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Biomedical subjects

M L Clark

Publications and source records attributed to M L Clark.

At least 37 records · Page 2Linked to original sources
PubMed1996

Reduction of visceral adipose tissue and improvement of metabolic indices: effect of dexfenfluramine in NIDDM.

Increased visceral adipose tissue is thought to contribute to impaired glucose tolerance. We studied 10 men with non-insulin dependent diabetes (NIDDM) before and after a 12-week intervention study using dexfenfluramine. Subjects had a mean body mass index (BMI) of 26.4 +/- 1.7 kg/m2 and had an abdominal distribution of body fatness (waist-to hip ratio > 0.9). Anthropometric indices, biochemistry, macronutrient intake from 7-day food records as well as a euglycaemic glucose clamp and magnetic resonance imaging (MRI) were performed at week 0 and week 12. Abdominal adipose tissue area measured by MRI was reduced from 854 +/- 270 cm2 to 666 +/- 231 cm2 (p = 0.003) due mainly to a selective 32% reduction in visceral fat area from 484 +/- 230 cm2 to 333 +/- 72 cm2 (p = 0.002). Insulin sensitivity improved from 0.29 +/- 0.13 [min-1 (mU/L)] to 0.54 +/- 0.21 [min-1 (mU/L)] (p = 0.01) and C-peptide levels reduced from 0.77 +/- 0.24 mumol/L to 0.58 +/- 0.15 mumol/L (p = 0.002). The reductions in fasting glucose and glycated haemoglobin failed to achieve significance. Fasting total cholesterol and triglyceride levels significantly reduced (p = < 0.001 and p = 0.021 respectively). There was a reduction in total energy intake (p = 0.005) due to a significant reduction in calories obtained from fat (p < 0.001). Thus dexfenfluramine was shown to be a useful adjunct therapy for the reduction of visceral fat in abdominally-obese men with NIDDM with an associated improvement in insulin sensitivity.

Adipose Tissue↗
PubMed1996

Carbohydrate metabolism in insulin resistance: glucose uptake and lactate production by adipose and forearm tissues in vivo before and after a mixed meal.

1. To examine whether insulin resistance in vivo is manifest equally in both muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and sex. 2. Compared with non-obese subjects, the forearm of the obese subjects was resistant to insulin stimulation of glucose uptake after a mixed meal. In contrast, adipose tissue showed little evidence of insulin stimulation of glucose uptake, and adipose tissue in subjects in both normal and obese groups behaved very similarly (assessed per 100 g of tissue). 3. For lactate flux, adipose tissue behaved very similarly (per 100 g of tissue) in obese and non-obese subjects, and was a consistent lactate exporter. 4. We conclude that insulin resistance of glucose uptake observed in the forearm of obese subjects is not evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin-resistant subjects is similar to that in lean control subjects, although it occurs at elevated circulating insulin and glucose concentrations.

Adipose Tissue↗
PubMed1996

Effects of adrenaline infusion on the interstitial environment of subcutaneous adipose tissue as studied by microdialysis.

1. Adrenaline was infused at a rate of 25 ng min-1 kg-1 into seven healthy volunteers and its effects on adipose tissue were studied by microdialysis. 2. Adrenaline infusion led to a rapid rise in plasma adrenaline concentration from a basal value of 0.15 +/- 0.03 nmol/l to a peak value of 1.82 +/- 0.15 nmol/l within 30 min (analysis of variance: P < 0.001). Plasma noradrenaline levels increased from the basal value of 1.48 +/- 0.21 nmol/l to 1.78 +/- 0.20 nmol/l within 30 min of infusion (analysis of variance: P < 0.05). Once the infusion was stopped the plasma adrenaline and noradrenaline levels returned to basal values within 15 min. 3. The arterialized blood glycerol concentration increased from the basal value of 47 +/- 6 mumol/l to 101 +/- 8 mumol/l (analysis of variance: P < 0.001), and the interstitial glycerol concentration increased from 181 +/- 17 mumol/l to 350 +/- 47 mumol/l (analysis of variance: P < 0.001) within 30 min of adrenaline infusion. Thereafter the concentrations declined gradually towards basal values. When the infusion was discontinued the levels declined further, below the basal value. 4. Adrenaline infusion caused a significant increase in the plasma glucose and blood lactate concentration (analysis of variance: P < 0.001 and P < 0.001), but no such effect was observed in the interstitial concentrations. 5. The basal dialysate concentrations of adrenaline and noradrenaline were 43 +/- 37 pmol/l and 1170 +/- 430 pmol/l respectively. There were difficulties in estimating the absolute interstitial concentrations of adrenaline and noradrenaline which are discussed. The dialysate adrenaline concentration increased to a peak value of 112 +/- 48 pmol/l (analysis of variance: P < 0.05) within 30 min. The dialysate noradrenaline concentration increased to a peak value of 2830 +/- 1470 pmol/l, but the rise was not significant. 6. These results show that the interstitial concentrations of metabolites and hormones can be significantly different from those of blood and plasma and these differences reflect tissue specialization.

Adipose Tissue↗
PubMed1996

Is the growth hormone concentration regulated by the morning rise in the plasma cortisol concentration?

Exogenous steroids affect plasma growth hormone (GH) concentrations and hypothalamic somatostatin levels either directly, by stimulating the anterior pituitary gland, or indirectly by partially inhibiting the response of the pituitary gland to stimuli. The effect of the circadian rhythm of cortisol on plasma GH concentrations is unknown. In normal subjects, highest plasma GH concentrations are recorded within the first two hours of onset of sleep. During the early morning the plasma GH concentration decreases and the plasma cortisol concentration increases. We investigated the effect of the early morning rise in plasma cortisol concentration on plasma GH concentrations. We studied 12 healthy volunteers on two occasions. On one occasion the early morning rise in plasma cortisol concentrations was reduced by administering metyrapone (750 mg, 4 hourly from 03.00), while on the other occasion no intervention was made. Plasma GH and cortisol concentrations were measured every 30 and 60 minutes respectively from 22.00 until 14.00. Metyrapone caused a significant reduction in the rise of plasma cortisol concentration, but the GH concentration was identical on both occasions. We conclude that the morning rise in cortisol concentration has no acute regulatory effect on the plasma GH concentration.

Adult↗
PubMed1996

L-Arginine, nitric oxide, and intestinal secretion: studies in rat jejunum in vivo.

BACKGROUND: L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginine is thought to have an important role as an intestinal secretagogue. AIM: To determine the effect of L-arginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. METHODS: A 25 cm segment of rat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0.1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mg/kg was examined in rats pretreated with either D-or L-arginine 500 mg/kg. RESULTS: L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7.3 v 17.0 microliters/min/g; p < 0.01). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p < 0.05). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28.4, respectively), which was enhanced by the addition of L-arginine (-30.0 and -41.0, respectively; both p < 0.05). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L- but not D-arginine. CONCLUSIONS: L-arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.

Animals↗
PubMed1996

Regulation of lipid metabolism in adipose tissue during early starvation.

We studied changes in lipid metabolism in adipose tissue in 24 healthy adults during early starvation (14-20 h) by cannulating the venous drainage of the subcutaneous adipose tissue of the anterior abdominal wall. Net nonesterified fatty acid (NEFA) efflux from adipose tissue increased steadily from 1,790 +/- 300 to 2,360 +/- 290 nmol.100 g-1.min-1 (P = 0.03), due to increasing transcapillary efflux of NEFA (release from adipocytes; P < 0.01). The reesterification rate after an overnight fast was close to zero; thus, reduction in the rate of reesterification played no part in the increased transcapillary efflux of NEFA. One-quarter of the net efflux of NEFA after an overnight fast arose from the action of lipoprotein lipase (LPL), although this relative contribution decreased during the study (P < 0.02). The increased transcapillary efflux of NEFA reflected a significant increase in the rate of action of hormone-sensitive lipase (HSL; P = 0.03). There was a strong relationship between mean arterial NEFA concentration and net NEFA release from adipose tissue (P < 0.001), implying that the particular depot studied reflects the behavior of adipose tissue as a whole. Thus the increasing efflux of NEFA from adipose tissue observed during early starvation is due to an increased rate of action of HSL, which may in turn be regulated by a fall in the plasma insulin concentration.

Adipose Tissue↗
PubMed1996

Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism.

Epinephrine has effects on both blood flow and metabolism in adipose tissue. To investigate how these effects might interact in vivo, epinephrine was infused into six healthy volunteers at a rate of 25 ng.kg-1.min-1. The rates of action of lipoprotein lipase and hormone-sensitive lipase in adipose tissue were calculated by measurement of arteriovenous differences across subcutaneous abdominal adipose tissue, and adipose tissue blood flow was measured. Epinephrine caused a significant rise in adipose tissue blood flow (P < 0.001), and the net efflux of nonesterified fatty acids (NEFA) from adipose tissue increased significantly (P < 0.05). Most of this efflux could be accounted for by hormone-sensitive lipase-derived NEFA efflux from cells (P < 0.05), but there was also a significant rise in the contribution of lipoprotein lipase-derived NEFA (P < 0.05). We conclude that adipose tissue blood flow plays an important role in the regulation of lipid metabolism, controlling substrate presentation for lipoprotein lipase and also preventing the local accumulation of fatty acids derived from both hormone-sensitive lipase and lipoprotein lipase.

Adipose Tissue↗
PubMed1996

Effects of morning rise in cortisol concentration on regulation of lipolysis in subcutaneous adipose tissue.

Cortisol has a well-defined circadian rhythm. The aim of the study was to examine the effect of the morning rise in cortisol concentration on lipolysis in adipose tissue. Ten healthy subjects were studied on two occasions, and six of these were studied on three occasions. During the first two occasions, either a control or cortisol suppression study was performed by using metyrapone, and on the third occasion exogenous cortisol replacement was given in addition to metyrapone. Lipolysis in the subcutaneous adipose tissue of the anterior abdominal wall was studied by measurement of arteriovenous differences. Reduction in the early morning rise in cortisol led to significantly decreased venoarterialized differences for nonesterified fatty acids (P < 0.05) and glycerol (P < 0.01), attributable in part to decreased hormone-sensitive lipase (EC 3.1.1.3) action (P < 0.05) in adipose tissue. At the same time the arterialized plasma triacylglycerol concentration increased (P < 0.005) with a significant reduction in the adipose lipoprotein lipase (EC 3.1.1.34) rate of action (P < 0.05). In the replacement study, values were identical to those of the control study, showing that metyrapone had no nonspecific effects on lipolysis. We conclude that the morning rise in plasma cortisol concentration plays an important role in the regulation of lipolysis in adipose tissue in normal healthy adults.

Adipose Tissue↗
PubMed1995

Modification and validation of a commercially available portable detector for measurement of adipose tissue blood flow.

Adipose tissue blood flow is measured from the clearance of radioactive xenon from a depot. Traditionally, a NaI detector has been used to measure the residual depot of xenon. However, this is sensitive to movement artefacts. We tested a commercially available lightweight CsI detector which can be strapped to the anterior abdominal wall. In pilot studies the CsI detector produced higher values for adipose tissue blood flow than did a conventional NaI detector. It was modified by inclusion of spacers to distance it from the skin. Flow results generated by the modified detector were similar to those generated by the NaI detector, both after an overnight fast and during the increased blood flow after a meal. Individual decay patterns generated by the CsI detector were, however, significantly smoother than those from the NaI detector.

Abdominal Muscles↗
PubMed1994

L-phenylalanine releases cholecystokinin (CCK) and is associated with reduced food intake in humans: evidence for a physiological role of CCK in control of eating.

Exogenous administration of cholecystokinin (CCK) reduces food intake in humans; however, it is not clear if endogenous CCK is a true satiety hormone. The aim of this experiment was to manipulate endogenous release of CCK using L-phenylalanine (L-PA), a potent releaser of CCK, and to measure subsequent food intake. On separate occasions, six normal-weight fasted subjects (four men, two women) were administered 10 g of L-PA, D-PA, or placebo 20 minutes before being presented with a standard meal of known calorie content. Preliminary experiments had shown that peak plasma concentrations of CCK were obtained 20 minutes after administering L-PA. The test meal was given to coincide with this peak. One hundred-millimeter visual analog scales (VAS) to assess hunger, desire to eat, and fullness were completed premeal, postmeal, and at intervals thereafter. Blood was taken before administering PA/placebo immediately premeal and postmeal and stored for measurement of CCK levels by bioassay. Subjects consumed 1,089 +/- 86 kcal after L-PA (P = .03) compared with 1,587 +/- 174 kcal after placebo and 1,492 +/- 126 kcal after D-PA. The reduction in calorie intake after L-PA was associated with a significantly greater sensation of fullness. Basal levels of CCK were 1.10 +/- 0.12 pmol/L; 20 minutes after L-PA, CCK levels increased to 5.49 +/- 0.83 pmol/L. There was no increase in CCK following D-PA or placebo. Release of CCK by L-PA is associated with a reduction in subsequent food intake, and this suggests that CCK is an important satiety hormone in humans.

Adult↗
PubMed1994

Forearm substrate utilization during exercise after a meal containing both fat and carbohydrate.

1. Whilst the provision of exogenous carbohydrate has been shown to be beneficial to endurance exercise performance, little attention has been paid to the possibility of dietary manipulation of the availability of fat. 2. Ten normal subjects were studied on two occasions: after an overnight fast (postabsorptive state) and after a meal containing 80 g of fat and 80 g of carbohydrate (fed state). Forearm substrate exchange was studied during 60 min of isometric forearm exercise (5 s contraction, 5 s relaxation). 3. In the fed state concentrations of plasma triacylglycerol (1510 +/- 150 versus 850 +/- 80 mumol/l, P < 0.01), blood ketone bodies (151 +/- 21 versus 80 +/- 10 mumol/l, P < 0.01) and plasma insulin (17 +/- 3 versus 7 +/- 1 m-units/l, P < 0.01) were elevated compared with the postabsorptive state; plasma glucose and non-esterified fatty acid concentrations were not significantly different. 4. Forearm blood flow and O2 consumption each increased about 6-fold during exercise, with no differences between the two nutritional states. The potential contribution of individual substrates to forearm O2 consumption (a calculation which is independent of blood flow) was assessed: for triacylglycerol it was significantly greater in the fed state (P < 0.01). The sum of the potential contributions of triacylglycerol, non-esterified fatty acids, glucose and ketone bodies to forearm O2 consumption was significantly greater, both before and during exercise, in the fed than in the postabsorptive state (P < 0.05), implying the sparing of endogenous (forearm) fuels. 5. These studies highlight the potential for manipulation of substrate supply during exercise by feeding meals containing both carbohydrate and fat.

Adult↗
PubMed1994

Glucose polymer in the fluid therapy of acute diarrhoea: studies in a model of rotavirus infection in neonatal rats.

1. Unlike standard glucose-electrolyte oral rehydration solutions, solutions containing polymeric glucose as substrate can significantly reduce stool output, duration of diarrhoea and total oral rehydration solution requirements. However, neither the underlying mechanisms nor the optimal size and concentration of glucose polymer has been defined. 2. We have used a model of rotavirus diarrhoea in neonatal rats to compare the effects on water and solute absorption of varying the concentration of a glucose polymer (mean chain length five glucose residues) in experimental oral rehydration solutions. Three polymer (P) solutions were compared with solutions of identical electrolyte content (mmol/l: sodium, 60; potassium, 20; chloride, 60; citrate, 10) containing equivalent amounts of free glucose (G) as substrate by perfusion of the entire small intestine in situ. The polymer (9, 18, 36 mmol/l; 159, 168, 186 mosmol/kg, respectively) and the monomer (45, 90, 180 mmol/l; 195, 240 320 mosmol/kg) solutions were perfused in normal and rotavirus-infected neonatal rats. 3. In normal intestine polymer solutions promoted greater water absorption [P9, mean 291.4 (SEM 16.4); P18, 331.9 (13.1); P36, 284.3 (11.8) microliters min-1 g-1] than their equivalent monomer solutions [G45, 220.8 (8.4); G90, 240 (21); G180,79.4 (14.5) microliters min-1 g-1; P < 0.02]. In rotavirus-infected intestine, water absorption from all solutions declined, but the fall was much less pronounced from the polymer solutions [P9, 232.8 (6); P18, 277.2 (20.5); P36, 166 (18.2) microliters min-1 G-1] than from their monomeric counterparts [G45, 116.7 (25.5); G90, 68.7 (12.4); G180, 21 (11.6) microliters min-1 g-1; P < 0.005].(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Immediate metabolic availability of dietary fat in combination with carbohydrate.

We tested the hypothesis that when fat is ingested in combination with carbohydrate, direct release of fatty acids into the plasma may occur. Eight normal subjects ingested two meals: high-fat (80 g fat, 80 g carbohydrate, and 18 g protein) and low-fat (< 1 g fat, otherwise closely matched). Over the subsequent 6 h, net fat oxidation was greater after the high-fat meal (20.7 vs 10.6 g, P < 0.01). Plasma nonesterified fatty acid (NEFA) concentrations were markedly suppressed after the low-fat meal, but relatively maintained after the high-fat meal (P < 0.01). The profile of plasma NEFAs changed after the high-fat meal, consistent with entry of meal-derived fatty acids into the NEFA pool. We suggest that after ingestion of combinations of carbohydrate and fat, the action of lipoprotein lipase on chylomicron-triacylglycerol leads to direct release of fatty acids into the plasma and increased fat oxidation.

Adult↗
PubMed1994

Absorption of a hypotonic oral rehydration solution in a human model of cholera.

The development of oral rehydration solutions (ORSs) has been one of the important therapeutic advances of this century. The optimal formulation, however, of ORSs for both cholera and other infective diarrhoeas is still debated. Part of the problem in developing ORSs has been the lack of adequate test systems for the assessment of new formulations before clinical trial. We have developed a jejunal perfusion, cholera toxin induced, secretory model in humans and have compared net water and solute absorption from a hypotonic ORS (HYPO-ORS: sodium 60 mmol/l, glucose 90 mmol/l, osmolality 240 mOsm/kg) and the British Pharmacopoeia recommended ORS (UK-ORS: sodium 35 mmol/l, glucose 200 mmol/l, osmolality 310 mOsm/kg) in six healthy volunteers. A plasma electrolyte solution (PES) was also perfused in all subjects to confirm a secretory state. Only HYPO-ORS reversed sodium secretion to absorption (p < 0.01). Both ORSs promoted net water absorption but this was greatest with HYPO-ORS (p < 0.01). Glucose and potassium absorption rates were similar for both ORSs whereas chloride absorption mirrored sodium absorption and was greatest from HYPO-ORS (p < 0.05). These results, in a biologically relevant model of secretory diarrhoea, suggest it may be possible to achieve improved rates of rehydration by the use of hypotonic ORS with mid range sodium concentrations.

Adult↗
PubMed1994

Symptom relief and quality of life after stenting for malignant bile duct obstruction.

Palliative treatment is appropriate for most patients with cancer of the head of pancreas. Insertion of a biliary stent relieves jaundice and pruritus but it is not known if stenting affects other symptoms or changes the quality of life. Nineteen patients have completed a standard questionnaire to assess symptom relief and quality of life after stent insertion. After stenting there was complete relief of jaundice and pruritus. Furthermore, there was also considerable improvement in anorexia and indigestion. All patients had anorexia before stent insertion, this was moderate/severe in 13 (68.4%). Anorexia was significantly better (p < 0.01) a week after stenting and this benefit was maintained at 12 weeks (p < 0.01). Sixteen (84.2%) patients complained of indigestion before stenting, moderate/severe in 11 (57.9%). This was significantly better (p < 0.01) a week after stenting with complete relief in six at eight weeks (p < 0.01). Fifteen (78.9%) felt that their mood was good/very good before stent insertion and this was unchanged even at the 12 week assessment. A similar result was obtained for physical health and level of activity. In conclusion stent insertion not only relieves jaundice and pruritus in these patients but also improves other symptoms and quality of life. The considerable improvement in appetite after stenting was of particular benefit.

Affect↗