.96 +/- 2.19 L/h and the renal clearance was 19.22 +/- 10.69 L/h, indicating that a tubular secretion of C10 takes place. The serum concentration of sebacate raised to the maximal value at the end of the infusion (180 minutes), corresponded to 480.50 +/- 43.02 micrograms/mL. Respiratory and metabolic parameters were evaluated by indirect calorimetry from the beginning of the infusion for 210 minutes. The O2 consumption (VO2 mL/min per square meter) remained essentially unchanged throughout the experiment (from 154.3 +/- 28.3 at 0 to 155.3 +/- 39.5 at time 180 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Kinetics and thermogenesis of medium-chain monocarboxylic and dicarboxylic acids in man: sebacate and medium-chain triglycerides.
The effects on oxygen consumption and carbon dioxide production of a constant intravenous infusion of 0.15 g of disodium sebacate (Sb), the sodic salt of a medium-chain dicarboxylic acid with 10 carbon atoms, per kilogram of body weight per hour over 5 hours and a 50% mixture of medium- and long-chain triglycerides (MCT/LCT) were compared in 10 healthy men. Oxygen consumption and carbon dioxide production were measured by indirect calorimetry. Mean oxygen consumption was about 19% higher than the basal oxygen consumption at the end of MCT/LCT infusion but was only 5% higher than the basal oxygen consumption when Sb was infused. There was an eightfold increase in plasma beta-hydroxybutyrate and acetoacetate concentrations and a threefold increase in serum insulin levels during MCT/LCT infusion, but no significant change in ketone bodies and insulin from basal values was observed during and after Sb infusion. Pharmacokinetic parameters were also computed, showing an average apparent volume of distribution of 167 mL/kg of body weight for MCTs and 112 mL/kg of body weight for Sb. The t1/2 of MCTs was 50 minutes and that of Sb was 78 minutes. Urinary excretion of Sb and its beta-oxidative by-product, suberic acid, globally accounted for 48% of the given amount of Sb. In spite of its urinary loss and slower tissue uptake compared with MCTs, Sb avoided ketone body formation or elevation in insulin levels and did not induce a significant increase in oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Dicarboxylic acids and glucose utilization in humans: effect of sebacate.
Dicarboxylic acids have been proposed as an alternate lipid energetic substrate for total parenteral nutrition. No data are yet available on the possible effect of dicarboxylic acids on glucose metabolism in humans. Thus, we examined the effect of a continuous intravenous infusion of the sodium salt of the 10-carbon atom alyphatic dicarboxylic acid, sebacate (Sb), on insulin-dependent glucose metabolism in four control subjects, four patients with insulin-dependent diabetes mellitus, and four obese subjects. All subjects received a constant 5-hour infusion of saline or sebacate (6.6 g/h), in a randomized order on two different days. After 3 hours of infusion, a 120-minute euglycemic, hyperinsulinemic clamp procedure was performed (insulin infusion rate = 40 mU/m2 per minute). Glucose uptake, plasma sebacate, insulin, glucagon, C-peptide, and ketone bodies were measured. No significant differences in insulinemia were found among groups either during the saline infusion or the sebacate infusion. On the contrary, glucose uptake (molar) was significantly reduced during the sebacate vs the saline day in all three groups: 6.7 +/- 0.04 vs 3.7 +/- 1.3 in control subjects (p < .001), 4.6 +/- 0.4 vs 2.5 +/- 1.2 in patients with insulin-dependent diabetes mellitus (p < .001), and 4.8 +/- 0.5 vs 2.7 +/- 0.2 mg/kg per minute in obese subjects (p < .001). In conclusion, Sb administration was associated with a glucose-sparing effect as shown by the reduced glucose uptake in all patients studied. Sebacate did not stimulate insulin secretion, inasmuch as no modification of C-peptide plasma levels was observed after 3 hours of Sb infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Decanoic Acids↗
Kinetics of medium-chain triglycerides and free fatty acids in healthy volunteers and surgically stressed patients.
To determine the hydrolysis rate of medium-chain triglycerides (MCTs) to medium-chain free fatty acids (MCFAs) and the disposition rate of MCFAs, five healthy volunteers (H) and eight surgically stressed patients (S) received 0.5 mL of Lipofundin 20% per kilogram body weight as an intravenous bolus. Serum MCTs (C8 and C10) and MCFAs were measured by high-performance liquid chromatography during the 120 minutes postinjection. A linear two-compartment model was found to be descriptive and robust: the apparent volumes of distribution were found to be similar in healthy and surgical subjects for both MCTs and MCFAs. The first-order transformation rate constant (hydrolysis) from MCTs to MCFAs was not significantly different between the H and S groups (overall 0.112 +/- 0.022/min, C8; 0.078 +/- 0.020/min, C10). The rate constant for tissue MCFA uptake from plasma was significantly different between S and H subjects both for C10 alone (H: 0.0337 +/- 0.0078; S: 0.1194 +/- 0.0240; p = .020) and for C8 and C10 together (H: 0.0382 +/- 0.0054; S: 0.1012 +/- 0.0168; p = .008), whereas it failed to attain significance when C8 alone was considered (H: 0.047 +/- 0.0077; S: 0.0829 +/- 0.0230; p = .210). These results show that use of MCTs is increased in surgical patients because of enhanced tissue uptake of the corresponding free fatty acids, whereas there does not seem to be an increase of MCT hydrolysis in response to acute disease. This would indicate that the stressed patient is in fact able to effectively use this alternative lipid substrate in the face of increased metabolic demand.
Adult↗
Pharmacokinetic profile of dodecanedioic acid, a proposed alternative fuel substrate.
Dodecanedioic acid (C12), a saturated, aliphatic dicarboxylic acid with 12 carbon atoms, was given as an intravenous bolus (800 mumol/kg of body weight [kgBW]) in male Wistar rats to study its pharmacokinetic profile. Because total plasma C12, which results from the sum of both free and albumin binding fractions, was measured by high-performance liquid chromatography, an in vitro experimental session was carried out to determine the binding curve of C12 in rat plasma. These data were then used to calculate the plasma C12 free fraction in in vivo experiments. The best fit obtained for the experimental data of albumin binding was obtained with the equation of reversible, saturable binding to one, two, or three classes of noninteracting equivalent sites. Only a single binding site was clearly identified with a dissociation constant of 147 mumol/L and a maximal predicted binding of 1.57 mol/mol albumin. The urinary excretion of C12 was 3.90 +/- 1.62% of the administered dose. The pharmacokinetic analysis was performed by one-compartment model with linear transfer to the tissues, taking into account simultaneously both plasma concentration and urine excretion data. The apparent volume of distribution of C12 was 0.248 +/- 0.035 L/kgBW, the apparent first order rate constant to the tissues was 0.0535 +/- 0.0123 min-1 and that from plasma to urine was 0.00206 +/- 0.00051 min-1. The C12 plasma half-life was 12.47 minutes. Renal clearance was 0.00051 L/kgBW per minute, whereas the systemic clearance was 0.0138 L/kgBW per minute. Because the renal clearance was much less than the rat inulin clearance reported in literature, the presence of C12 passive back-diffusion was hypothesized.
Animals↗
Pharmacokinetic analysis of dodecanedioic acid in humans from bolus data.
BACKGROUND: Excretion and tissue uptake of dodecanedioic acid (C12), a proposed alternative fuel substrate, was investigated in humans by bolus experiments. METHODS: Seven overnight-fasting healthy male volunteers received i.v. a bolus (1 g) of C12. Blood samples were collected after C12 administration at intervals of 15 minutes, and C12 serum concentration was measured by high-performance liquid chromatography. C12 excretion in 24-hour urine was measured. Binding of C12 in human serum was determined in separate equilibrium dialysis experiments by means of an isotopic compound (disodic salt of (1,12)14C-dodecanedioic acid). A two-compartment model was used for describing C12 kinetics. RESULTS: The excreted amount of C12 in 24-hour urine was found to be, on the average, 1.62% of administered dose. The apparent number of binding sites per albumin molecule was 3.1 +/- 0.2 (estimate +/- SE) with an affinity constant of 6.4 +/- 1.8 mM-1. The distribution volume of central compartment was 5.56 +/- 3.13 L and that of peripheral compartment was 87.4 +/- 30.4 L. The rate constant of exchange between compartments was 4.60 +/- 3.50 L/min, that or urinary excretion 25.6 +2- 15.5 mL/min, and that of tissue uptake 2.17 +/- 0.86 L/min. CONCLUSIONS: These results are promising for C12 utilization in parenteral nutrition, because C12 elimination in urine is low whereas tissue uptake appears to be rather efficient.
Binding Sites↗
Plasma clearance and oxidation of dodecanedioic acid in humans.
BACKGROUND: Dicarboxylic acids are water-soluble, contrary to monocarboxylic acids, and have a metabolic pathway intermediate between those of lipids and carbohydrates. Our goal was to investigate the plasma turnover and oxidation rate of dodecanedioic acid (C12) in eight healthy male volunteers. METHODS: A simultaneous infusion of both cold (0.24 mmol/min corresponding to 0.396 kcal/min) and radiolabeled (1.62 microCi/min) C12 free acid was performed. Blood specimens were sampled over a period of 360 minutes, and 24-hour urine samples were collected to measure the levels of C12 by high-performance liquid chromatography and liquid scintillation. Indirect calorimetry was continuously performed, and expired 14CO2 was collected. Binding of C12 in human plasma was determined in separate experiments using equilibrium dialysis. RESULTS: A linear one-compartment model was used to describe the kinetics of labeled C12. Its volume of distribution was 139.02 +/- 10.84 mL/kgbw (mean +/- SE), and its plasma elimination constant was 0.01 +/- 0.004 min-1. The 24-hour urinary excretion of C12 was 3.14 +/- 0.96 mmol, corresponding to about 7% of the administered dose. The amount of C12 oxidized, expressed as percent oxidation, was equal to 35.44 +/- 1.64%. The mean basal value of npRQ (0.80 +/- 0.006) significantly (p < .02) decreased during the infusion to 0.78 +/- 0.01, which is a value close to that theoretically calculated (0.77). The oxidation of free fatty acids was significantly increased at the end of the C12 infusion, whereas the glucose oxidation was reduced to about 50%. CONCLUSIONS: The experimental data suggest that C12 might represent a fuel substrate immediately available for tissue energy requirements, because a relevant amount of C12 is promptly oxidized. Its prompt oxidation and its conversion to succinic acid support the use of dodecanedioic acid in parenteral nutrition, especially in insulin-resistance conditions in which glucose uptake and oxidation is impaired.
Binding Sites↗
Comparison between dodecanedioic acid and long-chain triglycerides as an energy source in liquid formula diets.
BACKGROUND: Dicarboxylic acids (DA) are water-soluble substances with high-energy density proposed as an alternative lipid substrate for nutrition purposes. The aim of the present study was to investigate the interaction between glucose and DA or long-chain triglyceride (LCT) metabolism after oral administration. METHODS: Two test meals containing either dodecanedioic acid (C12, the 12-atom DA) or LCT, together with glucose and amino acids, were each administered to five healthy volunteers. Tracer amounts of 14C-dodecanedioic acid were added to the C12 meal to recover expired traced CO2 and estimate the minimum rate of C12 oxidation. Glucose, insulin, and C12 plasma levels were measured for 360 minutes after the test meal. Indirect calorimetry was performed for the duration of the study. RESULTS: LCTs proved ineffective in promoting their own oxidation after oral administration. On the contrary, C12 was promptly oxidized, a minimum of 21.9%+/-8.3% of the administered amount giving rise to the recovered expired CO2. This difference in metabolic fate was reflected in a sparing effect on glucose: suprabasal respiratory quotient and suprabasal carbohydrate oxidation were significantly (p < .05) lower under C12 administration than under LCT administration, with a difference of 0.024+/-0.015 in respiratory quotient (RQ) and a difference of 0.791+/-0.197 kJ/min in carbohydrate oxidation. In particular, carbohydrate oxidation increased by 54% over basal with LCT but only by 28% with C12 administration. RQ increased over basal by 5.8% with LCT but only by 3.0% with C12 administration. CONCLUSIONS: These results show a fundamental metabolic difference between conventional lipids and DAs, which is the basis for a possible role of DAs in clinical nutrition. The fate of spared glucose is likely to be storage in glycogen form when dodecanedioic acid is made available as an energy source.
Adult↗
Pharmacokinetics of sebacic acid in rats.
The pharmacokinetics of disodium sebacate (Sb) was studied in Wistar rats of both sexes. Sebacate was administered either as intra-peritoneal (i.p.) bolus (six doses ranging from 10 mg to 320 mg) or as oral bolus (two doses: 80 and 160 mg). Plasma and urinary concentrations of Sb and urinary concentrations of Sb and its products of beta-oxidation (suberic and adipic acids) were measured by an improved method using gas-liquid chromatography/mass-spectrometry. A single compartment with two linear elimination routes was selected after no increase in significance was shown by an additional compartment and after a saturable mechanism was found to be unsuitable. Both renal and non-renal elimination parameters were obtained by Marquardt non linear fitting of plasma concentrations together with urinary elimination. The data reported are calculated from the analysis on the whole population of rats and referred to an average body weight (bw) of 100 g. The Sb half-time was 31.5 min. The tissue elimination rate was 0.0122 min-1. The overall volume of distribution was found to be 26.817 ml/100 g bw. The renal clearance was 0.291 ml/min/100 g of bw, which is much less than the value of GFR reported in literature (about 1 ml/min/100 g bw), suggesting the presence of Sb reabsorption from the ultrafiltrate. The value of Sb renal clearance was found to be a concentration-independent function, suggesting the presence of a passive back-diffusion. The relative bioavailability of the oral form compared to the i.p. form was 69.09%, showing a good absorption of the drug.
Administration, Oral↗