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Biomedical subjects

W M Bennet

Publications and source records attributed to W M Bennet.

16 recordsLinked to original sources
PubMed1992

Clinical studies with the beta-adrenoceptor agonist BRL 26830A.

BRL 26830A is a beta-adrenoceptor agonist drug that shows a high degree of selectivity for thermogenesis and has potential as an antiobesity agent. We undertook a double-blind trial in 40 obese subjects who received either BRL 26830A or placebo for 18 wk. All were prescribed a 3.35 MJ (800 kcal) diet. Weight loss was 15.4 +/- 6.6 (SD) kg on BRL 26830A compared with 10.0 +/- 5.9 kg on placebo (P less than 0.02). The relative weight losses were 0.93% and 0.61%/wk, respectively. Urinary nitrogen excretion was similar in both groups and skinfold measurements indicated a 4-kg difference in fat lost, suggesting that weight loss was mainly from adipose tissue. Psychological assessments showed that BRL 26830A had no adverse effect on mood and no effect on hunger or satiety. Tremor was experienced by 12 of 16 treated subjects who completed the study. It was generally rated as mild, occurred 1 h after dosing, and tended to diminish with time on treatment. Subsequent analysis of the tremor suggested that it is an exaggeration of physiological tremor mediated through skeletal muscle beta 2 adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1992

Growth hormone and lean tissue catabolism during long-term glucocorticoid treatment.

OBJECTIVES: The aim of the study was to determine whether growth hormone (GH) treatment decreased net protein catabolism of lean tissues in patients receiving chronic glucocorticoid treatment. DESIGN: Whole body leucine kinetics were measured in post-absorptive conditions using a 1-14C-leucine infusion before and during GH administration (0.0125 mg/kg/day; 0.033 U/kg/day) for 7 days. PATIENTS: We studied four patients (age range 31-71 years) who had taken prednisone (mean +/- SEM 0.21 +/- 0.03 mg/kg/day, total dose 10-27.5 mg/day) for longer than 5 months for various lung diseases. RESULTS: During GH treatment leucine oxidation decreased (baseline 0.44 +/- 0.07 vs GH 0.37 +/- 0.05 mumol/kg lean body mass/min, P = 0.01) and non-oxidative leucine disposal increased (1.95 +/- 0.10 vs 2.05 +/- 0.09 mumol/kg lean body mass/min, P = 0.02) but leucine appearance was unaltered. CONCLUSIONS: We conclude that GH decreased amino acid catabolism and improved protein synthesis without altering protein breakdown in patients receiving chronic glucocorticoid treatment. There may be a role for GH in mitigating the protein catabolic side-effects of prolonged glucocorticoid treatment.

Body Composition↗
PubMed1992

Expression of messenger ribonucleic acids encoding neuropeptide-Y, substance-P, and vasoactive intestinal polypeptide in human pituitary.

The local production of autocrine or paracrine agents in endocrine tissues represents an important level of hormonal regulation. The synthesis of neuropeptide-Y (NPY), substance-P (SP), and vasoactive intestinal peptide (VIP) in the rat anterior pituitary gland has been well demonstrated. We have now studied their expression in human postmortem pituitary tissue. Northern blot analysis of poly(A)+ RNA from whole human pituitaries revealed mRNA encoding the precursors for NPY, SP, and VIP whose hybridization characteristics were indistinguishable from those of the same mRNAs described in previously characterized human tissues. VIP mRNA was detectable in all samples tested, with NPY and preprotachykinin-A mRNA (which encodes SP) detectable in a subset of the pituitaries. The concentration of immunoreactive NPY in whole human pituitary was 3.8 +/- 1.1 pmol/g wet wt in males and 2.9 +/- 0.5 pmol/g wet wt in females (mean +/- SEM; n = 10), that of SP was 3.1 +/- 0.4 pmol/g wet wt in males and 5.2 +/- 1.3 pmol/g wet wt in females (n = 10), and that of VIP was 8.1 +/- 2.9 pmol/g wet wt in males and 5.3 +/- 1.6 pmol/g wet wt in females (n = 10). Size-fractionation of pituitary extracts by gel permeation chromatography revealed single peaks of NPY and VIP-like immunoreactivity in the positions of the standards, while SP-like immunoreactivity mostly eluted in the position of synthetic SP, with two minor immunoreactive peaks eluting earlier. The low levels of NPY, SP, and VIP and their mRNAs in the human pituitary are consistent with peptides having an autocrine/paracrine, rather than endocrine, mode of action.

Adult↗
PubMed1992

Metabolic effects of three weeks administration of the beta-adrenoceptor agonist BRL 26830A.

BRL 26830A is a thermogenic beta-adrenergic agonist drug which has an anti-obesity effect in animals and diet-restricted obese man. This study was undertaken in obese subjects who were not calorie restricted to assess the effect of three weeks drug administration on energy expenditure and glucose, amino acid and fatty acid metabolism in the post-absorptive and fed states. Stable isotope tracers were employed to determine kinetic data both at baseline and during adrenaline infusion. There was no evidence of BRL 26830A causing a major shift in fuel metabolism or having an anabolic effect. Baseline plasma concentrations of glycerol (P less than 0.01) and palmitate (P less than 0.01) were reduced, glucose remained within the normal range, whereas insulin decreased after BRL 26830A. The hypoaminoacidaemic effect of adrenaline was attenuated by BRL 26830A (P less than 0.01 for branched-chain amino acids, P less than 0.05 for total amino acids). The results suggest that BRL 26830A improves insulin sensitivity and causes selective down-regulation of adrenergic receptors. The increased insulin sensitivity may be a useful therapeutic effect for this class of drug and suggests a possible role in the treatment of obese non-insulin dependent diabetic patients.

Adrenergic beta-Agonists↗
PubMed1991

Effect of adrenaline infusion on fatty acid and glucose turnover in lean and obese human subjects in the post-absorptive and fed states.

1. Energy expenditure, plasma glucose and palmitate kinetics and leg glycerol release were determined simultaneously both before and during adrenaline infusion in lean and obese human subjects. Seven lean subjects (mean 96.5% of ideal body weight) were studied in the post-absorptive state and also during mixed nutrient liquid feeding, eight obese subjects (mean 165% of ideal body weight) were studied in the post-absorptive state and six obese subjects (mean 174% of ideal body weight) were studied during feeding. 2. Resting energy expenditure was higher in the obese subjects, but the thermic response to adrenaline, both in absolute and percentage terms, was similar in lean and obese subjects. Plasma adrenaline concentrations attained (3 nmol/l) were comparable in all groups and the infusion had no differential effects on the plasma insulin concentration. Before adrenaline infusion the plasma glucose flux was higher in the obese than in the lean subjects in the fed state only (45.8 +/- 3.8 versus 36.6 +/- 1.0 mmol/h, P less than 0.05); it increased to the same extent in both groups with the adrenaline infusion. 3. Before the adrenaline infusion plasma palmitate flux was higher in the obese than in the lean subjects (by 51%, P less than 0.01, in the post-absorptive state and by 78%, P less than 0.05, in the fed state). However, there was no significant change during adrenaline infusion in the obese subjects (from 13.5 +/- 1.00 to 15.0 +/- 1.84 mmol/h, not significant, in the post-absorptive state and from 14.4 +/- 2.13 to 15.7 +/- 1.74 mmol/h, not significant, in the fed state), whereas there were increases in the lean subjects (from 8.93 +/- 1.10 to 11.2 +/- 1.19 mmol/h, P less than 0.05, in the post-absorptive state, and from 8.06 +/- 1.19 to 9.86 +/- 0.93 mmol/h, P less than 0.05, in the fed state). 4. Before adrenaline infusion the palmitate oxidation rate was also higher in the obese than in the lean subjects (1.86 +/- 0.14 versus 1.22 +/- 0.09 mmol/h, P less than 0.01, in the post-absorptive state and 1.73 +/- 0.25 versus 1.12 +/- 0.12 mmol/h, P less than 0.05, in the fed state). However, in response to adrenaline the fractional oxidation rate (% of flux) increased less in the obese than in the lean subjects, especially in the post-absorptive state (from 13.8 +/- 1.02 to 14.9 +/- 1.39%, not significant, versus from 13.7 +/- 0.98 to 19.3 +/- 1.92%, P less than 0.05). These effects were independent of feeding.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Plasma pool source for fibrinogen synthesis in postabsorptive conscious dogs.

To assess the contributions of leucine and alpha-ketoisocaproate (KIC) derived from the portal vein vs. hepatic artery for hepatic protein synthesis, 14-postabsorptive dogs were infused simultaneously with [1-14C]- and [4,5-3H]leucine or [1-14C]- and [4,5-3H]KIC. On one occasion one tracer was infused via a leg vein and the other via mesenteric infusion catheters, and dogs were restudied with both tracers infused systemically. The ratios of systemically to portally infused tracers in portal and arterial plasma leucine were used as indexes of the radioactivity in the potential precursor pools and in fibrinogen-bound leucine as a paradigm of hepatic protein synthesis. In the dogs given leucine tracers, the relative proportions of systemically to portally infused radioactivity in portal free leucine (0.50 +/- 0.06) were lower (P less than 0.001) than in arterial free leucine (1.22 +/- 0.03) and not different from that bound in fibrinogen (0.43 +/- 0.02). In the dogs infused intraportally with KIC, these values were 0.81 +/- 0.04, 0.97 +/- 0.05, and 0.74 +/- 0.05, respectively. In the control studies these ratios were not significantly different from the expected value of 1.0. The results suggest that, in postabsorptive dogs, fibrinogen is exclusively synthesized from portally delivered leucine with little or no contribution from the hepatic artery, whereas portally delivered KIC contributes little directly to fibrinogen synthesis. These data are consistent with zonation of hepatic amino acid metabolism and/or protein synthesis.

Animals↗
PubMed1991

Galanin in the normal human pituitary and brain and in pituitary adenomas.

Galanin-like immunoreactivity (IR) was measured by radioimmunoassay in extracts of non-tumorous and tumorous human pituitaries and in multiple sites in the human brain. Galanin-IR was present in considerable quantities in the non-tumorous pituitaries (21.4 +/- 1.2 pmol/g wet weight; mean +/- S.E.M., n = 30). In 25 pituitary tumours, galanin-IR was detectable in extracts of only nine, with a mean concentration of 11.5 +/- 4.4 pmol/g. Galanin-IR was undetectable in the remaining 16. Of ten brain sites, galanin-IR was detected only in the hypothalamus, where the concentration was 9.1 +/- 1.8 pmol/g (n = 5). On fast protein liquid chromatography of the non-tumorous pituitary extracts, galanin-IR mostly eluted in a peak with a retention time similar to that of synthetic porcine galanin. On gel permeation chromatography, galanin-IR eluted as a peak with an elution coefficient (Kav) of 0.72, also similar to that of porcine galanin, with additional preceding (Kav 0.62) and following (Kav 0.77) peaks of galanin-IR. These results show that healthy human pituitary and hypothalamus contain substantial amounts of galanin, whereas it is present in variable amounts or not at all in pituitary tumours. Chromatographic analysis suggests that pituitary galanin is present in three molecular forms, with the majority corresponding to synthetic porcine galanin.

Adenoma↗
PubMed1991

Effects of insulin and amino acids on leg protein turnover in IDDM patients.

To determine whether the responses of muscle protein metabolism to insulin and amino acids in patients with insulin-dependent diabetes mellitus (IDDM) were different from those in nondiabetic subjects, leg tissue kinetics of [15N]phenylalanine and [1-13C]leucine and its metabolites were measured in eight insulin-withdrawn IDDM patients and eight nondiabetic subjects during basal insulinemia and during infusion of insulin (0.29 nmol.min-1.m-2). The diabetic patients were studied in the absence of amino acids, and both groups were studied during infusion of a mixed-amino acid solution (AA). In the diabetic patients, insulin alone and combined with additional AA reduced leg tissue phenylalanine release by 42 and 41%, respectively (both P less than 0.05), but uptake was unchanged. Leg tissue leucine oxidation was unchanged by insulin alone but was increased (P = 0.012) fourfold during insulin infusion with additional AA. In the nondiabetic subjects, insulin with AA infusion increased leg tissue phenylalanine uptake (45.7 +/- 7.5 to 73.1 +/- 7.3 nmol.min-1.100 g-1, P less than 0.01). Insulin-stimulated glucose uptake in the diabetic patients (1.60 +/- 0.28 mumol.min-1.100 g-1, P = 0.04). These results suggest that, in IDDM patients, 1) infusion of insulin fails to stimulate muscle protein synthesis even when combined with a substantially increased provision of AA, and 2) compared with nondiabetic subjects, muscle protein synthesis as well as glucose uptake exhibit blunted responses to insulin.

Adult↗
PubMed1990

Inability to stimulate skeletal muscle or whole body protein synthesis in type 1 (insulin-dependent) diabetic patients by insulin-plus-glucose during amino acid infusion: studies of incorporation and turnover of tracer L-[1-13C]leucine.

Despite its anabolic effects on protein balance, acute administration of insulin has been reported to have no effect on skeletal muscle or whole body protein synthesis in man. However, insulin also reduces plasma and intramuscular amino acid availability, which may limit protein synthesis. We have therefore measured the acute effects of insulin on skeletal muscle (anterior tibialis) protein synthesis and whole body leucine turnover in eight insulin-withdrawn Type 1 (insulin-dependent) diabetic patients. They were studied initially when insulin deficient, but during infusion of mixed amino acids at a rate sufficient to raise plasma amino acids by 30% i.e. to 4 mmol/l in total; measurements were continued when insulin was infused together with an increased rate of amino acids to maintain insulinopoenic plasma amino acid concentrations. Using 13C-alpha-ketoisocaproate in plasma as an index of the intracellular precursor labelling, incorporation of [1-13C]leucine into skeletal muscle protein was 0.068 +/- 0.007%/h during insulin withdrawal and was unaltered during insulin infusion. The value is higher than observed in muscle of healthy man, possibly because of a stimulatory effect of endogenous intramuscular amino acids. Also, calculated on the basis of alpha-ketoisocaproate labelling, non-oxidised whole body leucine disappearance (i.e. whole body protein synthesis) was 110 +/- 4 mumol.kg-1.h-1 during insulin withdrawal; this also was unchanged during insulin infusion. Despite stable or increased plasma concentrations of most amino acids, the intramuscular concentrations of a number of amino acids decreased during insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1990

The effect of amino acid infusion on leg protein turnover assessed by L-[15N]phenylalanine and L-[1-13C]leucine exchange.

A stable isotope technique depending on the use of [15N]phenylalanine and [1-13C]leucine to assess exchange was utilized to measure the components of protein turnover of the human leg and the effects of amino acid infusion. Eight healthy subjects (28.5 +/- 2.5 years) were studied when post-absorptive in the basal state and again during infusion of a mixed amino acid solution (55 g l-1, 1.52 ml kg-1 h-1). During the basal period leucine oxidation by the leg was 4.4 +/- 2.0 nmol 100 g-1 min-1 and this increased threefold during amino acid infusion (13.6 +/- 3.1 nmol 100 g-1 min-1, mean +/- SEM, P = 0.003). Amino acid infusion abolished the net negative balance between incorporation of leucine into, and release from, protein (basal, -31.8 +/- 5.8; during infusion, +3.1 +/- 7.1 nmol 100 g-1 P = 0.001). Phenylalanine exchange showed a similar pattern (basal, -13.7 +/- 1.8; during infusion, -0.8 +/- 3.0 nmol 100 g-1 min-1, P = 0.003). Basal entry of leucine into leg protein (i.e. protein synthesis) was 70.0 +/- 10.8 nmol 100 g-1 min-1 and this increased during amino acid infusion to 87.3 +/- 14.1 nmol 100 g-1 min-1 (P = 0.11). Phenylalanine entry to protein also increased with amino acid infusion (29.1 +/- 4.5 vs. 38.3 +/- 5.8 nmol 100 g-1 min-1, P = 0.09). Release from protein of leucine (101.8 +/- 9.1 vs. 84.2 +/- 9.1 nmol 100 g-1 min-1, P = 0.21) and of phenylalanine (42.8 +/- 4.2 vs. 39.1 +/- 4.2 nmol 100 g-1 min-1, P = 0.50) was unchanged by amino acid infusion. The results suggest that, in the post-absorptive state in man, infusion of mixed amino acids, without additional energy substrates; reverses negative amino acid balance by a mechanism which includes stimulation of muscle protein synthesis but which does not alter protein breakdown. Interpretation of the results obtained concurrently on whole-body protein turnover suggests that the increase in muscle protein synthesis contributes substantially to the whole-body increase, but the fall in whole-body breakdown with exogenous amino acids is independent of changes in muscle.

Adult↗
PubMed1990

Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia.

The effect of insulin on leg and whole body protein turnover was determined by leg exchange and plasma kinetics of [15N]phenylalanine and [1-13C]leucine during amino acid (AA) sufficiency. Eight healthy subjects were studied during AA infusion alone and during infusion of glucose and insulin (0.29 nmol.m-2.min-1) with additional AA. Insulin strongly stimulated the positive leg AA balance seen with AA (AA alone, 2.6 +/- 6.1 vs. insulin + AA, 33.1 +/- 5.8 nmol phenylalanine . 100 g leg-1.min-1; P less than 0.001). Phenylalanine uptake by leg tissues rose during insulin plus AA (47.3 +/- 11.5 vs. 73.1 +/- 7.3 nmol. 100 g-1.min-1; P = 0.022) but with only a slight reduction in leg phenylalanine release (44.7 +/- 8.1 vs. 40.0 +/- 7.9 nmol.100 g-1.min-1). Leg nonoxidative leucine plus alpha-ketoisocaproate (KIC) uptake was increased slightly with insulin (129 +/- 26 vs. 146 +/- 21 nmol.100 g-1. min-1), but leg leucine oxidation increased fourfold (P = 0.012). Leg leucine plus KIC release was reduced by insulin (120 +/- 17 vs. 84 +/- 10 nmol.100 g-1.min-1; P = 0.005); endogenous leucine appearance of leucine and phenylalanine decreased with insulin (leucine, 1.97 +/- 0.08 vs. 1.65 +/- 0.10; phenylalanine, 0.76 +/- 0.03 vs. 0.54 +/- 0.08 mumols.kg-1.min-1; P less than 0.02). The results suggest that insulin, given with sufficient amino acids, may stimulate leg and whole body protein balance by mechanisms including stimulation of protein synthesis and inhibition of protein breakdown.

Adult↗
PubMed1989

Clinical utility of assays of glycosylated haemoglobin and serum fructosamine compared: use of data on biological variation.

Assessment of the relative clinical usefulness of glycosylated haemoglobin (HbA1) and serum fructosamine is complicated by their markedly different half-lives. They have therefore been compared using a number of indices derived from data on biological variation, as applied in a study of blood glucose control in newly diagnosed diabetic patients. The within-subject (CVI) and between-subject (CVG) variation of fructosamine and HbA1 were assessed in 8 stable diabetic patients. A slightly smaller relative change, or critical difference, is required between serial HbA1 results than between fructosamine results before a significant change can be said to have occurred. The heterogeneity of within-subject variance is also less for HbA1, rendering the critical difference more generally applicable. HbA1 may therefore be more appropriate for long-term monitoring. Monitoring of blood glucose control of a group of 26 newly diagnosed diabetic patients before the commencement of therapy and 1, 2, and 3 months later by serum fructosamine or HbA1 provided very similar information. Fructosamine responds more rapidly with changes of blood glucose control. However, whether this confers any clinical advantage will depend upon the frequency of testing.

Aged↗
PubMed1978

Gentamicin binding to serum and plasma proteins.

Gentamicin binding to serum proteins was studied by equilibrium dialysis at 37 degrees C and pH 7.4 in the presence of both physiologic and adjusted concentrations of ionized calcium and magnesium. The percentage of bound drug was inversely related to the concentration of these two divalent cations, raning from 27% bound with no calcium and magnesium present to 17% bound in the presence of four times physiologic concentrations. No significant difference in the extent of drug-protein binding was noted in a comparison of sera from healthy and uremic subjects. Heparin also was found to affect gentamicin binding. Increasing heparin concentration in serum increased apparent gentamicin-protein binding to 34% in the presence of physiologic amounts of calcium and magnesium. Buffered heparin solutions without plasma proteins bound up to 65% of total drug concentration. Gentamicin-protein binding may have implications regarding pharmacokinetics and renal cortical uptake.

Blood Proteins↗
PubMed1978

Comparative nephrotoxicity of gentamicin and tobramycin in rats.

A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model.

Animals↗