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Biomedical subjects

S W Coppack

Publications and source records attributed to S W Coppack.

At least 73 records · Page 4Linked to original sources
PubMed1994

Fasting plasma triacylglycerol concentrations predict adverse changes in lipoprotein metabolism after a normal meal.

The changes in lipoprotein metabolism which follow the ingestion of a large fat load have been well described. The hypothesis was tested that similar changes in lipoprotein metabolism would occur after a relatively normal meal. Plasma and lipoprotein triacylglycerol, cholesterol and apolipoprotein concentrations were determined in twenty subjects (ten female) given a mixed meal containing approximately one-third of the daily intake of major nutrients in the typical Western diet. Fasting plasma triacylglycerol concentrations (range 0.38-2.70 mm/l) and the postprandial rise in plasma triacylglycerol varied considerably between subjects and were significantly associated (P < 0.01). The rise in plasma triacylglycerol corresponded to marked increases in the triacylglycerol concentration of the triacylglycerol-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins). TRL cholesterol also increased after the meal. An increase in high-density-lipoprotein (HDL)-triacylglycerol following the meal was accompanied by a decrease in HDL-cholesterol concentration, presumably due to the action of the cholesteryl-ester transfer protein. The increases in HDL-triacylglycerol and in TRL-cholesterol were correlated with the postprandial rise in triacylglycerol in the TRL (P < 0.01). We conclude that potentially adverse changes occur in both triacylglycerol-rich and high-density lipoproteins following a typical mixed meal, as they do after large fat loads. The changes are exaggerated in those subjects with greater fasting plasma triacylglycerol concentrations.

Adult↗
PubMed1994

Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition.

There is net outward flow of fatty acids from adipose tissue in the fasted state but net inward flow and storage in the postprandial state. We investigated how this is regulated. Arteriovenous differences were measured across a subcutaneous adipose depot in six normal subjects before and for 5 h after a meal containing 80 g fat and 80 g carbohydrate. In five further experiments, insulin was infused at 40 mU.m-2.min-1 from 30 min after the meal, clamping the plasma glucose. Net transcapillary fatty acid flow changed from negative (outward flow from tissue to capillaries) in the postabsorptive state to consistently positive (net inward flow, implying fat storage) after the meal despite continued net efflux of fatty acids into venous blood. In the "clamped" experiments (with additional insulin), net fatty acid efflux in the venous blood was suppressed and positive transcapillary flux (storage) was more marked. Regulation of fatty acid flow appeared to depend on coordinated changes in hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action and fatty acid esterification. Additional insulin caused no further suppression of HSL or activation of LPL but markedly stimulated fatty acid retention (presumed to represent esterification). In the absence of additional insulin, a high proportion of the fatty acids liberated by LPL are released into the venous plasma in both postabsorptive and postprandial states. We hypothesize that this "loss" of fatty acids is necessary to give precise control to the pathway of fat storage.

Absorption↗
PubMed1994

In vivo regulation of lipolysis in humans.

Fatty acids are important oxidative fuel for liver, kidney, skeletal muscle, and myocardium. There has been much interest in the role of fatty acids in the pathogenesis of non-insulin-dependent diabetes because they compete with glucose for oxygen and inhibit whole body glucose disposal via the 'Randle cycle,' Control of lipolysis in adipose tissue determines systemic fatty acid supply. A wide range of hormones and other substances have been recognized as regulators of lipolysis, but insulin and catecholamines appear to be the most important. The regulation of lipolysis, in most circumstances, provides a supply of lipid fuel exceeding the rate of lipid oxidation, requiring reesterification to triglyceride of surplus circulating free fatty acids. Thus, free fatty acid supply is usually not matched to the demand for lipid oxidation, and there is no known mechanism for accurately sensing such demand. This lax regulation may be disadvantageous in conditions such as aging, stress, obesity, and diabetes, where the antilipolytic effect of insulin is impaired and lipolysis is therefore increased. In these conditions, the surfeit of fatty acid may impair glucoregulation. In addition, the excess lipolysis may induce hypertriglyceridemia (via increased very low density lipoprotein production) and thus contribute to atherogenesis. Considerable additional research is needed in order to fully understand both normal lipolytic regulation and the abnormalities of lipolysis which accompany pathological conditions.

Adipose Tissue↗
PubMed1993

Periprandial regulation of lipid metabolism in insulin-treated diabetes mellitus.

We have examined the regulation of lipid and glucose metabolism in the postabsorptive and postprandial states in six subjects with insulin-treated diabetes mellitus, and compared them with eight nondiabetic subjects. Blood or plasma concentrations of metabolites and fluxes across forearm and subcutaneous adipose tissue were studied after an overnight fast and for 6 hours after a mixed meal (3.1 MJ, 41% from fat). In the postabsorptive state, regulation of lipid metabolism in the two groups appeared basically similar except that a wider spread of plasma (free) insulin concentrations in the diabetic group led to a wider range of values of plasma nonesterified fatty acid (NEFA) release from adipose tissue, plasma NEFA concentrations, and blood ketone body concentrations. Extraction of ketone bodies across adipose tissue was positively correlated with arterial concentration in both groups (as it was in the forearm), confirming the ability of human adipose tissue to utilize ketone bodies. A single subcutaneous injection of insulin before the meal in the diabetic group produced a plasma free-insulin profile that was blunted and prolonged compared with the postprandial response in the control group. Postprandial forearm glucose uptake followed very closely the plasma (free) insulin concentration. Postprandial suppression of NEFA release from adipose tissue was essentially normal in the diabetic group, and the normal postprandial decrease in plasma NEFA concentrations was reproduced extremely closely. Forearm and adipose tissue blood flow did not differ between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1993

Subcutaneous adipose tissue metabolism studied by local catheterization.

Adipose tissue is a metabolically active tissue which plays a key role in regulating the concentrations of circulating lipid fuels. In recent years, two new techniques have become available for the study of human adipose tissue metabolism in vivo: microdialysis, and catheterization of the venous drainage from the subcutaneous abdominal adipose tissue. Blood obtained by the latter method shows all the characteristics expected of adipose tissue drainage. The characteristics of this tissue are quite distinct from those of the superficial (mainly skin) or the deep (mainly muscle) tissues of the forearm. The depot studied appears to be typical of adipose tissue as a whole in terms of non-esterified fatty acid release. In comparison with the microdialysis technique, the arterio-venous difference technique allows easier quantification of substrate uptake and release, and allows the study of hydrophobic molecules (e.g. fatty acids, triacylglycerol). On the other hand, it does not allow the study of more than one depot, nor the local introduction of effectors of metabolism (e.g. adrenergic agents). The two techniques are clearly complementary.

Adipose Tissue↗
PubMed1993

Post-prandial VLDL subfraction metabolism in normal and obese subjects.

The metabolic behaviour of very low density lipoprotein subfractions Sf 60-400 (VLDL1) and Sf 20-60 (VLDL2) was studied in five normal weight and five obese subjects following an overnight fast and after the consumption of a mixed meal. The VLDL1 showed increases in triacylglycerol (TG) and cholesterol concentrations after the meal, while the VLDL2 response was much smaller. The obese individuals had higher concentrations of TG, apolipoprotein B and cholesterol in both VLDL subfractions, but when the TG and cholesterol were expressed in terms of their content per VLDL particle, there was no difference between control and obese subjects. The abnormality in the obese group was identified as an elevated number of VLDL particles, of normal composition, which may predispose these individuals to coronary heart disease.

Adult↗
PubMed1992

Steroid hormone interconversions in human adipose tissue in vivo.

The objective of this study was to demonstrate directly, by measurement of arteriovenous concentration differences, the interconversion of steroid hormones in human subcutaneous adipose tissue in vivo. Simultaneous arterial (or arterialized) and adipose tissue-venous plasma samples were collected from eight men and seven women, for measurement of estradiol, estrone, testosterone, and androstenedione concentrations by radioimmunoassay. Despite the heterogeneity of the groups (premenopausal and postmenopausal women, one subject with insulin-dependent diabetes mellitus), some very consistent findings emerged. Both estrogens were added to plasma during passage through adipose tissue in almost all subjects (P less than .01 for each hormone). In all the men but one, testosterone was removed from plasma, and the arteriovenous difference was correlated with the arterial concentration (r = .70, P = .05). In all the women but one (in whom there was no change), the testosterone concentration increased during passage through adipose tissue. The handling of androstenedione was less consistent. This study demonstrates the feasibility of direct measurement of the peripheral production or utilization of steroid hormones, and confirms the belief that adipose tissue is an important site for such interconversions.

Adipose Tissue↗
PubMed1992

Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.

Physiological actions of insulin include suppression of fat mobilization from adipose tissue and activation of adipose tissue lipoprotein lipase. Here, we report measurements of adipose tissue hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action in vivo in 10 normal and eight obese subjects, with the latter group having varying degrees of glucose intolerance. HSL and LPL actions (per gram of adipose tissue) were similar in the two groups, after an overnight fast. In the normal subjects, HSL action was suppressed after a meal (by 75% +/- 6% between 60 to 300 minutes, P less than .01), and the action of LPL was increased (clearance of circulating triacylglycerol [TAG] increased by 140% +/- 57% at 300 minutes, P less than .05). Despite hyperinsulinemia, these responses were blunted in the obese subjects (P less than .05 for each change being less than in normal group). The adipose tissue of the obese subjects showed continued nonesterified fatty acid (NEFA) release at a time when NEFA mobilization was completely suppressed in the normal group. Both impaired suppression of HSL and low fractional retention of fatty acids for reesterification within the adipose tissue contributed to this abnormal NEFA release. Impaired activation of LPL was associated with a greater absolute increase in plasma TAG concentration postprandially in the obese. In obese subjects, adipose tissue HSL and LPL fail to respond to immunoreactive insulin postprandially, which may be an important maladaptation in terms of lipoprotein metabolism and risk of coronary heart disease.

Adipose Tissue↗
PubMed1991

No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man.

In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose.kg ideal body weight-1.min-1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p less than 0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p less than 0.005) and C-peptide (p less than 0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/l). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for 'glucose toxicity' to the Beta-cells.

Adult↗
PubMed1991

Glycerol and lactate uptake in human forearm.

Arteriovenous differences for lactate and glycerol reported across the human forearm are inconsistent in direction and magnitude. Such inconsistency could represent the effects of differing forearm compositions. The hypothesis was tested by examination of 37 studies of forearm arteriovenous differences for lactate, glycerol, glucose, and oxygen (only measured in 25 studies) in 23 normal subjects after overnight fast. In 16 studies, glycerol was taken up rather than released by the forearm, and in 12 of these the arteriovenous difference was greater than could be accounted for by analytical variation. The arteriovenous differences for glycerol and lactate were positively correlated (r = .44, P less than .01). The hypothesis that glycerol and lactate uptake might reflect a more "oxidative" forearm was not borne out, since neither glycerol nor lactate arteriovenous differences correlated with that for oxygen, although oxygen and glucose arteriovenous differences and fluxes were correlated (fluxes: r = .60, P less than .01). The arteriovenous difference for glycerol was positively related to body mass index, arguing against a variable contribution from fat. The hypothesis that the direction of glycerol and lactate exchange would reflect the forearm composition was not borne out by the analysis of repeated studies on the same individual, which showed that the variation within subjects was not significantly less than that between subjects. Therefore, we conclude that in approximately 40% of studies in normal subjects after an overnight fast, the forearm will show glycerol uptake, although we have been unable to identify any physiological reason for this phenomenon. Peripheral glycerol uptake has implications for studies in which glycerol release is taken as a measure of lipolysis.

Adult↗
PubMed1991

Amino acid metabolism in human subcutaneous adipose tissue in vivo.

1. Arteriovenous differences for alanine, glutamate and glutamine were measured across subcutaneous adipose tissue and forearm muscle in normal subjects. 2. After an overnight fast, adipose tissue showed net production of alanine and glutamine and uptake of glutamate in each of 11 subjects. 3. In seven subjects, adipose tissue blood flow was measured and the measurements were continued for 6 h after eating a mixed meal. The pattern of amino acid metabolism across the adipose tissue was remarkably little disturbed after the meal, except for a short period of apparent uptake of alanine as the concentration of that amino acid rose. 4. The pattern of amino acid metabolism across adipose tissue was qualitatively similar to that across the forearm, although it differed quantitatively in that glutamate uptake was more prominent (compared with glutamine release) in the adipose tissue. 5. The rates of alanine and glutamine release observed suggest that adipose tissue may play a substantial role in the whole-body production of these amino acids.

Adipose Tissue↗
PubMed1991

Effect of insulin on intracellular pH and phosphate metabolism in human skeletal muscle in vivo.

1. 31P nuclear magnetic resonance spectroscopy and the hyperinsulinaemic-euglycaemic clamp were used simultaneously to assess the effect of insulin on intracellular pH and the major phosphorus-containing metabolites of normal human skeletal muscle in vivo in four normal subjects. 2. Insulin and glucose were infused for 120 min. Plasma insulin increased approximately 10-fold over preclamp levels (5.6 +/- 0.9 m-units/l pre-clamp and 54 +/- 5 m-units/l over the last hour of infusion; mean +/- SEM, n = 4). Plasma glucose concentration did not change significantly (5.4 +/- 0.2 mmol/l pre-clamp and 5.5 +/- 0.1 mmol/l over the last hour of infusion). 3. Insulin and glucose infusion resulted in a decline in the intracellular pH of forearm muscle of 0.027 +/- 0.007 unit/h (P less than 0.01), whereas in control studies of the same subjects, pH rose by 0.046 +/- 0.005 unit/h (P less than 0.001). 4. In the clamp studies, intracellular inorganic phosphate concentration rose by 18%/h, whereas ATP, phosphocreatine and phosphomonoester concentrations did not change. In plasma, inorganic phosphate concentration was 1.16 +/- 0.05 mmol/l before infusion, and this decreased by a mean rate of 0.14 mmol h-1 l-1. No change was observed in any of these intracellular metabolites in the control studies. 5. The results show that, under physiological conditions, insulin does not raise intracellular pH in human muscle, and thus cannot influence muscle metabolism by this mechanism. The results also suggest that insulin causes a primary increase in the next flux of inorganic phosphate across the muscle cell membrane.

Adult↗
PubMed1991

Peripheral triacylglycerol extraction in the fasting and post-prandial states.

1. Triacylglycerol extraction by subcutaneous adipose tissue and forearm muscle was studied in nine normal subjects after an overnight fast and after the consumption of a mixed meal. 2. There was an inverse correlation between the total plasma fractional triacylglycerol extraction across the adipose tissue and the fasting arterial plasma triacylglycerol concentration. In contrast, there was no correlation between the lower fractional triacylglycerol extraction across the forearm muscle and the fasting plasma triacylglycerol concentration. 3. Chylomicron-triacylglycerol concentrations in arterial(ized) plasma increased post-prandially and peaked at 240-300 min. There was a comparable increase in the very-low-density lipoprotein-triacylglycerol concentration, peaking at 300 min. 4. Clearance of chylomicron-triacylglycerol by adipose tissue increased after the meal (P less than 0.05). In contrast, the clearance of very-low-density lipoprotein-triacylglycerol by adipose tissue decreased post-prandially (P less than 0.05). 5. Although there was significant uptake of chylomicron-triacylglycerol by the forearm muscle post-prandially, this was less than by the adipose tissue. Very-low-density lipoprotein-triacylglycerol was unaffected by passage through the forearm muscle at any time. 6. We conclude that the extraction of lipoprotein-triacylglycerol by human adipose tissue is important in determining the fasting plasma triacylglycerol concentration. Chylomicron-triacylglycerol, appearing in the plasma post-prandially, may compete with very-low-density lipoprotein-triacylglycerol for clearance by adipose tissue lipoprotein lipase, and this mechanism may explain, at least in part, the post-prandial rise in very-low-density lipoprotein-triacylglycerol. Forearm muscle, in contrast, appears to play a much smaller role in the extraction of plasma triacylglycerol, especially that in the very-low-density lipoprotein fraction.

Adipose Tissue↗