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Biomedical subjects

D M Bier

Publications and source records attributed to D M Bier.

At least 55 records · Page 3Linked to original sources
PubMed1992

Role of GH in regulating nocturnal rates of lipolysis and plasma mevalonate levels in normal and diabetic humans.

To define the role that nocturnal increments in growth hormone (GH) play in maintaining lipolysis, glycerol turnover was measured in six patients with GH deficiency and six normal subjects during sleep. Glycerol production initially decreased in both groups but then increased to 1.44 +/- 0.20 mumol.kg-1.min-1 by 0800 h in normal subjects, whereas GH deficiency was associated with a continuous fall to 0.77 +/- 0.10 mumol.kg-1.min-1, P less than 0.02. Nonesterified fatty acid levels paralleled these changes. Six GH-deficient patients received basal GH replacement including a pulse during sleep, which resulted in normal fasting fatty acid levels (P less than 0.05, replaced vs. chronic deficiency). To assess a possible link between the normal nocturnal increase in plasma mevalonate (the product of the rate-limiting step in cholesterol synthesis) and sleep-associated GH release, 11 GH-deficient patients and 11 normal subjects were studied. Peak nocturnal and fasting mevalonate concentrations were not correlated with GH level. We conclude that nocturnal growth hormone secretion is essential for maintaining lipolysis but that it is not related to normal increments in mevalonate and, by inference, to cholesterol synthesis during sleep.

Adult↗
PubMed1992

Epinephrine's ketogenic effect in humans is mediated principally by lipolysis.

To quantify epinephrine's effects on acetoacetate and beta-hydroxybutyrate kinetics, we infused subjects with 0.3 and 2.5 micrograms/min epinephrine, either alone or with a concomitant somatostatin infusion with insulin, glucagon, and growth hormone replaced at postabsorptive levels (islet clamp). Additional subjects received no epinephrine but sequential infusions of heparin plus 10% Intralipid at rates of 0.5 and 3.0 ml/min. Both epinephrine and Intralipid increased ketone body appearance (unaffected by islet clamp), augmented the interconversion rates between ketone bodies and, during the 2.5 micrograms/min infusion, caused a marked increase in beta-hydroxybutyrate appearance. The fraction of plasma free fatty acid (FFA) flux appearing as plasma ketones increased from 6 to 7% in the basal state to 11% at the high-epinephrine infusion. This fraction was also unaffected by the islet clamp and was not different from values obtained at similar Intralipid plus heparin-induced elevations in plasma FFA levels. We conclude that epinephrine's ketogenic effect in humans is primarily the result of its lipolytic effect, is accompanied by a significantly increased rate of ketone body interconversion, is manifest largely as an increase in plasma beta-hydroxybutyrate appearance at high plasma epinephrine values, and is not limited by portal insulin at post-absorptive levels.

3-Hydroxybutyric Acid↗
PubMed1992

Forearm ketone body metabolism in normal and in insulin-dependent diabetic patients.

In insulin deficiency, there is excessive arterial delivery of free fatty acid (FFA) to muscles where they are converted to acetoacetyl-CoA and acetyl-CoA. These intermediates may be metabolized further to acetoacetate and beta-hydroxybutyrate, which can be released into the venous circulation. When ketone body (KB) tracers are infused in vivo, they are diluted across muscle tissue. This dilution may be due to 1) KB newly formed within muscle (ketogenesis); 2) exchange of tracer between labeled and unlabeled acetyl-CoA and acetoacetyl-CoA, intermediates common to the metabolism of both FFA and KB (pseudoketogenesis). Thus this study assessed whether such label exchange could be detected across the human forearm and whether an increased delivery of FFA in insulin-sufficient controls provoked dilution of labeled KB tracer comparable to that observed in insulin-deficient diabetics. Five normal and five insulin-dependent diabetic (IDDM) subjects were infused with labeled [3,4-13C2]-acetoacetate. [13C]KB enrichments were lower in forearm vein than in the artery, and dilution of labeled KB was always higher than that which could be explained by arterial-venous differences of unlabeled KB. When arterial FFA concentrations in normals were raised (Intralipid+heparin) to values comparable to those of the diabetics, no additional increase in forearm arteriovenous dilution of labeled KB was observed. Neither in the basal state nor under conditions of increased plasma FFA were we able to detect venous appearance of KB labeled in the first and in the second carbon atoms, a necessary consequence of pseudoketogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Plasma glucose kinetics during exercise in subjects with high and low lactate thresholds.

The purpose of this study was to test the hypothesis that the rate of plasma glucose oxidation during exercise is inversely related to muscle respiratory capacity. To this end, 14 subjects were studied: in 7 of these subjects, the blood lactate threshold (LT) occurred at a relatively high intensity [i.e., at 65 +/- 2% of peak cycle ergometer oxygen uptake (VO2 peak)], whereas in the other 7 subjects, LT occurred at a relatively low intensity (i.e., at 45 +/- 2% of VO2 peak). VO2peak did not differ between the two groups, but citrate synthase activity in the vastus lateralis muscle was 53% higher (P < 0.05) in the high LT group. A primed continuous infusion of [U-13C]glucose was used to quantify rates of glucose appearance (Ra), disappearance (Rd), and oxidation (R(ox)) during 90 min of exercise at 55% VO2peak. Although both absolute and relative rates of oxygen uptake during exercise were similar in the two groups, mean Ra and Rd were 17% lower (P < 0.001) in the high LT group, and mean R(ox) was 25% lower (21.0 +/- 2.6 vs. 27.9 +/- 2.6 mumol.min-1.kg-1; P < 0.001). The percentage of total energy derived from glucose oxidation was inversely related to muscle citrate synthase activity (r = -0.85; P < 0.01). These data support the concept that skeletal muscle respiratory capacity has a major role in determining the metabolic response to submaximal exercise.

Adult↗
PubMed1992

Lipoproteins containing the truncated apolipoprotein, Apo B-89, are cleared from human plasma more rapidly than Apo B-100-containing lipoproteins in vivo.

We have reported previously on two truncations of apolipoprotein B (apo B-40 and apo B-89) in a kindred with hypobetalipoproteinemia. Premature stop codons were found to be responsible for both apo B-40 and apo B-89, but the physiologic mechanisms accounting for the reduced plasma concentrations of these proteins have not been determined in vivo. This study investigates the metabolism of apo B-89 in two subjects heterozygous for apo B-89/apo B-100 and in one apo B-40/apo B-89 compound heterozygote. In both heterozygotes total apo B concentration is approximately 30% of normal and apo B-89 is present in lower concentrations in plasma than apo B-100. After the administration of [1-13C]leucine as a primed constant infusion over 8 h, 13C enrichments of plasma leucine as well as enrichments of VLDL-, IDL-, and LDL-apo B-89 leucine and VLDL-, IDL-, and LDL-apo B-100 leucine were measured over 110 h. Enrichment values were subsequently converted to tracer/tracee ratios and a multicompartmental model was used to estimate metabolic parameters. In both apo B-89/apo B-100 heterozygotes apo B-89 and apo B-100 were produced at similar rates. Respective transport rates of apo B-89 and apo B-100 for subject 1 were 2.13 +/- 0.18 and 2.56 +/- 0.13 mg.kg-1.d-1, and for subject 2, 6.59 +/- 0.18 and 8.23 +/- 0.39 mg.kg-1.d-1. However, fractional catabolic rates of VLDL, IDL, and LDL particles containing apo B-89 were 1.4-3 times higher than the rates for corresponding apo B-100-containing particles. Metabolic parameters of apo B-89 in the apo B-40/apo B-89 compound heterozygote compared favorably with those established for apo B-89 in apo B-89/apo B-100 heterozygotes. Thus, the enhanced catabolism of VLDL, IDL, and LDL particles containing the truncated apolipoprotein is responsible for the relatively low levels of apo B-89 seen in these subjects.

Adult↗
PubMed1992

Low prevalence of autoantibodies to the insulin-like growth factor I receptor in children with short stature.

Inhibition of IGF-I action by circulating IGF-I receptor autoantibodies is a potential mechanism of IGF-I resistance in growing children. To define the prevalence of IGF-I receptor antibodies in short-statured children, we have examined serum and plasma samples from a well-characterized group of 34 short, prepubertal, growth hormone-sufficient children and three growth hormone-deficient children. IGF-I receptor purified from human placental membranes was radioiodinated by the solid phase radioiodination method. Serum from a patient with severe insulin resistance immunoprecipitated 28.9-44.7% of the 125I-labeled IGF-I receptor. The ranges (mean +/- 3 SD) of 125I-labeled IGF-I receptor immunoprecipitated by 1:10 diluted and by undiluted nonimmune human serum were 1.99 +/- 0.63% and 4.42 +/- 1.32%, respectively. Immunoprecipitation of the 125I-labeled IGF-I receptor by eight samples from six children was greater than 3 SD above the mean when assayed at a 1:10 dilution. Nevertheless, when assayed undiluted, only one of these samples immunoprecipitated slightly more 125I-labeled IGF-I receptor than nonimmune serum. We conclude from these data that immunoprecipitating autoantibodies to the IGF-I receptor are not commonly present in short-statured children.

Adolescent↗
PubMed1992

Energy expenditure, lipolysis, and glucose production in preterm infants treated with theophylline.

Theophylline is administered to preterm infants with pulmonary disease to improve pulmonary function and reduce apneic episodes. Because it potentially mediates both alpha- and beta-receptor-effector mechanisms, we tested the hypothesis that it increases lipolysis, gluconeogenesis from glycerol, and energy expenditure in 16 preterm infants, eight of whom were treated therapeutically with theophylline for apnea of prematurity (T) and eight of whom were controls (C). Mean +/- SD postnatal ages were 4.8 +/- 1.9 wk (T) and 2.4 +/- 0.9 wk (C) (p < 0.01). Corrected gestational ages were 35 +/- 1.6 wk (T) and 34 +/- 0.5 wk (C) (p = NS). Body weights were 1.69 +/- 0.13 kg (T) and 1.70 +/- 0.23 kg (C) (p = NS). All infants were clinically stable, breathing room air, fed enterally, and receiving no diuretics, steroids, or antibiotics. Lipolysis, hepatic glucose production, and gluconeogenesis from glycerol were measured using [2-13C]glycerol and [6,6-3H2] glucose tracers. Body water and energy expenditure were measured by the 2H2(18)O method. Body water volumes were 68.5 +/- 3.4% body weight (T) and 70.2 +/- 3.4% (C) (p = NS), suggesting fat was 10-13% of body weight in both groups. Mean daily energy expenditure was 65 +/- 22 kcal/kg body weight/d (T) versus 59 +/- 5 kcal/kg body weight/d (C) (p = NS). Between 4 and 6 h after a feeding, glucose production rates were 40.5 +/- 4.3 mumol/kg/min (T) and 37.6 +/- 4.8 mumol/kg/min (C) (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1992

Effects of cyclosporine on insulin secretion and insulin sensitivity in dogs with intrasplenic islet autotransplants.

Concern about cyclosporine causing adverse effects on glucose metabolism is based mainly on in vitro studies and in vivo data in rodents. However, data on large mammals and humans are much more controversial. Because the drug is used as therapy accompanying pancreatic or isolated islet transplantations, studies in large animals are needed to assess whether cyclosporine inhibits beta-cell function and causes glucose intolerance. To address these issues, we examined intravenous glucose tolerance, islet beta-cell function, and insulin sensitivity in a group of adult mongrel dogs with intrasplenic islet autografts, with and without cyclosporine treatment. Similar fasting plasma glucose and insulin values were found before and after pancreatectomy and islet transplantation. After intravenous glucose, plasma glucose values decreased more slowly in dogs that had undergone transplantation, but no additional adverse effect as a result of cyclosporine was observed. During euglycemic clamp studies, performed at both physiologic and pharmacologic insulin concentrations, the drug had no effect on the total amount of metabolized glucose, and glucose production was unaffected by cyclosporine treatment. Thus intramuscular cyclosporine therapy does not seem to inhibit insulin secretion from heterotopic islets or to affect peripheral and hepatic insulin sensitivity in dogs with intrasplenic islet autografts.

Animals↗
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

Growth hormone and insulin-like growth factor I: nutritional pathophysiology and therapeutic potential.

The growth hormone--insulin-like growth factor I axis has been appreciated for more than 30 years and the effects of malnutrition on this axis for more than 20 years. Over the last decade, advances in molecular biology have permitted enhanced understanding of feedback regulation between growth hormone and IGF-I at the gene level, including limited information on nutritional influences. Similarly, the availability of recombinant human growth hormone has allowed controlled clinical studies demonstrating its net anabolic actions at hypocaloric dietary energy intake levels and its ability to enhance height velocity in children with various causes of diminished growth. Although investigational use of recombinant IGF-I in humans has been limited, its actions are likely to complement those of growth hormone during periods of profound dietary energy deficit. From the information presented, two hypotheses are developed. First, recombinant IGF-I administration will enhance substrate anabolic events during the acutely malnourished state when dietary intake is severely limited. Second, administration of recombinant human growth hormone will accelerate protein anabolism and catch-up growth during the period of recovery from protein-energy malnutrition. Given current clinical investigational tools and the availability of both recombinantly-produced hormones, these are testable hypotheses.

Growth Disorders↗
PubMed1991

Plasma glucose kinetics in a well-trained cyclist fed glucose throughout exercise.

We hypothesized that when plasma glucose availability is maintained by carbohydrate (CHO) ingestion, trained cyclists can utilize plasma glucose at very high rates during the later stages of prolonged exercise (10). To test this hypothesis, a well-trained male cyclist was studied during exercise to fatigue at 70% VO2max when ingesting glucose throughout exercise. A primed continuous infusion of [U-13C]glucose was begun after 60 min of exercise to measure rates of plasma glucose appearance (Ra), disappearance (Rd), and oxidation (R(ox)). Ra and Rd rose progressively throughout exercise, peaking at 6.85 and 6.99 mmol/min, respectively, at fatigue (i.e., 133 min). Most (93%) of this glucose was oxidized; during the final 30 min of exercise, R(ox) averaged 6.10 mmol/min and accounted for approximately half of total CHO oxidation. These results support the hypothesis that trained cyclists can oxidize plasma glucose at very high rates during the later stages of prolonged exercise when fed CHO.

Adult↗
PubMed1991

Leucine kinetics from [2H3]- and [13C]leucine infused simultaneously by gut and vein.

In amino acid tracer kinetic studies of the fed state, ingested amino acid may be taken up during its initial transit through splanchnic tissues and thus not enter the plasma compartment where tracer is infused. To investigate this possibility, adult human subjects received simultaneous intravenous (iv) and intragastric (ig) leucine tracer infusions, first during a postabsorptive (PA) 4-h primed continuous ig infusion of L-[1-13C]-leucine and L-[5,5,5-2H3]leucine iv, followed on a separate day by a fed infusion, in which an ig infusion of a liquid formula was started 2 h before the tracer infusion and continued throughout the tracer study. Subjects were accustomed to a constant experimental diet supplying 1.5 g protein.kg-1.day-1 and 41-45 kcal.kg-1.day-1 for 7 and 12 days before the PA and fed studies, respectively. For the PA study, plasma enrichment for the ig tracer was 3.34 +/- 0.27 (SE) mol + excess and for the iv tracer it was 4.18 +/- 0.10 (P less than 0.02). Enrichments of alpha-keto-isocaproic acid (KIC) were 3.24 +/- 0.16 (ig) and 3.02 +/- 0.14 (iv), respectively [not significant (NS)]. For the fed study, plasma leucine enrichment for the ig tracer was 2.15 +/- 0.14 and for the iv tracer was 2.84 +/- 0.09 (P less than 0.02). KIC enrichments were 2.02 +/- 0.08 (ig) and 2.24 +/- 0.08 (iv), respectively (NS). In the PA study, the ratio of the plasma leucine enrichments for the ig and iv tracers was 0.80 +/- 0.06 and in the fed experiment, 0.76 +/- 0.05, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.

The use of amino acids labeled with stable isotopes represents a relatively new approach for determining kinetic parameters of apolipoprotein metabolism; thus, several aspects of experimental protocols need to be defined. The aims of the present study were to determine whether a) different amino acid tracers or b) different methods of tracer administration affected apolipoprotein (apo) B kinetic parameters obtained by multicompartmental modeling, and c) to compare very low density lipoprotein (VLDL)-apoB metabolic parameters determined by multicompartmental modeling with those estimated by linear regression or by monoexponential analysis. [1-13C]leucine and [15N]glycine were given either as bolus injections or as primed constant infusions. A bolus of one amino acid was administered simultaneously with a primed constant infusion (8 h) of the other amino acid into four healthy normolipidemic subjects (age 23.0 +/- 1.4 yr; BMI 20.9 +/- 0.9 kg.m-2). VLDL-, intermediate density lipoprotein (IDL)-, and low density lipoprotein (LDL)-apoB enrichments were followed over 110 h. For subsequent analysis these values were converted to tracer/tracee ratios. Using the multicompartmental model, the fractional catabolic rate (FCR) for VLDL-apoB was estimated to be 0.36 +/- 0.09 h-1 after the administration of the tracer as a primed constant infusion and 0.35 +/- 0.07 h-1 when the tracer was administered as a bolus. The values for VLDL-apoB production were 14.6 +/- 6.5 mg.kg-1.d-1 and 14.1 +/- 5.4 mg.kg-1.d-1, respectively. The corresponding values for LDL-apoB were 0.027 +/- 0.016 h-1 (0.026 +/- 0.018 h-1) for the FCR and 10.5 +/- 3.7 mg.kg-1.d-1 (10.4 +/- 3.8 mg.kg-1.d-1) for the production following administration of the tracer as a primed constant infusion and a bolus, respectively. Approximately 47% of VLDL-apoB ultimately reached the LDL fraction via the VLDL-IDL-LDL pathway. Thirty-five percent of LDL-apoB did not originate from this cascade pathway, but was shunted from a rapidly turning over VLDL compartment directly into the LDL fraction. While there was some variation between individuals, VLDL-apoB and LDL-apoB parameters derived from the bolus and the primed constant infusions showed no significant differences and were closely correlated. Metabolic parameters were also independent of the two amino acids tested. Although values for FCRs of VLDL-apoB obtained from linear regression (0.36 +/- 0.19 h-1) or monoexponential analysis (0.50 +/- 0.36 h-1) did not differ significantly from those obtained by the multicompartmental model, there was considerable variation and no significant correlation in a given individual.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

Analysis of plasma hippurate in humans using gas chromatography-mass spectrometry: concentration and incorporation of infused [15N]glycine.

To allow in vivo determination of synthetic rates for individual proteins, physiological incorporation of infused [15N]glycine into urinary hippuric acid has been used as an indicator of intrahepatic tracer dilution. Although the kidneys might contribute to hippurate production, the relationship between hepatic, plasma, and urinary hippurate has not yet been established in humans. To further investigate these issues we developed a fast, sensitive, and reliable method for measuring simultaneously hippurate concentrations and in vivo tracer incorporation into hippurate in plasma and urine using stable isotopes and gas chromatography-mass spectrometry. We then tested this assay under several experimental conditions. Reference compounds [( 15N]- and [ring-2H5]hippurate) were synthesized and gave linear standard curves. Postabsorptive hippurate plasma levels in healthy subjects ranged from 1.2 to 10.5 microM and protein binding was 79 +/- 6% (mean +/- SD). Following a bolus dose of [15N]glycine tracer appeared in plasma hippurate; enrichment in hippurate was indistinguishable from that in glycine after an equilibration period of 20 min, indicating a close relationship between intracellular glycine and plasma hippurate. A 16-h infusion of [15N]glycine resulted in identical enrichment levels in urinary and plasma hippurate; glycine enrichment in a hepatic export protein (VLDL-ApoB) was approaching plasma hippurate but not plasma free glycine enrichment. The ability to monitor plasma hippurate is of practical advantage compared to the sampling of urine. Furthermore it allows the monitoring of rapid events in the intrahepatic dilution of an infused glycine tracer. This assay may, therefore, become an important tool in the study of hepatic protein metabolism.

Administration, Oral↗
PubMed1990

Plasma amino acid kinetics during acute states of glucagon deficiency and excess in healthy adults.

The effects of glucagon deficiency and excess on plasma leucine, lysine, and alanine were examined in six healthy young adult men, with primed continuous infusions of L-[1-13C]- or L-[5,5,5-2H3]leucine, L-[alpha-15N]-lysine, and L-[3-13C]alanine for 150 min before and during 210 min of either a glucagon-deficient euglycemic state (experiment 1), a basal glucagon state (experiment 2), or a glucagon-excess state (experiment 3). Steady-state plasma hormone levels were achieved by infusion of somatostatin (250 micrograms/h) and insulin (0.07 mU.kg-1.min-1), without (experiment 1) or with an infusion of glucagon at 0.7 ng.kg-1.min-1 (experiment 2) or 2.5 ng.kg-1.min-1 (experiment 3). Plasma branched-chain amino acid (AA) concentrations did not change with altered glucagon status, whereas significant differences were observed for plasma lysine, alanine, glycine, serine, threonine, proline, tyrosine, citrulline, and ornithine levels (0.05 greater than P greater than 0.001). Plasma leucine, lysine, and alanine fluxes and the rate of de novo alanine synthesis showed no significant changes with either glucagon deficiency or excess. These findings lead to the conclusion that glucagon-induced alterations in plasma AA profiles are not due to changes in the rate of appearance of AA from peripheral tissues but rather a consequence of changes in the fate of AA within the splanchnic region.

Adult↗