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Biomedical subjects

M W Haymond

Publications and source records attributed to M W Haymond.

At least 19 recordsLinked to original sources
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

Meal stimulation of albumin synthesis: a significant contributor to whole body protein synthesis in humans.

The present studies were performed to test the hypothesis that the liver, by increasing the synthesis of specific plasma proteins during the absorption of an amino acid meal, may play an important role in the temporary "storage" of ingested essential amino acids and to explore the effects of glucocorticosteroids and recombinant human growth hormone (rhGH) on these processes. The fractional synthetic rates of albumin and fibrinogen were determined using simultaneous infusions of intravenous [1-14C]leucine and intraduodenal [4,5-3H]leucine after 22 h fasting and during absorption of glucose and amino acids in four groups of normal subjects treated for 1 wk with placebo, prednisone (0.8 mg.kg-1.day-1), rhGH (0.1 mg.kg-1.day-1), or combined treatment. When compared with the fasted state and independent of the route of tracer delivery and hormonal treatment, albumin, but not fibrinogen, synthesis increased (P < 0.0001) during absorption of a mixed glucose amino acid meal in all groups. This increase in albumin synthesis accounted for 28% of the increase in whole body protein synthesis associated with feeding and for 24, 22, and 14% in the prednisone, rhGH, and combined treatment groups, respectively. These data suggest that the stimulation of albumin synthesis observed during feeding prevents irreversible oxidative losses of a significant fraction of ingested essential amino acids and may serve as a vehicle to capture excess dietary amino acids and transport them to peripheral tissues to sustain local protein synthesis.

Adult↗
PubMed1992

Human growth hormone but not insulin-like growth factor I positively affects whole-body estimates of protein metabolism.

Human growth hormone (rhGH) increases estimates of whole-body protein synthesis, but has little effect on rates of proteolysis in both the postabsorptive state and during meal absorption. In addition, rhGH stimulates protein synthesis in skeletal muscle tissue. In contrast, insulin decreases estimates of whole-body and forearm proteolysis while decreasing or, in the presence of infused (or ingested) amino acids, sustaining estimates of protein synthesis. Using high-dose prednisone as a controlled model for protein catabolism in normal volunteers, high-dose rhGH together with prednisone prevents the protein catabolic effects of prednisone alone. GH is thought to mediate its effects via the generation of insulin-like growth factor I (IGF-I). However, high rates of infusion of rhIGF-I induce hypoglycemia and decrease estimates of whole body proteolysis, suggestive of a predominant insulin-like effect. When rhIGF-I is infused at a rate that achieves plasma IGF-I concentrations similar to those observed during rhGH treatment and yet avoids hypoglycemia, estimates of proteolysis and protein synthesis were not affected in the absence or presence of prednisone treatment. Thus, the mechanism of action of rhGH on body protein metabolism remains to be elucidated. However, rhGH alone or in combination with rhIGF-I may provide a new management strategy in a variety of protein catabolic conditions in humans.

Adrenal Cortex Hormones↗
PubMed1992

The effects of human growth hormone and prednisone on whole body estimates of protein metabolism.

Human growth hormone (GH) increases estimates of whole body protein synthesis, but has little effect on the rates of proteolysis either post-absorptively or when absorption occurs during a meal. In contrast to insulin, GH stimulates protein synthesis in skeletal muscle tissue. Prednisone in high doses induces protein catabolism and has been used as a controlled model for catabolic illness. Prednisone increases the rates of proteolysis and amino acid oxidation, but has little effect on estimates of protein synthesis. The administration of high doses of GH together with prednisone prevents the protein catabolic effects of prednisone alone. Thus, GH may provide a new management strategy in patients with significant protein catabolic conditions.

Growth Hormone↗
PubMed1992

Low dose recombinant human insulin-like growth factor-I fails to affect protein anabolism but inhibits islet cell secretion in humans.

The in vivo effects of recombinant human insulin-like growth factor-I (rhIGF-I) on whole body protein metabolism were studied to ascertain whether rhIGF-I has comparable effects as those reported with rhGH use in humans. The doses of rhIGF-I chosen achieved similar plasma IGF-I concentrations as those achieved after 7 days of rhGH injections. Eight normal volunteers were studied using [1-13C]- and [1-14C]leucine tracers, before, 4 h, and 28 h after a continuous infusion of rhIGF-I at 5 micrograms kg-1 h-1 (n = 6) and 10 micrograms kg-1 h-1 (n = 2). Two additional subjects were studied in a protein catabolic state after 7 days of high dose (0.8 mg kg-1 day-1) glucocorticosteroid administration. Plasma concentrations of rhIGF-I were similar using either 5 or 10 micrograms kg-1 h-1 and increased to values approximately 300% above baseline by 28 h of infusion. No decrease in the plasma glucose concentration was observed during the 28-h infusion; however, plasma insulin, C-peptide, and glucagon concentrations significantly decreased, whereas plasma free fatty acids were not affected. No changes were observed in the rate of proteolysis (as estimated by the rate of leucine appearance), the rate of leucine oxidation, or the rate of protein synthesis in the absence or presence of glucocorticosteroid treatment. Plasma concentrations of insulin-like growth factor binding protein-3 did not change during the rhIGF-I infusion whereas they increased 50% in subjects who received rhGH, and in whom rhGH caused a potent protein anabolic effect. These results suggest that rhIGF-I may have a somatostatin-like effect. In addition, we found that rhIGF-I infusion is insufficient to promote protein anabolism. This may be due to the failure of rhIGF-I alone to induce a pivotal GH-dependent cofactor(s) necessary for IGF-I to elicit an anabolic effect on protein metabolism in humans.

Adult↗
PubMed1991

Protein metabolism in obesity: effects of body fat distribution and hyperinsulinemia on leucine turnover.

To examine whether moderate obesity and differences in body fat distribution are associated with abnormalities of protein metabolism, leucine turnover was measured in three groups of age-matched premenopausal women. Ten upper-body-obese (UB Ob), 10 lower-body-obese (LB Ob), and 10 nonobese (Non Ob) women were studied in an overnight postabsorptive condition (basal) and again during an infusion of low physiologic amounts of insulin (insulin clamp). Results showed that basal leucine carbon flux was greater (P less than 0.05) in UB Ob and LB Ob women than in Non Ob women (2.96 +/- 0.08 vs 3.14 +/- 0.16 vs 2.68 +/- 0.08 mumol.kg lean body mass-1.min-1, respectively; mean +/- SEM). Leucine carbon flux was not suppressed during the insulin-clamp study in UB Ob women but was in the LB Ob and Non Ob women. We conclude that moderate obesity is associated with increased proteolysis and that insulin's antiproteolytic actions are impaired in upper-body obesity. These findings could have implications for future studies of and treatment of obesity.

Adipose Tissue↗
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

Isolated hypoisoleucinemia impairs whole body but not hepatic protein synthesis in humans.

It is not known whether an acute decrease in the plasma concentration of any essential amino acid, as occurs during insulin infusion, impairs protein synthesis. To test this hypothesis in humans, selective hypoisoleucinemia or hypothreoninemia was induced by insulin infusion while maintaining normal or elevated plasma concentrations of the other amino acids via their selective infusion. The effects on protein synthesis were assessed using leucine kinetics and fractional synthetic rates of the two hepatic proteins albumin and fibrinogen. Results were compared with those of a combined insulin and complete amino acid infusion. Hypoisoleucinemia increased leucine oxidation (P less than 0.03) and decreased nonoxidative leucine disposal (P less than 0.04) and net leucine balance (P less than 0.03), whereas hypothreoninemia had no effect on any of these parameters. Neither hypoisoleucinemia or hypothreoninemia altered albumin and fibrinogen fractional synthetic rates when compared with the control study. Because of the known relationships between intra- and extracellular amino acid concentrations, the hypoisoleucinemia was most likely associated with a decreased intracellular concentration of isoleucine; such would not be the case for hypothreoninemia. Thus acute limited availability of a single essential amino acid can adversely affect nonhepatic protein synthesis.

Adult↗
PubMed1991

Differential effects of insulin deficiency on albumin and fibrinogen synthesis in humans.

Insulin deficiency decreases tissue protein synthesis, albumin mRNA concentration, and albumin synthesis in rats. In contrast, insulin deficiency does not change, or, paradoxically, increases estimates of whole body protein synthesis in humans. To determine if such estimates of whole body protein synthesis could obscure potential differential effects of insulin on the synthetic rates of individual proteins, we determined whole body protein synthesis and albumin and fibrinogen fractional synthetic rates using 5-h simultaneous infusions of [14C]leucine and [13C]bicarbonate, in six type 1 diabetics during a continuous i.v. insulin infusion (to maintain euglycemia) and after short-term insulin withdrawal (12 +/- 2 h). Insulin withdrawal increased (P less than 0.03) whole body proteolysis by approximately 35% and leucine oxidation by approximately 100%, but did not change 13CO2 recovery from NaH13CO3 or estimates of whole body protein synthesis (P = 0.21). Insulin deficiency was associated with a 29% decrease (P less than 0.03) in the albumin fractional synthetic rate but a 50% increase (P less than 0.03) in that of fibrinogen. These data provide strong evidence that albumin synthesis in humans is an insulin-sensitive process, a conclusion consistent with observations in rats. The increase in fibrinogen synthesis during insulin deficiency most likely reflects an acute phase protein response due to metabolic stress. These data suggest that the absence of changes in whole body protein synthesis after insulin withdrawal is the result of the summation of differential effects of insulin deficiency on the synthesis of specific body proteins.

Adult↗
PubMed1991

Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism.

To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2.min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P less than 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P less than 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.

3-Hydroxybutyric Acid↗
PubMed1991

Differential effects of prednisone and growth hormone on fuel metabolism and insulin antagonism in humans.

Human growth hormone (hGH) and prednisone cause insulin resistance and glucose intolerance. However, it is unknown whether hGH and prednisone antagonize insulin action on protein, fat, and carbohydrate metabolism by a common or independent mechanism. Therefore, protein, fat, and carbohydrate metabolism was assessed simultaneously in four groups of eight subjects each after 7 days of placebo, recombinant DNA hGH (rhGH; 0.1 mg.kg-1.day-1), prednisone (0.8 mg.kg-1.day-1), or rhGH and prednisone administration after an 18-h fast and during gut infusion of glucose and amino acids (fed state). Fasting plasma glucose concentrations were similar during placebo and rhGH but elevated (P less than 0.001) during combined treatment, whereas plasma insulin concentrations were higher (237 +/- 57 pmol/ml, P less than 0.001) during combined than during placebo, rhGH, or prednisone treatment (34, 52, and 91 pM, respectively). In the fed state, plasma glucose concentrations were elevated only during combined treatment (11.3 +/- 2.1 mM, P less than 0.001). Plasma insulin concentrations were elevated during therapy with prednisone alone and rhGH alone (667 +/- 72 and 564 +/- 65 pmol/ml, respectively, P less than 0.001) compared with placebo (226 +/- 44 pmol/ml) but lower than with the combined rhGH and prednisone treatment (1249 +/- 54 pmol/ml, P less than 0.01). Protein oxidation [( 14C]leucine) increased (P less than 0.001) with prednisone therapy, decreased (P less than 0.001) with rhGH treatment, and was normal during the combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Metabolism of ketone bodies by skeletal muscle in starvation and uncontrolled diabetes.

Previous studies have suggested that skeletal muscle may be responsible for as much as 25% of ketone body (KB) production in poorly controlled diabetes. In the present studies, acetoacetate (AcAc) and beta-hydroxybutyrate production was quantitated in the canine hindlimb from surgically placed arterial and venous catheters in conscious insulin-withdrawn diabetic (n = 5) and 4-day fasted (n = 7) dogs. A two-pool modeling technique, using simultaneous infusions of 13C acetoacetate and 14C beta-hydroxybutyrate (beta OHB) was employed to quantitate total body and hindlimb KB kinetics. Total KB production was 9.4 and 39.3 mumol.kg-1.min-1 in the fasted and diabetic animals, respectively. Hindlimb KB production was negligible in both groups. The two-pool model estimates of hindlimb KB utilization were similar to the values obtained by an arterial-venous difference calculation. In conclusion, the hindlimb does not contribute to de novo synthesis of KBs in either fasted or diabetic dogs. Since species differences in KB metabolism occur, it is possible that muscle may be a site for KB production in humans.

Animals↗
PubMed1990

Isoflurane and whole body leucine, glucose, and fatty acid metabolism in dogs.

Following 4 h of general anesthesia with halothane [1.5 minimum alveolar concentration (MAC)]-nitrous oxide (50% in oxygen), whole body protein synthesis is decreased and the rate of leucine oxidation is increased in dogs. To evaluate the effects of general anesthesia with isoflurane on whole body fuel metabolism and the effects of duration of anesthesia on these processes, eight dogs were studied, once in the conscious state (over 9 h) and again prior to and during isoflurane anesthesia (1.5 MAC) for 3.5 h (n = 8). Three additional dogs were studied in the conscious state and over 5 h of anesthesia. Changes in protein, fatty acid, and glucose metabolism were estimated using isotope dilution techniques, employing simultaneous infusions of L-[1-14C]leucine, [6-3H]glucose and [9,10-3H]palmitate. Ten minutes after the beginning of the administration of isoflurane, total leucine carbon flux, leucine oxidation, and leucine incorporation into proteins decreased (P less than 0.05), resulting in a slight decrease in the ratio of leucine oxidation to nonoxidative leucine disappearance (LOX/NOLD, P less than 0.05), an indicator of leucine catabolism. Throughout the 5 h of anesthesia, whole body protein synthesis remained decreased (P less than 0.01), whereas leucine flux and oxidation increased progressively throughout the remainder of the study, resulting in a more than 80% increase in the ratio of LOX/NOLD. After 10 min of isoflurane anesthesia, both plasma free fatty acid concentrations and palmitate turnover had decreased by more than 70% (P less than 0.001) and remained suppressed (P less than 0.001) throughout the remainder of the anesthesia, consistent with decreased lipolysis. Glucose production was increased 10 min (P less than 0.05) following induction of anesthesia and peripheral glucose utilization was decreased following 3.5 h of isoflurane anesthesia (P less than 0.05). These data strongly suggest a widespread and immediate metabolic effect of isoflurane anesthesia, which includes peripheral insulin resistance to glucose disposal, decreased lipolysis, and a progressive increase in protein wasting with increasing duration of anesthesia.

Anesthesia, General↗
PubMed1990

Underestimation of glucose turnover corrected with high-performance liquid chromatography purification of [6-3H]glucose.

We have recently reported that during infusion of commercially available [6-3H]glucose, a radioactive nonglucose contaminant may accumulate in plasma causing errors in the measurement of glucose turnover. To determine whether purification of this tracer by HPLC (high-performance liquid chromatography) before infusion would eliminate the contaminant in plasma and remove the underestimation of glucose turnover reported during hyperinsulinemia, four normal subjects each underwent two 5-h euglycemic clamps during infusion of insulin (1 mU.kg-1.min-1). Glucose turnover was measured with either commercially available [6-3H]glucose or with HPLC-purified [6-3H]glucose. HPLC analysis of samples from the clamps done with commercially available [6-3H]glucose showed that 9.7% of the infused tracer and 26% of the "plasma glucose 3H radioactivity" were contaminants. In contrast, no contaminant was observed in the plasma during infusion of HPLC-purified [6-3H]glucose. During the last hour of the clamp, mean glucose turnover using commercially available [6-3H]glucose was less (P less than 0.01) than the mean glucose infusion rate (7.6 +/- 0.3 vs. 10.5 +/- 0.3 mg.kg-1.min-1) yielding apparent "negative" (P less than 0.001) hepatic glucose release. In contrast, when HPLC-purified [6-3H]glucose was employed, glucose turnover equaled the glucose infusion rate (10.4 +/- 0.9 vs. 10.2 +/- 0.9 mg.kg-1.min-1) and hepatic glucose release was no longer negative. We conclude that removal of a tritiated nonglucose contaminant in [6-3H]glucose by HPLC yields correct estimations of glucose turnover at steady state.

Adult↗
PubMed1990

Validation of two-pool model for in vivo ketone body kinetics.

Previous studies have indicated that simultaneous infusions of two ketone body tracers ([13C]acetoacetate and [14C]beta-hydroxybutyrate) provide accurate estimates of exogenous ketone body inflow when an open two-pool model is employed. In the present studies, net hepatic ketone body production was determined from surgically placed arterial, portal venous, and hepatic venous catheters in conscious diabetic (n = 6) and 4-day fasted (n = 7) dogs. [13C]acetoacetate and [14C]beta-hydroxybutyrate were infused simultaneously, and ketone body production was calculated from either acetoacetate (AcAc) single-isotope data, beta-hydroxybutyrate (beta-OHB) single-isotope data, the sum of individual fluxes, or the two-pool model. In fasted animals, both the AcAc single-isotope calculation and the sum of individual fluxes overestimated net hepatic production by approximately 50% (P less than 0.05), whereas the beta-OHB single-isotope calculation and the two-pool model gave accurate estimates. In the diabetic animals, the beta-OHB single-isotope calculation underestimated net hepatic production by approximately 30% (P less than 0.05). The sum of individual fluxes overestimated net hepatic production by approximately 46% (P less than 0.05), whereas both the AcAc single-isotope calculation and the two-pool model gave accurate estimates. In conclusion, single-isotope methods give erroneous estimates of net hepatic production of ketone bodies. In contrast, a two-pool model provided an accurate estimate of net hepatic production and thus appears to be suitable for determination of ketone body kinetics in humans.

3-Hydroxybutyric Acid↗
PubMed1990

Systemic pH modifies ketone body production rates and lipolysis in humans.

To investigate whether changes in systemic pH influence ketone body production or utilization, total ketone body (TK) kinetics were measured with [3-14C]acetoacetate and D-beta-[1,3-13C2]hydroxybutyrate tracers in overnight fasted subjects during metabolic alkalosis (NaHCO3 infusion) or acidosis [NH4Cl ingestion or arginine (Arg)-HCl infusion]. Somatostatin, with insulin, glucagon, and growth hormone replacement, was infused in all studies. Blood pH and HCO3- (mM) increased from baseline (0-30 min) to 180-210 min by 0.08 +/- 0.02 and 7 +/- 1 with NaHCO3 and decreased by 0.08 +/- 0.2 and 7 +/- 1 or 5 +/- 1 with NH4Cl or Arg-HCl (all P less than 0.005). Over this period blood TK (microM) differed between the NaHCO3 (+198 +/- 65) and both NH4Cl (-90 +/- 53) and Arg-HCl (-154 +/- 55) (P less than 0.05). These changes resulted from parallel alterations in TK production rate of appearance (Ra TK, mumol.kg-1.min-1), because changes from baseline in Ra 14C TK also differed between NaHCO3 (+1.9 +/- 0.8) and NH4Cl (-1.0 +/- 0.6) and Arg-HCl (-2.0 +/- 0.5) (P less than 0.05). Ra TK calculated with single- or dual-tracer techniques were similar. Blood free fatty acids (FFA) increased with NaHCO3, and FFA and glycerol decreased with NH4Cl and Arg-HCl, suggesting that FFA availability mediated the pH effects on hepatic ketogenesis. These results demonstrate that modest changes in systemic pH modify FFA availability and TK production rates.

Acid-Base Equilibrium↗