1 United States Department of Agriculture, Agricultural Research Service (USDA/ARS) Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; 2 USDA/ARS Growth Biology Laboratory, Beltsville, Maryland 20705; and 3 Department of Animal and Dairy Science, Pennsylvania State University, University Park, Pennsylvania 16802
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ABSTRACT |
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Somatotropin (ST) administration enhances protein deposition
and elicits profound metabolic responses, including hyperinsulinemia. To determine whether the anabolic effect of ST is due to
hyperinsulinemia, pair-fed weight-matched growing swine were treated
with porcine ST (150 µg · kg body wt1 · day
1) or diluent for 7 days (n = 6/group,
~20 kg). Then pancreatic glucose-amino acid clamps were performed
after an overnight fast. The objective was to reproduce the insulin
levels of 1) fasted control and ST pigs (basal insulin, 5 µU/ml), 2) fed control pigs (low insulin, 20 µU/ml), and
3) fed ST pigs (high insulin, 50 µU/ml). Amino acid and
glucose disposal rates were determined from the infusion rates
necessary to maintain preclamp blood levels of these substrates. Whole
body nonoxidative leucine disposal (NOLD), leucine appearance
(Ra), and leucine oxidation were determined with primed,
continuous infusions of [13C]leucine and
[14C]bicarbonate. ST treatment was associated with higher
NOLD and protein balance and lower leucine oxidation and amino acid and glucose disposals. Insulin lowered Ra and increased leucine
oxidation, protein balance, and amino acid and glucose disposals. These
effects of insulin were suppressed by ST treatment; however, the
protein balance remained higher in ST pigs. The results show that ST
treatment inhibits insulin's effects on protein metabolism and
indicate that the stimulation of protein deposition by ST treatment is not mediated by insulin. Comparison of the protein metabolic responses to ST treatment during the basal fasting period with those in the fully
fed state from a previous study suggests that the mechanism by which ST
treatment enhances protein deposition is influenced by feeding status.
protein synthesis; insulin-like growth factor I; amino acid catabolism; growth hormone
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INTRODUCTION |
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EXOGENOUS ADMINISTRATION of somatotropin (ST) to domestic animals increases daily weight gain and the efficiency with which dietary amino acids are utilized for protein deposition (19). This enhanced efficiency in response to ST administration is particularly evident in swine, in which porcine ST administration simultaneously lowers feed intake and increases protein deposition (2, 5, 6).
The regulation of protein deposition occurs through changes in the balance between the rates of protein synthesis and proteolysis. Our recent studies in pigs suggest that ST treatment improves protein balance by reducing protein degradation rather than by stimulating protein synthesis (45, 46). However, other studies primarily suggest that ST treatment does not alter protein degradation but, rather, increases protein synthesis (4, 17, 22, 42). Because nutrient intake profoundly stimulates protein synthesis (9, 11, 25, 41), our studies were performed in animals in the fed steady state, whereas most other studies were performed during postabsorption (17, 22, 23, 42). In addition, our studies were performed in young, rapidly growing animals (45, 46), but those by other investigators were performed in mature animals near market weight or in adult humans (4, 17, 22, 42). Because protein synthesis rates are inherently high in young animals and decrease with development (9, 10, 28), we postulated that the ability of ST administration to further enhance the inherently high rates of protein synthesis in young, rapidly growing, fully fed animals may be minimal. It is possible that ST treatment can enhance protein synthesis during the postabsorptive period, when the rate of protein synthesis is reduced by fasting, and one objective of the present study was to examine this possibility.
The administration of ST is generally accompanied by an increase in both insulin and glucose concentrations (8, 15, 35, 49, 51). This response has traditionally been attributed to the antagonistic effects of ST on insulin's actions (32, 33, 43, 51), and it has been shown that the increase in plasma glucose with ST treatment is due, at least in part, to a reduction in the stimulation of glucose uptake by insulin (1, 20, 38, 48). This appears to be largely reflective of changes in the uptake of glucose by adipocytes (16, 48). Whether there is insulin resistance of protein metabolism during ST treatment has not been determined. Testing whether protein turnover becomes resistant to insulin during ST treatment was a second objective of this study.
It is well established that insulin is a potent anabolic agent (25, 26, 39). Our studies in young swine indicate that insulin mediates the stimulation in skeletal muscle protein synthesis that follows a meal and that this response decreases with development (50). Studies in adult humans suggest that the protein anabolic effect of insulin results from a decrease in the rate of proteolysis rather than a stimulation of protein synthesis (27, 30, 36). Thus the process by which, and the degree to which, insulin stimulates protein deposition likely vary with stage of development.
Because ST administration to growing animals enhances protein deposition in association with increased insulin concentrations (45), the third aim of the present study was to test the hypothesis that the protein anabolic effect of ST treatment is due to the increased circulating insulin concentrations that occur with ST treatment. To achieve these three objectives, pancreatic glucose-amino acid clamps were performed in control and ST-treated young pigs after an overnight fast. Insulin was infused at rates designed to achieve insulin concentrations that are characteristic of 1) the fasting state of control and ST pigs, 2) the fed state of control pigs, and 3) the fed state of ST pigs. Whole body protein turnover and amino acid oxidation rates were determined.
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MATERIALS AND METHODS |
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Animals and design.
Twelve crossbred (Landrace × Yorkshire × Hampshire × Duroc) barrows (Agriculture Headquarters, Texas Department of Criminal Justice, Huntsville, TX) weighing 13 kg (~10 wk) were housed in individual cages, fed a 24% protein diet (Producers Cooperative Association, Bryan, TX) at 6% of their body wt, and provided water ad
libitum. The pigs were adjusted to the diet for 7 days and then
randomly assigned to one of two treatment groups, either diluent
(saline) (control, n = 6) or recombinant porcine ST
(Southern Cross Biochemicals, Melbourne, Australia; n = 6)
at a rate of 150 µg · kg body wt1
day
1 for 7 days. This dose of ST is slightly greater than
the dose that has been demonstrated (see Ref. 18) to maximally
stimulate protein accretion in swine (100 µg · kg body
wt
1 · day
1). The dose of saline or
ST was divided into two daily injections (75 µg/kg body wt) and
administered into the neck region (alternating sides for each
injection). Body weights were measured daily, and the dietary intake
and treatment doses were adjusted accordingly. ST-treated pigs were
offered the diet at 6% of their body wt per day, and control pigs were
pair-fed to the intake level of the ST-treated pigs to minimize
confounding effects of differences in food intake. The daily feed
allowance was divided into two meals to coincide with the injection times.
Pancreatic glucose-amino acid clamps.
Control (18.2 ± 2.8 kg) and ST-treated (20.2 ± 2.1 kg) pigs
were fasted overnight (12 h) before the infusion studies. On the day of
the infusions, ST-treated pigs were administered their daily dose of ST
(150 µg/kg body wt) or diluent 60 min before infusion. Clamps were
performed using techniques similar to those previously described
(47, 50), except that an ST infusion was
given to suppress endogenous insulin secretion, and replacement doses
of glucagon and replacement or elevated doses of insulin were provided
(Fig. 1). Over a 30-min period before the
clamp procedure was initiated, basal blood glucose (YSI 2300 STAT Plus, Yellow Springs Instruments, Yellow Springs, OH) and branched-chain amino acid (BCAA) concentrations were determined to establish the
average fasting concentrations to be used in the glucose-amino acid
clamp procedure (50). The clamp was initiated with a
primed (4.5 µg/kg), continuous (18 µg · kg1 · h
1; BACHEM, Torrance, CA) ST
infusion. After a 10-min infusion of ST, an infusion of replacement
glucagon (72 ng · kg body wt
1 · h
1; Eli Lilly, Indianapolis, IN) was initiated and
continued to the end of the clamp period. Insulin was infused at 20, 75, and 200 ng · kg
0.66 · min
1 to reproduce the insulin concentrations normally
present in the 1) fasting state of control and ST pigs (5 µU/ml; basal), 2) fed state of control pigs (20 µU/ml;
low insulin), and 3) fed state of ST pigs (50 µU/ml; high
insulin) (45). Each pig was continuously infused for
8 h on two separate days, with 1 day separating the two infusion
days. On the 1st day, the basal insulin (20 ng · kg
0.66 · min
1) dose was infused from
10 to 240 min, and the low insulin (75 ng · kg
0.66 · min
1) dose was primed over
a 10-min period and then infused at a constant rate (12 ml/h) from 250 to 480 min. Following the same protocol, on the 2nd day the basal (20 ng · kg
0.66 · min
1) and the
high insulin (200 ng · kg
0.66 · min
1) doses were administered. Venous blood samples (0.2 ml) were obtained every 5 min and immediately analyzed for glucose and BCAA concentrations, as previously described (50). A
2.5-min enzymatic kinetic assay was used to determine total BCAA
concentrations. Dextrose 70% (Baxter Healthcare, Deerfield, IL)
solution and TrophAmine 10% (McGaw, Irvine, CA) were infused to
maintain glucose and amino acid values at the preclamp level.
Additional blood samples were collected every 30 min throughout the
480-min infusion for measurement of glucose, insulin, glucagon, and
C-peptide concentrations. Concentrations of insulin-like growth factor
I (IGF-I), amino acids, ST, and blood urea nitrogen (BUN) were measured
at 0, 240, and 480 min. On the 2nd day of the insulin infusions, the
pigs were killed at 480 min of infusion by exsanguination under
anesthesia.
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Analysis of tracer enrichment.
Plasma -ketoisocaproic acid (
-KICA) was isolated by cation
exchange chromatography (AG-50W resin, Bio-Rad, Hercules, CA). To each
eluant, 10 N sodium hydroxide and 0.36 M hydroxylamine hydrochloric
acid were added. Samples were heated at 60°C for 30 min and cooled at
4°C, and the pH was adjusted to <2. Keto acids were extracted with
ethylacetate and dried under nitrogen at room temperature. The
-KICA
was derivatized by adding
N-methyl-N-t-butyl dimethylsilyl
trifluoroacetamide + 1% t-butyl dimethyl-chlorosilane (MTBSTFA + 1% TBDMCS; Regis Chemical, Morton Grove, IL). The
isotopic enrichment of
-[13C]KICA was determined by
electron impact ionization (EI) gas chromatography-mass spectrometry
(GC-MS) (Hewlett-Packard 5989 B GC-mass spectrometer equipped with a
Hewlett-Packard 5890 Series II GC; Hewlett-Packard, Palo Alto, CA) by
monitoring ions at mass-to-charge ratios (m/z) of 316 and
317. The 14C radioactivity of blood supernatants and
infusates was measured using ScintiVerse II (Fisher Scientific) in a
liquid scintillation counter (TM Analytic, Elk Grove Village, IL).
Plasma substrates and hormones.
Heparinized blood samples were obtained and centrifuged, and the plasma
was frozen at 70°C. Plasma glucose concentrations were analyzed
using a glucose oxidase reaction (YSI 2300 STAT Plus, Yellow Springs
Instruments) during the pancreatic glucose-amino acid clamp. BUN
concentrations were measured with the use of an end-point enzyme assay
(Roche, Somerville, NJ).
Calculations.
Whole body protein turnover was calculated using the following
standardized steady-state equations
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Statistics. Analysis of variance for repeated measures (SPSS) was used to assess the effects of ST treatment, insulin, and their interaction. When significant interactions were detected, values at each insulin dose were compared with basal values or, when appropriate, preclamp values, using paired t-tests. Also, values in ST-treated pigs were compared with values in control pigs at each insulin dose. Because values did not differ significantly between the two basal periods in either ST or control pigs, the basal values were averaged and are presented as single basal values. Also, values did not differ significantly between the two preclamp periods; therefore, the preclamp values were averaged and are presented as single preclamp values. Results are presented as means ± SD. Probability values of <0.05 were considered statistically significant and are not presented in the text.
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RESULTS |
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Plasma hormones and substrates.
The plasma hormone and substrate concentrations shown in Tables
1 and 2 are
mean values obtained during each of the infusion periods. Plasma ST
concentrations were elevated in ST-treated pigs compared with the
negligible levels in control pigs during the preclamp and the basal,
low, and high insulin infusion periods (Table 1). On the day of the
infusion, ST-treated pigs were administered one ST injection 1 h
before the initiation of the insulin infusions. Therefore, plasma ST
values in ST-treated pigs were higher during the preclamp period than
during the later clamp periods. Although insulin infusion was
associated with a fall in total and free insulin-like growth factor I
(IGF-I) concentrations, IGF-I concentrations remained twofold higher in
ST-treated than in control pigs throughout the infusion periods.
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Amino acid and glucose disposal.
Because our previous studies demonstrated that the amino acids infused
during hyperinsulinemic glucose-amino acid clamps were not catabolized,
but likely utilized and deposited, the amino acid infusion rate can be
used as an indication of insulin-stimulated whole body net amino acid
disposal (47). Amino acid infusion was not required during
the basal period (Fig. 2). Insulin
stimulated amino acid disposal; however, ST treatment blunted the
stimulation of amino acid disposal at the low dose of insulin. On the
basis of the changes in dextrose infusion rate during the last hour of
each insulin infusion period, glucose disposal was lower in ST-treated
pigs than in control pigs during all insulin infusion periods (Fig. 2).
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Whole body protein turnover.
Plasma -KICA concentrations were at substrate and isotopic steady
state during the last hour of the basal, low, and high insulin
infusions when samples were obtained for calculation of protein
turnover (data not shown). Leucine flux did not differ significantly
between ST-treated and control pigs (Fig.
3). Insulin increased leucine flux during
the low and high insulin infusion periods in control pigs, but only
during the high insulin infusion period in ST-treated pigs. Leucine
oxidation was lower in ST-treated pigs compared with controls during
the basal (
47%) and low (
64%) insulin infusion periods. Insulin
increased leucine oxidation during the low and high insulin infusion
periods in control pigs but only during the high insulin infusion
period in ST-treated pigs. NOLD was higher in ST-treated pigs compared
with control pigs during the basal (+23%) and low (+52%) insulin
infusion periods. NOLD was unaffected by insulin. Leucine appearance
from protein (endogenous Ra) did not differ between
ST-treated and control pigs. Insulin decreased endogenous
Ra during the low and high insulin infusion periods in
control pigs but only during the high insulin infusion period in
ST-treated pigs.
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DISCUSSION |
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The results of the present study suggest that the protein anabolic effect of ST administration is not due to the increased insulin concentrations that occur with ST treatment. Moreover, pancreatic glucose-amino acid clamp studies indicate that ST treatment produces insulin resistance not only for glucose disposal but also for amino acid disposal, leucine oxidation, leucine flux, and protein degradation. This supports the idea that the increase in protein balance with ST treatment is likely a direct effect of ST. Comparison of the results of the current study performed in the fasted state with those of our previous study performed in the fully fed state (45) suggests that the mechanism by which ST improves protein balance is affected by feeding status. The combined results of the two studies indicate that ST treatment blunts the reduction in protein synthesis that occurs with fasting while enhancing the reduction in proteolysis that occurs with feeding. These dual effects thereby maximize the efficiency of dietary protein utilization.
ST induces insulin resistance. Our results demonstrate that 7 days of ST treatment in 20-kg swine produced the characteristic stimulation of the somatotropic axis (6, 15, 46, 51), as indicated by the twofold increase in circulating concentrations of total and free IGF-I. The characteristic diabetogenic effect (8, 15, 49, 51) was also produced by ST treatment in both the current and previous studies (45), as evidenced by the elevation in plasma glucose concentrations in both the fasting and fed states and the increased plasma insulin concentrations in the fed but not the fasting state.
Pancreatic glucose-amino acid clamps were largely successful in producing the desired hormone and substrate concentrations. C-peptide concentrations were markedly reduced, indicating that the ST infusion effectively suppressed endogenous insulin secretion. The maintenance of circulating glucagon concentrations during the clamp periods indicated that replacement levels of glucagon were achieved. During the basal, low, and high insulin infusion periods, we largely reproduced the circulating insulin concentrations observed in the fasting state of control and ST-treated pigs (5 µU/ml), the fed state in control pigs (20 µU/ml), and the fed state in ST-treated pigs (50 µU/ml) (45). However, at the high insulin dose, plasma insulin levels were slightly lower in ST-treated than in control pigs because of an elevation in insulin clearance. Circulating concentrations of glucose, BCAA, and EAA were largely maintained at the fasting, preclamp level during the pancreatic glucose-amino acid clamps. However, circulating concentrations of NEAA and TAA were not completely maintained, likely because of the use of an amino acid solution (TrophAmine) that is relatively deficient in some NEAA. The results of the pancreatic glucose-amino acid clamp indicate that ST treatment in young, growing swine induced insulin resistance of glucose disposal. This resistance of ST-treated pigs was present at each insulin dose. Although hyperinsulinemic-euglycemic clamp studies performed in mature swine treated with ST (48) showed resistance of glucose disposal to a low but not a high dose of insulin, the high dose of insulin used in those studies produced supraphysiological insulin concentrations (400 µU/ml) rather than the physiological level of insulin (50 µU/ml) achieved by our highest insulin dose. The reduction in glucose disposal with ST treatment (1, 20, 38) has been attributed to a reduction in glucose uptake in adipose tissue, rather than in skeletal muscle (16, 48). The results of the current study showed that ST treatment produced insulin resistance not only of glucose metabolism but also of protein metabolism. For all variables that responded to insulin, i.e., whole body amino acid disposal, leucine flux, leucine oxidation, endogenous leucine appearance, and whole body proteolysis, the response to insulin was blunted in ST-treated pigs at the low dose of insulin. These results indicate that ST treatment reduces the sensitivity, but not the responsiveness, of protein metabolism to insulin (33). NOLD was unaffected by insulin, similar to the lack of effect of insulin on whole body and forearm protein synthesis reported in adult humans (7, 13, 27). Although we (50) and others (26) have shown that insulin stimulates protein synthesis in skeletal muscle of much younger growing pigs, the whole body protein synthesis measured in the current study represents the average result of numerous tissues, which may have opposing responses to insulin. There have been few studies of the effects of ST on insulin-stimulated protein metabolism. However, a report that suggests that insulin's ability to suppress proteolysis and stimulate glucose disposal in the forearm is blunted by ST treatment in adult humans (24) supports the results of the current study. Thus the increase in protein balance with ST treatment is likely a direct effect of ST, rather than an indirect effect of the ST-induced hyperinsulinemia. However, it cannot be ruled out that the response may be an indirect effect of some factor other than insulin, such as IGF-I (21).Protein anabolic response to ST. The regulation of protein deposition is dependent on the balance between the rates of protein synthesis and proteolysis. The results of the current work suggest that ST treatment of young 20-kg swine improves protein balance by increasing the basal rate of whole body protein synthesis with no change in the rate of proteolysis in the postabsorptive state. These results are consistent with studies in mature swine, steer, and humans (17, 23, 42, 44), also performed in the postabsorptive state, which showed that the protein anabolic effect of ST is generated by an increase in protein synthesis rather than a reduction in proteolysis.
However, comparison of the results of the current study, conducted in the fasting state under basal conditions, with our previous study performed in the fully fed state (45) suggests a more complex mechanism for the enhancement in protein deposition by ST treatment (Fig. 4). In the fully fed 20-kg pigs in the previous study, ST treatment increased protein deposition through a marked suppression of protein degradation rather than by a stimulation of protein synthesis at either the whole body or organ level (45). Because both feeding and immaturity are positive regulators of protein synthesis (9, 10, 28, 39), the results suggest that there may be minimal potential for ST treatment to further enhance the already high rate of protein synthesis that is present in rapidly growing, fully fed animals. By contrast, when protein synthesis is measured in the fasting condition, ST-treated pigs have higher rates of protein synthesis than controls, apparently as a result of the greater reduction in the protein synthesis rates with fasting in controls than in ST-treated animals. Thus ST treatment of young growing swine ameliorates the reduction in protein synthesis that occurs with fasting.
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Perspectives. The classic metabolic response to ST treatment in domestic animals is an increase in the efficiency with which the diet is used for growth (2, 5, 6, 19). The combined results of our current and previous (45) studies suggest that ST treatment of young growing swine enhances metabolic efficiency by minimizing the loss of protein during fasting and maximizing the protein gained during meal absorption. This is accomplished by blocking the reduction in protein synthesis that occurs with fasting, enhancing the reduction in proteolysis that occurs with feeding, and reducing amino acid catabolism in both the fed and fasting conditions. This conservation of protein results in an improvement in overall protein balance. Whether these responses are unique to the young, growing swine or are also present in older, larger pigs remains to be determined.
Pancreatic glucose-amino acid clamp studies demonstrate that the improvement in protein balance with ST treatment is not due to the ST-induced hyperinsulinemia. ST treatment of young growing swine induces insulin resistance not only for glucose metabolism but also for protein metabolism. Thus the increase in protein balance with ST treatment is likely a direct effect of ST or some factor other than insulin. ![]() |
ACKNOWLEDGEMENTS |
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We thank M. Fiorotto and D. Burrin for helpful discussions. We appreciate the technical assistance of J. Wen, M. Haymond, J. Cunningham, M. Stubblefield, F. Biggs, and J. Vargas. We also thank E. O. Smith for statistical assistance, L. Loddeke for editorial review, A. Gillum for graphics, and M. Alejandro for secretarial assistance. We acknowledge Eli Lilly for the generous donation of porcine insulin, and McGaw for the generous donation of TrophAmine.
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FOOTNOTES |
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This project has been funded by the US Department of Agriculture, National Research Initiative Grant 96-35206-3657, the US Department of Agriculture, Agricultural Research Service (USDA/ARS) under Cooperative Agreement no. 58-6250-6-001, and the National Institute of Child Health and Human Development Training Grant T32-HD-07445.
This work is a publication of the USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
Present address of R. C. Vann: Coastal Plains Experiment Station, University of Georgia, Tifton Campus, PO Box 748, Tifton, GA 31793-0748.
Address for reprint requests and other correspondence: T. A. Davis, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates St., Houston, TX 77030 (E-mail: tdavis{at}bcm.tmc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 12 October 1999; accepted in final form 1 February 2000.
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