1 Università degli Studi di Milano, 20131 Milan; 2 Departments of Medicine and 3 Neurosurgery, Istituto Scientifico H San Raffaele, 20132 Milan; and 4 Università di Trieste, 34100 Trieste, Italy
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ABSTRACT |
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Insulin resistance in acromegaly
causes glucose intolerance and diabetes, but it is unknown whether it
involves protein metabolism, since both insulin and growth hormone
promote protein accretion. The effects of acromegaly and of its
surgical cure on the insulin sensitivity of glucose and amino
acid/protein metabolism were evaluated by infusing
[6,6-2H2]glucose,
[1-13C]leucine, and [2-15N]glutamine during
a euglycemic insulin (1 mU · kg1 · min
1)
clamp in 12 acromegalic patients, six studied again 6 mo after successful adenomectomy, and eight healthy controls. Acromegalic patients, compared with postsurgical and control subjects, had higher
postabsorptive glucose concentration (5.5 ± 0.3 vs. 4.9 ± 0.2 µmol/l, P < 0.05, and 5.1 ± 0.1 µmol/l)
and flux (2.7 ± 0.1 vs. 2.0 ± 0.2 µmol · kg
1 · min
1,
P < 0.01, and 2.2 ± 0.1 µmol · kg
1 · min
1,
P < 0.05) and reduced insulin-stimulated glucose
disposal (+15 ± 9 vs. +151 ± 18%, P < 0.01, and 219 ± 58%, P < 0.001 from basal). Postabsorptive leucine metabolism was similar among groups. In acromegalic and postsurgical subjects, insulin suppressed less than in
controls the endogenous leucine flux (
9 ± 1 and
12 ± 2 vs.
18 ± 2%, P < 0.001 and P < 0.05), the nonoxidative leucine disposal (
4 ± 3 and
1 ± 3 vs.
18 ± 2%, P < 0.01 and
P < 0.05), respectively, indexes of proteolysis and
protein synthesis, and leucine oxidation (
17 ± 6% in
postsurgical patients vs.
26 ± 6% in controls,
P < 0.05). Within 6 mo, surgery reverses insulin resistance for glucose but not for protein metabolism. After
adenomectomy, more leucine is oxidized during hyperinsulinemia.
acromegaly; glucose metabolism; growth hormone; leucine metabolism
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INTRODUCTION |
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GROWTH HORMONE RECEIVES WIDESPREAD ATTENTION because of its anabolic properties and, consequently, for its potential clinical applications in hormone-deficient, elderly, and hypercatabolic patients. Growth hormone, however, is not free from adverse effects when excessively concentrated. Acromegalic subjects are frequently glucose intolerant or diabetic. For this reason, the interaction of growth hormone and insulin on glucose metabolism was extensively studied. In this respect, growth hormone counteracts insulin action (6, 16, 32). In contrast, the interaction of the two hormones on the full spectrum of their metabolic actions is scarcely defined. Of particular interest is the regulation of protein anabolism. Both hormones share a positive effect on protein balance that is of potential therapeutic interest. Many studies have investigated the mechanisms by which insulin promotes protein anabolism. Insulin increases the synthesis of specific proteins in target organs (3, 11), but it decreases the synthesis of others, the net effect resulting in no stimulation of protein synthesis. In contrast, insulin per se consistently reduces the proteolytic rate (9, 14). The latter is currently believed to be the most important mechanism explaining the effect of insulin on protein accretion. Both growth hormone and IGF-I stimulate protein synthesis in humans in vivo (24). Interestingly, a study performed in the human forearm showed that the simultaneous administration of the two hormones acutely reduced the antiproteolytic effect of insulin, suggesting that, in the muscular tissue, growth hormone-induced insulin resistance also involves protein metabolism (13). It is unknown whether at the whole body level the resulting effect of growth hormone is to blunt the anticatabolic effects of insulin. Molecular studies have shown that chronic growth hormone interacts in a complex fashion with the insulin-signaling pathways: growth hormone inhibits the upstream elements of the cascade (34, 36, 37), leading to the insulin effects on glucose, lipid, and protein metabolism, but it independently activates the downstream kinases (MAP kinases and p70 S6 kinase) specifically involved in the stimulation of protein synthesis (19, 29).
These pieces of in vivo and in vitro evidence support the hypothesis that chronic growth hormone counteracts insulin action on proteolysis and protein synthesis and still promotes protein anabolism. To address this issue, we tested the insulin sensitivity of glucose and protein metabolism in a clinical model of chronically elevated growth hormone, i.e., in acromegalic patients. In this population, key questions concerned 1) the degree of impairment in the antiproteolytic action of insulin compared with glucose metabolism, and 2) the reversibility of such impairments with the surgical treatment of acromegaly.
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METHODS |
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Materials. L-[1-13C]leucine, L-[2-15N]glutamine, and D-[6,6-2H2]glucose were purchased from MassTrace (Woburn, MA). Chemical and isotopic purity of the tracers was determined by gas chromatography-mass spectrometry (GC-MS). Before every infusion study, sterile solutions of the tracers were prepared using aseptic technique. Accurately weighed amounts of the labeled compounds were dissolved in weighed volumes of sterile, pyrogen-free saline and filtered through a 0.22-µm Millipore filter before use. An aliquot of the sterile solution was initially verified to be pyrogen free before administration to human subjects. Solutions were prepared no more than 24 h before use and were kept at 4°C before administration.
Subjects. Twelve acromegalic subjects affected by benign growth hormone-secreting pituitary adenoma were studied before surgery (ACRO; 6 females and 6 males, age 47 ± 4 yr, body weight 74 ± 4 kg, body mass index 26.0 ± 1.0 kg/m2). The study was repeated in six of the subjects 6 mo after surgery (POST). Eight healthy controls were also studied with the same protocols (CON; 4 females and 4 males, age 42 ± 4 yr, body weight 69 ± 4 kg, body mass index 24.2 ± 1.1 kg/m2). In selected subjects, dual-X-ray absorptiometry (DEXA) was performed with a Lunar-DPX-IQ scanner (Lunar, Madison, WI) to assess body composition. Regional analysis was performed in the arms, trunk, and legs with three-compartment processing (30).
Euglycemic hyperinsulinemic clamp.
One week before their admission, the subjects were placed on an
adequate energy and protein (1.2 g · kg1 · day
1)
diet that continued until the last study was completed. The diet was
required to reduce intersubject variability induced by the different
subjects' dietary practices. Acromegalic subjects were studied as
inpatients during their assessment before surgery and at their
readmission 6 mo after surgery. Subjects were generally admitted for
2-4 days before receiving the clamp. On the evening before each
infusion study, the subjects consumed their evening meal by 8:30 PM,
and then they drank only water until completion of the study on the
next day at 2:00 PM. At 7:00 AM on the infusion day, a venous catheter
was placed in the subject's arm for infusion of the tracers of glucose
and amino acids, and insulin and dextrose when necessary. A second
catheter was placed retrograde in a hand vein, and the subject's hand
was placed in a warming box to obtain arterialized venous blood
samples. The catheters were kept patent with a slow infusion of sterile
saline. At the beginning of both studies, priming doses of
[1-13C]leucine (4.5 µmol/kg),
[2-15N]glutamine (4.5 µmol/kg), and
[6,6-2H2]glucose (12.0 µmol/kg) were
administered intravenously and were immediately followed by the
continuous infusion of the same tracers (4.5, 7.5, and 13.3 µmol · kg
1 · h
1,
respectively) for 5 h. The study was composed of two periods of
identical duration (2.5 h each): basal for tracer equilibration and
euglycemic hyperinsulinemic clamp, performed as previously described (21). Briefly, insulin was infused at the rate
of 1 mU · kg
1 · min
1
to achieve and maintain insulin concentrations of ~420 pmol/l, and
20% dextrose was infused at a variable rate to maintain the glucose
concentration at 5 mmol/l. To this purpose, plasma glucose concentrations were measured at bedside every 5 min. Blood and breath
samples were drawn just before the start and at 15-min intervals during
the last 45 min of the 2.5-h basal period and throughout the 2.5-h
clamp period.
Analytical methods. Plasma amino acid concentrations and enrichments were measured by electron impact GC-MS. Before derivatization, amino acids were isolated from plasma by use of cation exchange columns, as previously described (2). Amino acids eluted from the columns were evaporated to dryness and derivatized to form the tert-butyldimethylsilyl (TBDMS) derivative. The [M-57]+ ions at mass-to-charge ratios (m/z) = 260 and 264 were monitored for unlabeled alanine and [2H4]alanine, respectively. The [M-57]+ ions at m/z = 336 and 338 were monitored for unlabeled phenylalanine and [2H2]phenylalanine, respectively. The [M-57]+ ions at m/z = 302, 303, and 309 were monitored for unlabeled leucine, [1-13C]leucine, and [2H7]leucine, respectively. The [M-57]+ ions at m/z = 431, 433, and 436 were monitored for unlabeled glutamine, [1,2-13C2]glutamine, and [2H5]glutamine, respectively. TBDMS-glutamine was chromatographically resolved from TBDMS-glutamate. The KIC enrichments and concentrations were measured after the eluant from the columns was derivatized to the trimethylsilyl-quinoxalinol derivative (2). Injections of the derivatives were made into a GC-MS instrument (model 5970; Hewlett-Packard, Palo Alto, CA) that was operated using electron impact ionization. The ions at m/z 259 and 260 were monitored for unlabeled KIC and [1-13C]KIC, respectively. The KIC peak was resolved from that of KIC and was used for the quantification of the KIC concentrations. For all measurements, the background corrected tracer enrichments in mole percent excess were calculated as previously defined (22). The measurement of 13CO2 in the expired air KIC was performed by isotope ratio mass spectrometry (VG Isogas; VG Instruments, Middlewich, UK).
Plasma hormone concentrations were measured by radioimmunoassay with commercial kits, as previously described (30).Calculations.
The glucose and glutamine kinetics were calculated using Steele's
equations for the nonsteady state (35), as we previously described (2). The rate of appearance of the unlabeled
substrates (Ra,
µmol · kg1 · h
1)
was calculated using the equation
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(1) |
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(2) |
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(3) |
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(4) |
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(5) |
Statistical analysis. t-Tests for paired data were used to compare ACRO and POST, and t-tests for independent data were used to compare ACRO with CON and POST with CON. The Bonferroni correction was applied to both tests. Comparisons between equilibration period and study period within each study group were performed by means of a two-tailed paired t-test. The major end point of this study was to evaluate the changes in insulin sensitivity induced by acromegaly and by its surgical cure. The effect of insulin was calculated as the percent change from the basal state during the last hour of the insulin clamp. The effect of insulin was then compared among groups.
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RESULTS |
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Glucose metabolism.
The postabsorptive glucose concentration was higher in ACRO
than in POST but similar to CON (Table
1). The postabsorptive glucose flux was
higher in ACRO than in POST and CON. During the clamp, the
insulin stimulation of glucose disposal was markedly impaired in ACRO
compared with both POST and CON. The endogenous glucose production was
less suppressed in ACRO than in CON during the clamp. The
postabsorptive glucose clearance was not different among groups
(2.72 ± 0.14 vs. 2.19 ± 0.17 vs. 2.32 ± 0.14 ml · kg1 · min
1
in ACRO, POST, and CON, respectively), and during the clamp it increased in ACRO by only 20 ± 6% compared with 151 ± 24%
in POST and 208 ± 69% in CON (P < 0.05 and
P < 0.001 vs. ACRO, respectively).
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Amino and keto acid concentrations.
The postabsorptive leucine concentration was comparable among groups
(Table 2). During the clamp, leucine
decreased in all groups to a plateau that was lower in POST than in
ACRO. The effect of the clamp to decrease the leucine concentration was
smaller in ACRO than in POST and in CON. The absolute KIC concentration was not different among groups, but the effect of the clamp to reduce
the KIC concentration was smaller in ACRO than in POST and in CON.
Phenylalanine was reduced in ACRO postabsorptively. The effect of the
clamp was to reduce phenylalanine in all groups, but this effect was
smaller in ACRO and in POST than in CON. The alanine
concentration was similar among the groups and was not affected by the
clamp. Glutamine was not different among groups and was similarly
suppressed during the clamp.
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Leucine and glutamine kinetics.
Postabsorptively, the endogenous leucine flux, an index of proteolysis,
and the leucine oxidation and the nonoxidative leucine disposal, an
index of protein synthesis, were comparable among the groups (Table
3). During the clamp, proteolysis was
less suppressed in ACRO and in POST than in CON. Leucine oxidation during the clamp was less suppressed in POST compared with both ACRO
and CON. The nonoxidative leucine disposal was suppressed by insulin
only in CON and (to an intermediate level) in POST, whereas it was not
suppressed in ACRO before the intervention. The glutamine flux was
comparable among groups and was suppressed in all groups during the
clamp. Apparently, the insulin suppression of glutamine flux was more
pronounced in ACRO than in the other groups, but a significant
difference was not detected with the statistical analysis model used.
Significance was reached (P = 0.04) when the
suppression in ACRO was compared with that of the pooled POST and CON
groups, even though this statistical approach was not used extensively
because POST was paired and CON was unpaired to ACRO.
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Hormones and metabolites.
The postabsorptive insulin concentration was increased more in ACRO
before the intervention than in the other groups, whereas it was
comparable during the clamp (Table 4).
The postabsorptive C-peptide concentration was higher in both ACRO and
POST compared with CON, and in POST it also remained higher during the
clamp. In ACRO, the glucagon concentration during the clamp was higher than in POST, whereas the cortisol concentration was lower than in CON.
The growth hormone and IGF-I concentrations were markedly increased in
ACRO before the intervention, and they were completely normalized after
the intervention.
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Body composition before and after surgery. We evaluated whether surgical cure of acromegaly induced changes in body composition that could have affected protein metabolism. The six subjects who were studied both before and after surgery (3 females, 3 males) had a body weight and a body mass index that did not change significantly among studies (from 79 ± 7 to 81 ± 6 kg and from 27.2 ± 1.5 to 27.9 ± 1.6 kg/m2, respectively). In four acromegalic subjects, DEXA scans were performed to assess body composition. Two of them (1 male and 1 female) had measurements both before and after surgery, whereas one female was measured exclusively before surgery and one female exclusively after surgery. Overall, percentages of lean and fat mass were 67.3 ± 3.2 and 29.5 ± 2.6% before surgery and 64.2 ± 1.8 and 33.3 ± 1.7% after surgery. The two subjects who were studied both before and after surgery gained 2.8 and 4.8 kg of fat mass and lost 1.6 and 1.1 kg of lean mass, respectively.
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DISCUSSION |
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This study investigated the insulin sensitivity of glucose and protein metabolism in acromegalic patients with a benign pituitary adenoma before and after successful adenomectomy. All subjects had a marked and chronic elevation of growth hormone and IGF-I. These hormones were completely normalized 6 mo after the intervention. The surgical cure of acromegaly caused the complete reversal of the alterations in glucose metabolism that were evident before the intervention. That acromegaly caused a marked and reversible impairment in insulin-mediated glucose disposal was an expected finding (15, 17, 18, 27). It is remarkable that, in our subjects (similarly to the previously studied nondiabetic acromegalic patients), the postabsorptive glucose concentration and flux were only 10 and 30% increased, with the paradox of a resulting glucose clearance that was higher, albeit not significantly, compared with the control groups. In contrast, the impairment in insulin-stimulated glucose disposal was almost complete. One should infer that, beyond the compensatory effects of postabsorptive hyperinsulinemia, the glucose effectiveness in acromegalic patients is increased at the expense of insulin sensitivity, suggesting that growth hormone and IGF-I exert insulin-like effects to promote glucose uptake in the postabsorptive state. To support this idea, opposite changes were obtained by replacing growth hormone in growth hormone-deficient adults: insulin sensitivity decreased and glucose effectiveness increased (31). Our findings on the effects of acromegaly on glucose metabolism are in line with the idea that the marked insulin insensitivity for the stimulation of glucose uptake does not necessarily imply an absolute defect in postabsorptive glucose uptake. This is also suggested by molecular studies that showed that chronic elevation in growth hormone does not impair basal glucose uptake or the activity of the insulin-signaling pathway: when not insulin stimulated, it just impairs the insulin stimulation of these elements (36).
Plasma amino and keto acid concentrations were similar in ACRO and CON except for a modest (11%) reduction in phenylalanine levels in acromegalic subjects before treatment. Proteolysis, leucine oxidation, and protein synthesis were similar to those in CON. We did not find a significant effect of acromegaly on postabsorptive protein kinetics, but there was a tendency for proteolysis to be decreased in the acromegalic subjects, which was more marked after surgery. Taken together with other studies, our data suggest that increased circulating growth hormone can increase proteolysis in adults if they are growth hormone deficient (20, 25) but not if they have an adequate (12) or increased growth hormone secretion. In contrast, the insulin control of proteolysis was severely impaired. The defective suppression of proteolysis was paralleled by a defective suppression of leucine, KIC, and phenylalanine concentrations during the clamp. Our data agree with studies showing that growth hormone acutely inhibits the insulin-dependent suppression of proteolysis in the forearm (13). Suppression of proteolysis is the main mechanism by which insulin promotes protein accretion in humans in vivo in the whole body (9, 14). It is now known that this action is mediated by the ubiquitin-proteasome-dependent pathway, but regulation by the intracellular signaling pathways is still unclear (26).
Interestingly, the defective suppression of proteolysis did not imply a lesser anabolic effect by hyperinsulinemia. The insulin suppression of leucine oxidation was completely maintained; thus a greater proportion of the proteolytic flux was shunted toward protein synthesis during hyperinsulinemia in ACRO. Growth hormone and IGF-I have the effect of decreasing leucine oxidation in various conditions (7, 8, 12, 20, 25). ACRO patients were insulin resistant for the suppression of proteolysis and not for the oxidation of leucine, whereas POST subjects were insulin resistant for both aspects of insulin action on protein metabolism. As a consequence, hyperinsulinemia resulted in a stimulus that was more anabolic in ACRO than in POST.
It is unclear why, 6 mo after adenomectomy, the insulin resistance for glucose metabolism was completely reversed whereas the insulin resistance for protein metabolism was persisting. One possibility is that slow changes in protein mass were still occurring 6 mo after surgery and that the insulin resistance for the suppression of leucine oxidation in POST reflected a tendency toward an increased overall protein catabolism. It was shown that acromegaly causes a reduction in fat mass and an increase in fat-free mass, which are largely due to extracellular water retention, and these changes are reversible within 6 mo after surgery (28, 38). The changes in body cell mass, if any, are small; thus the effect of the surgical cure of acromegaly may be undetected in the short term. The mean change in absolute body weight in the subjects who were studied before and after surgery was a gain of 1.6 ± 1.9 kg, not significantly different from zero. We did not measure systematically the changes in lean body mass induced over time by adenomectomy in the acromegalic patients. In the two subjects who were studied by DEXA scan before and 6 mo after the operation, we found a modest increase in fat mass. Thus interpretation of the insulin resistance after surgery remains speculative. It should be noted that changes in body cell mass relative to total body weight could have affected the absolute rates of protein kinetics that were normalized by the total body weight. However, the changes in body cell mass, if any, were probably very small according to the literature (5, 28, 38) and the modest weight changes we measured in our subjects. Thus we cannot exclude the possibility that the absolute protein kinetic rates may have been affected by small changes in body composition in ACRO and in POST. However, the measurements of insulin sensitivity of proteolysis, leucine oxidation, and protein synthesis, the goals of this study, are not biased by changes in body composition, being normalized to the postabsorptive values.
Finally, we investigated possible changes in glutamine kinetics induced
by acromegaly, because it was previously shown that growth hormone in
stressed patients markedly reduced muscular glutamine production
(4). The postabsorptive glutamine flux was similar among
groups, but insulin significantly reduced the glutamine flux only in
ACRO, where this insulin effect was significantly greater than in the
pooled control groups. Interestingly, in ACRO, the suppression of
glutamine flux was much greater than the suppression of leucine flux
(28 vs.
9%, P < 0.05). In contrast, in the other groups, the suppression of glutamine flux was similar to that of
leucine flux [
5 vs.
12% in POST and
12 vs.
18% in CON, P = nonsignificant (NS)]. Circulating glutamine
derives from two possible sources: proteolysis and de novo synthesis,
i.e., the transamination of
-ketoglutarate and glutamate with other
amino acids that are subsequently oxidized. Even though the amino acid composition of the proteins broken down in the study period was unknown
and the assumption of constant ratios among amino acids in proteins can
lead to experimental errors (33), the marked reduction in
glutamine flux despite a defective insulin suppression of leucine flux
strongly indicates a reduction in de novo glutamine synthesis. Our data
suggest that, in ACRO, hyperinsulinemia simultaneously reduced amino
acid oxidation and their transamination in the organs (the muscle) that
export glutamine as a means to dispose amino nitrogen to the liver for
urea synthesis. The suppression of glutamine de novo synthesis was not
evident in POST subjects, who also had a defective suppression of
leucine oxidation during the clamp. These data support the idea that
glutamine de novo synthesis and amino acid oxidation are related
processes and suggest that, in acromegaly, insulin is more effective in
sparing amino acids from oxidation and in reducing nitrogen export to
the liver via glutamine shuttling.
In conclusion, acromegalic patients are severely insulin resistant for both glucose and protein metabolism, indicating a generalized defect in insulin signaling. Six months after operation, insulin resistance for glucose metabolism is completely reversed. In contrast, a marked antagonism with the insulin effect on proteolysis and leucine oxidation still persists. The effects of growth hormone on protein metabolism are not reversed by surgery in the short term.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Battezzati, Amino Acids and Stable Isotopes Laboratory, San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milano, Italy (E-mail: battezzati.alberto{at}hsr.it).
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. Section 1734 solely to indicate this fact.
First published October 8, 2002;10.1152/ajpendo.00020.2002
Received 22 January 2002; accepted in final form 10 September 2002.
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