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Original Studies |
Laboratoire de Nutrition Humaine, Universite d’Auvergne, Institut National de la Recherche Agronormique and Centre de Recherche en Nutrition Humaine, 63009 Clermont-Ferrand, France
Address all correspondence and requests for reprints to: Dr. Yves Boirie, Laboratoire de Nutrition Humaine, B.P. 321, 58 rue Montalembert, 63009 Clermont-Ferrand Cedex 1, France.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Lean body protein mass decreases with aging, which may be the consequence of a reduced action of insulin on protein metabolism. The effect of insulin on protein metabolism during human aging has scarcely been investigated, especially together with glucose metabolism (14, 15). A relevant study dedicated to insulin’s action during aging concluded that there was a normal reduction of whole body protein breakdown in elderly subjects on the basis of four separate euglycemic insulin studies (14). Noticeably, insulin levels were higher in the elderly than in the young group during the clamps, whereas plasma amino acids concentrations were not maintained at their basal levels during insulin infusion. However, amino acid replacement appears to be an important issue when evaluating insulin action on protein metabolism, as evidenced by a second study of the same group and others (15, 16). The effect of hyperaminoacidemia on leucine flux with and without insulin has been investigated, but the high amino acid infusion rate might have obscured the effect of insulin (15). In addition only a high dose insulin infusion was tested, not allowing assessment of the insulin dose response. Noticeably, gender differences have never been analyzed in these studies, as only five or six elderly men were included in these studies, but recent data indicate that gender may affect leucine metabolism in a population of young subjects (17). Finally, more insight into tissue protein metabolism is needed to assess the effect of insulin on specific functions in aging humans. For this, indirect isotopic approaches, such as measurements of fractional synthesis rates of albumin and other plasma proteins, have been used (18, 19). As the albumin fractional synthesis rate may be an indicator of liver protein metabolism in humans and due to the fact that plasma albumin concentrations may be lower in the elderly population, the albumin metabolism response to insulin has to be investigated in healthy elderly humans.
Thus, in the present study we assessed whole body glucose and protein metabolism during an euglycemic and euaminoacid hyperinsulinemic clamp in healthy elderly subjects. To precisely define the metabolic differences between young and elderly subjects, we measured the response to insulin at two different insulin infusion rates. The data indicate that glucose metabolism is impaired at both doses of insulin infusion in elderly people. In addition, less inhibition of whole body protein breakdown was observed at the low dose of insulin infusion. These findings support the hypothesis that insulin action on protein metabolism may be impaired with aging. These alterations may contribute to the loss of fat-free mass and sarcopenia observed with aging.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fourteen young men and women (Y; 24.1 ± 0.9 yr; mean
± SEM, 20.5 ± 0.4 kg/m2) and
12 healthy elderly men and women (E; 69.4 ± 0.6 yr; 24.6 ±
0.8 kg/m2) participated in the study. All
subjects had normal physical examinations without any medical history
of digestive, renal, cardiovascular, endocrine, or any chronic disease.
The physical characteristics of the subjects are indicated in Table 1
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Materials
D-[6,6-2H2]Glucose [96 molar percent excess (MPE)], L-[1-13C]leucine (99 MPE), and sodium [13C]bicarbonate (99 MPE) were obtained from MassTrace, Inc. (Woburn, MA). The isotopic and chemical purities of leucine were checked by gas chromatography mass spectrometry. Solutions of tracers were tested for sterility and pyrogenicity before use and were prepared in sterile apyrogen water. The 20% glucose solution for the clamp was exclusively composed of beat glucose (Braun Medical AG, Emmenbrücke, Switzerland) to avoid 13C contamination in expired 13CO2 for calculation of leucine oxidation. Human insulin (Actrapid, Novo Nordisk Pharmaceutique SA) was diluted in sterile saline just before the infusion. Throughout each experiment, tracers were membrane filtered through 0.22-µm pore size filters.
Experimental protocol
Data were collected with subjects in the postabsorptive state after a 10-h overnight fast. One polyethylene catheter was retrogradely inserted into a dorsal vein of the hand, and arterialized blood was obtained by introduction of the hand into a 70 C heated ventilated box. A second catheter was inserted into the antecubital vein of the contralateral arm for tracer, amino acid, and insulin infusions. A third catheter was inserted into the same arm for the administration of 20% glucose at rates adjusted for periodic plasma glucose measurements. After a prime dose of [13C]bicarbonate (6 mg/5 mL within 1 min), a primed (4.2 µmol/kg within 1 min) continuous (0.07 µmol/kg·min) infusion of L-[1-13C]leucine in combination with a continuous (0.03 mg/kg·min) infusion of D-[6,6-2H2]glucose were started and continuously infused for 7 h. After 180 min of baseline, a primed continuous infusion of insulin was started at a rate of 0.2 mU/kg·min (period 1, CL1) for 120 min to achieve a plasma insulin increment of 20 µU/mL. The plasma glucose concentration was determined every 5 min using a glucose oxidase method (glucose analyzer 2, Beckman, Fullerton, CA) and was maintained constant by a periodic adjustment of the 20% glucose infusion according to the negative feedback principle. After the first 120-min clamp period, a higher rate of insulin delivery at 0.5 mU/kg·min (second clamp period, CL2) was applied for the following 120 min. To avoid an insulin- mediated decline in plasma amino acids, an amino acid solution (5% Primene, Baxter, Maurepas, France) was infused in addition to glucose at a rate of 3.5 x 10-3 mL/kg·min at CL1 and at 6.4 mL/kg·min at CL2 based on preliminary studies. According to the different amino acid infusion rates at CL1 and CL2, unlabeled leucine was administered at 0.14 and 0.25 µmol/kg·min, respectively.
Blood and breath samples were taken before any infusions and at 20-min
intervals during the last hour of each period, i.e. in the
basal state (from 120–180 min), in the first period (CL1; from
240–300 min), and in the second clamp period (CL2; from 360–420 min).
From the whole blood, plasma supernatant was separated, an internal
standard was added, and the sample was kept at -20 C until further
analysis. Breath samples were transferred and kept in 10-mL Vacutainers
(Becton Dickinson and Co., Grenoble, France). Total carbon
dioxide production rates were measured at an isotopic plateau during
the last hour of the two plateaus by open circuit indirect calorimetry
(Deltatrac, Datex, Geneva, Switzerland) to determine leucine oxidation.
Body composition was determined by isotopic dilution of water labeled
with deuterium for six subjects and with 18O for
all other subjects (results in Table 1
).
Analytical determinations
Plasma [2H2]glucose, [13C]leucine, and [13C]ketoisocaproate (KIC) enrichments were measured by selected ion monitoring electron impact gas chromatography-mass spectrometry (5971A, Hewlett-Packard Co., Palo Alto, CA) as previously described (20). Albumin isotopic enrichments for fractional synthesis rate measurements were analyzed with gas chromatography-combustion-isotope ratio mass spectrometry after precipitation, hydrolysis, and derivatization as previously described (19). 13CO2 isotopic enrichments were measured with a gas isotope ratio-mass spectrometer (µGas System, Fisons Instruments, VG Isotech, Middlewich, UK).
Plasma insulin concentrations were measured by RIA (CIS, Gif- sur-Yvette, France). After deproteinization with sulfosalicylic acid, plasma amino acid concentrations were determined by ion exchange liquid chromatography (LS 6300, Beckman Coulter, Inc., Palo Alto, CA).
Calculations
Endogenous glucose production and glucose disposal rates were calculated from the dilution of labeled glucose in plasma using a monocompartment model and Steele’s equations (21). Briefly, the glucose disposal rate was obtained by calculating total glucose flux considering the time changes in concentrations, and enrichment of plasma glucose and glucose production was estimated by subtraction of the unlabeled glucose infusion rate from the total glucose rate of appearance.
Leucine kinetics were calculated according to the reciprocal pool model using KIC as an indicator of intracellular leucine enrichment (22). Leucine kinetics were normalized for fat-free mass to consider the differences in body composition between young and elderly subjects. The total leucine rate of appearance (Ra; micromoles per kg FFM/min) was calculated from plasma isotopic dilution of [13C]leucine. This flux includes the tracer infusions and unlabeled leucine infused to maintain leucine concentrations at CL1 and CL2. From this equation, whole body protein breakdown (micromoles per kg FFM/min) was calculated by subtracting from the total leucine Ra, the infused labeled leucine and the leucine administered with the amino acid solution. Leucine oxidation (micromoles per kg FFM/min) was then calculated by measuring 13CO2 production (micromoles per kg FFM/min) as the product of CO2 production and 13CO2 enrichment (APE) divided by [13C]KIC enrichment, as KIC is the immediate precursor of irreversible leucine decarboxylation in cells. Nonoxidative leucine disposal (NOLD; micromoles per kg FFM/min), an index of whole body protein synthesis, was obtained as the difference between total leucine Ra and leucine oxidation.
The albumin fractional synthesis rate was estimated by measuring time-related changes in albumin-bound [13C]leucine enrichments, divided by the enrichment in the precursor pool, i.e. plasma [13C]KIC isotopic enrichment. Thus, the fractional synthesis rate of albumin (FSR) was calculated as the ratio of the albumin enrichment slope between 300 and 420 min (CL2) divided by plasma [13C]KIC enrichment at CL2 plateau and was expressed as percentage per day.
Statistical analysis
Results are expressed as the mean ± SEM. Body composition and biological data between the groups were compared using a factorial ANOVA. Glucose and leucine kinetics were compared between the two groups by two-way ANOVA for repeated measurements, with age and gender being the classifying factors. Moreover, to consider the different levels of insulin concentrations between the groups during the clamp, the changes in the slopes between CL1 or CL2 vs. basal period for glucose and leucine, and the changes in albumin FSR between baseline and CL2 were also analyzed using a two-way factorial ANOVA.
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Results |
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Fat contribution to body weight was higher in elderly subjects
than young subjects (20.7 ± 1.6% vs. 28.6 ±
2.3%, Y vs. E, P < 0.05; see Table 1).
Fat-free mass was not statistically different between young and elderly
individuals (49.0 ± 2.1 vs. 47.1 ± 2.7 kg, Y
vs. E, P = NS), and body mass index (BMI)
was statistically different between young and elderly subjects
(P < 0.05). Considering gender, a statistical
difference for FFM and body fat content was found between males and
females in Y and E (see Table 1), but not for BMI.
Plasma glucose and insulin
Basal plasma glucose before the OGTT was not different between the two groups (91 ± 3 for Y and 94 ± 3 mg/dL for E; P = NS) nor was the fasting insulin concentration (9.6 ± 0.9 vs. 8.1 ± 0.9 µU/mL, Y vs. E, P = NS). During the OGTT, plasma glucose was higher in E than in Y at 60 and 90 min (116 ± 8 and 105 ± 6 vs. 156 ± 7 and 127 ± 7 mg/dL, at 60 and 90 min, Y vs. E respectively, P < 0.05), despite a higher plasma insulin concentration (48.1 ± 4.8 vs. 69.1 ± 6.9 µU/mL at 60 min, Y vs. E, P < 0.05). During the clamp, no differences between the two groups were observed for glucose, but plasma insulin was systematically and statistically higher in E than in Y at CL1 (17.1 ± 1.0 vs. 12.5 ± 0.6 µUI/mL, E vs. Y, P < 0.05), and at CL2 (35.7 ± 1.3 vs. 27.4 ± 1.4 µUI/mL, E vs. Y, P < 0.05).
Glucose metabolism
Endogenous glucose production was not different between groups at
baseline, as indicated in Table 2. The
insulin-mediated reduction of endogenous glucose production was similar
in both groups at CL1 (-36.6 ± 5.7% vs. 41.9 ±
5.5%, Y vs. E, P = NS) and CL2 (-60.0
± 8.5% vs. -66.5 ± 9.0%, Y vs. E,
P = NS). The glucose infusion rate to maintain plasma
glucose was lower in E than in Y, and the insulin-mediated increase in
glucose disposal was lower in E than in Y at CL1 (29.7 ± 9.9%
vs. 6.2 ± 10.2%, Y vs. E,
P < 0.05) and CL2 (137.2 ± 19.8% vs.
101.8 ± 22.1%, Y vs. E, P < 0.05;
see Table 2 and Fig. 1A).
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Plasma amino acid concentrations were not different between the
two groups at baseline. Amino acid replacement during insulin infusions
permitted the global maintenance of all amino acids concentrations.
Amino acid levels changed in various directions, such as lysine, which
increased, whereas other amino acids, such as methionine,
phenylalanine, and valine, remained unchanged (Table 3). Essential and total amino acid
concentrations were not modified during the clamp in the young and
elderly subjects, respectively.
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Leucine kinetics were calculated at each plateau. CV values for
the KIC isotopic enrichments at plateau were 2.89%, 4.42%, 4.92%,
and 3.58% at baseline for the young men, women, elderly men, and women
respectively. They were 3.71%, 4.48%, 3.08%, and 3.26% at CL1, and
1.56%, 3.28%, 3.42%, and 2.31% at CL2, respectively. The Tot Leu Ra
corrected by fat-free mass was not different at baseline between the
groups or for protein breakdown, synthesis rate (as estimated by
nonoxidative leucine disposal), or leucine oxidation (see Table 2).
However, total leucine Ra, protein breakdown, leucine oxidation and
NOLD were affected by gender whatever the age group (see Fig. 1B; all
P < 0.05).
At CL1, protein breakdown was reduced in the two groups but
insulin-mediated inhibition of protein breakdown was more pronounced in
Y (-13.5 ± 1.4%) than in E (-8.8 ± 1.3%, Y
vs. E, P < 0.05). In absolute values, as
indicated in Table 2, rates of protein breakdown were different at CL1,
but not at CL2, between young and elderly subjects. When the
differences in insulin concentration between the groups were
considered, the slopes of protein breakdown inhibition were
statistically different between Y and E (-0.020 ± 0.004
vs. -0.050 ± 0.006; P < 0.05; see
Fig. 1). This was observed whatever the gender (-0.027 ± 0.007;
-0.013 ± 0.004 vs. -0.050 ± 0.011,
-0.051 ± 0.007, E men, E women vs. Y men, Y women,
P < 0.05; E vs. Y, P = NS,
men vs. women). At CL2, inhibition of protein breakdown from
baseline was similar in both groups (-22.0 ± 1.4%
vs. -18.8 ± 1.7%, Y vs. E,
P = NS; see Fig. 1B) with an identical slope of
inhibition between CL1 and CL2 (-0.012 ± 0.004 vs.
-0.013 ± 0.005, E vs. Y, P = NS).
When endogenous leucine Ra was directly expressed over insulin
concentration, the significance of the differences between young and
elderly subjects was even markedly increased; whole body protein
breakdown/insulin was 0.392 ± 0.033 and 0.363 ± 0.024 for
young and elderly at baseline (P = NS), 0.156 ±
0.008 vs. 0.120 ± 0.008 at CL1 (P <
0.01), and 0.064 ± 0.003 vs. 0.050 ± 0.002 at
CL2 (P < 0.01). As indicated in Fig. 1, the gender
effect at baseline for total leucine flux disappeared in response to
insulin when a two-way ANOVA for repeated measurements was performed.
Leucine oxidation was not different at baseline between Y and E, but
during insulin clamp an increase in leucine oxidation
(P < 0.05 vs. baseline) was observed in the
two groups at CL1 and CL2. Finally, whole body protein synthesis as
NOLD was not different and was not stimulated by insulin at CL1 and CL2
in Y or E.
Albumin synthesis rate
The albumin fractional synthesis rate at baseline was not
different between Y and E (5.86 ± 0.21% vs. 6.45
± 0.34%/day, Y vs. E, P = NS), and insulin
infusion stimulated albumin synthesis by 28% in Y (7.46 ±
0.25%/day) and 35% in E (8.74 ± 0.54%/day), so the absolute
synthesis rate in the two groups was similar (see Fig. 2). There was no gender effect at
baseline (6.06 ± 0.22%, 5.71 ± 0.34%, 6.62 ±
0.44%, and 6.27 ± 0.54%/day for Y men, Y women, E men, and E
women, respectively; P = NS) and during insulin
infusion (7.79 ± 0.32%, 7.21 ± 0.35%, 9.21 ±
0.66%, and 8.26 ± 0.87%/day, for Y men, Y women, E men,
and E women respectively; P = NS).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From our results, it appears that the sensitivity to insulin of glucose and protein metabolism may be differently affected during aging, as illustrated in other circumstances such as diabetes (25), obesity (27), or other severe insulin resistance syndromes (23). In the present study this idea is still true, but only at high dose insulin, because glucose disposal was reduced in elderly subjects, and inhibition of protein breakdown was normal at CL2, but not at CL1. However, the interpretation of the data at CL2 are still questionable, because plasma insulin concentrations during the two insulin levels of the clamp were systematically higher in E than in Y for the same insulin infusion rate. Noticeably, amino acid infusion rates should be adapted for the changes in fat-free mass and thus be calculated per kg fat-free mass. However, despite a slightly higher amino acid concentration in the elderly, which may help to inhibit more protein breakdown, a higher protein breakdown in the elderly people than in the young individuals was observed at CL1. The question of a higher plasma insulin concentration has been raised by studies examining the effect of insulin in elderly subjects, and the mechanism of higher insulin levels in elderly people has been reported to be the result of decreased insulin clearance (28, 29, 30). The differential metabolic response is intriguing, because insulin after binding to its receptor stimulates numerous activating signals as well as those for glucose metabolism, protein metabolism, or the other cellular events. This observation suggests that specific signaling pathways may be affected during aging.
Among the studies concerned with both glucose and amino acid metabolism response to insulin, only one study has examined aging humans (14). This study analyzed the effects of four doses of insulin infusion on five elderly subjects during separate clamps. Unfortunately, this study used a cross-sectional design and did not include exactly the same subjects for all clamp studies. The researchers came to the conclusion that protein metabolism responded normally to insulin in elderly subjects. The different conclusion in our work requires some comments. First, as in our study a trend toward a higher plasma insulin concentration was also found in this previous work (23 vs. 16 µU/mL and 37 vs. 29 µU/mL, old vs. young subjects at insulin infusion rates close to our CL1 and CL2 levels), but this observation was not considered in the interpretation of the data. Second, there was a dramatic fall in plasma amino acid concentrations at every insulin levels that was not prevented by amino acid replacement. As baseline amino acid maintenance is critical for the interpretation of the results in protein metabolism studies (10, 31), this may partly explain some of the differences we found. Third, we wanted to check for the first time whether gender may have affected the response to insulin. Recent data indicate that gender differences in leucine metabolism may be present at baseline in a young population (17). We confirm that this difference also exists in the elderly population, but the response to insulin of protein metabolism was not statistically different between the gender groups when using two-way ANOVA for repeated measurements. This has never been reported to our knowledge in elderly subjects. Finally, the reason to further investigate the question of a possible dysregulation of protein metabolism during aging is based on animal and human observations. For instance, it has been shown that glucocorticoid-induced stress was responsible for a decreased response to insulin of protein breakdown in old animals (32). A report from nondiabetic obese subjects has also demonstrated subtle differences in insulin sensitivity of whole body protein metabolism (26). Actually, the changes observed in the latter study were close to our observation, as low insulin levels induced less reduction in protein breakdown, whereas high insulin levels strongly inhibit protein breakdown to the same extent as in nonobese patients. Our volunteers were not obese, as their BMI were lower than 30 kg/m2, but changes in body composition as upper adiposity may potentially affect insulin action on protein metabolism as it has been shown by Jensen et al. (33). Noticeably, the metabolic implications of the changes in body composition rather than age by itself was the main conclusion of the large European study on insulin resistance and aging (34). This may also be applied to protein metabolism in the case of aging. The question of insulin resistance for protein metabolism has been indirectly raised by analyzing the changes in amino acid concentrations during an oral load of glucose (35). The results suggested insulin resistance in elderly subjects, especially toward branched chain amino acids, which are predominantly metabolized in muscle. During an OGTT, insulin stimulation normally reduces whole body protein breakdown and produces a decline in plasma amino acid concentration. By measuring amino acid concentrations during OGTT, Marchesini et al. have shown that this decline was of lesser magnitude in elderly subjects, suggesting less inhibition of protein breakdown (35). A final intriguing observation in our work was the fact that during feeding, less inhibition of protein breakdown was constantly found if protein breakdown calculations were corrected for splanchnic extraction of dietary amino acids. In the two different studies in which we considered the splanchnic extraction of dietary amino acids by using dual tracer administration, protein breakdown inhibition during the meal was of lower magnitude in the elderly groups (19, 36). Even if many other substrates have additional effects on protein breakdown, this is in keeping with the hypothesis that insulin is less effective in reducing protein breakdown in elderly subjects.
On a biochemical note, it is not possible from this study to extrapolate about the tissue and the mechanism of any age-related dysregulation of protein breakdown, but as muscle represents a large contribution to whole body protein turnover and appears to be more sensitive to insulin than the splanchnic tissues (13), it is reasonable to think that muscle is particularly involved in these alterations. For instance, after meal intake a decreased stimulation of muscle protein synthesis rate has been reported in old animals (37), whereas a normal response to a meal or to physical activity was demonstrated in elderly healthy human subjects (38). These studies suggest that metabolic alterations of protein metabolism associated with aging are not unanimously accepted, but that the response of muscle proteins to stimulating factors may be altered. If so, progressive muscle loss with aging may be explained by a decrease in insulin sensitivity of muscle protein, and this means that insulin resistance as a mechanism for age-related sarcopenia has to be further investigated. For instance, the molecular mechanism of protein wasting in insulin-deficient diabetic rats is activation of the ubiquitin ATP-dependent proteolytic system, implying that the regulation of this proteolytic pathway may be altered with aging (39). Finally, in our work we determined the response of the albumin fractional synthesis rate in response to insulin. The albumin fractional synthesis rate is up- regulated by insulin as primarily shown by De Feo et al. (40), but the effect of age on albumin synthesis has been less defined. Studies of albumin metabolism in aging subjects have indicated a sort of dysadaptation to changes in protein intake, with albumin synthesis remaining at a high level despite a reduction in dietary protein content (41). More recently, Nair’s group found that the albumin synthesis rate was identical in young and elderly humans (42). We investigated the response of albumin synthesis to insulin in young and old men and women, and the stimulation of albumin synthesis by insulin was elevated to the same extent in young and elderly subjects. As the albumin concentration is usually lower in aging humans, and the albumin synthesis rate is not different in elderly in the basal state or after insulin administration, the question of a possible dysregulation of albumin degradation in this population remains uncertain. Unfortunately, no methodology is available to easily measure in vivo albumin breakdown rate in humans.
In conclusion, changes in insulin sensitivity differentially affects glucose and amino acid metabolism in elderly men and women, but alterations in the regulation of protein metabolism by insulin may occur at physiological insulin elevations in the elderly subjects. These changes may contribute to a progressive loss of body proteins, especially at the muscle level. Further studies, particularly at the cellular and molecular levels, are needed to precisely examine the defects in the regulation of the proteolytic pathways regulated by insulin. As for glucose metabolism, it is still questionable whether any intervention improving insulin sensitivity is able to improve the response of protein metabolism to insulin in elderly subjects.
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Acknowledgments |
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Received May 19, 2000.
Revised October 25, 2000.
Accepted October 27, 2000.
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) and during the clamp at CL2 (
) in young
and elderly subjects. *, P < 0.05
vs. baseline value.