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Unité du Métabolisme Protéino-Energétique, Unité Mixte de Recherche, Université d’Auvergne/Institut National de la Recherche Agronomique, Centre de Recherches en Nutrition Humaine, Centre Hospitalier de l’Université, 63009 Clermont-Ferrand, France
Address all correspondence and requests for reprints to: Dr. Yves Boirie, Unité du Métabolisme Protéino-Énergétique, Laboratoire de Nutrition Humaine, BP 321, 58 rue Montalembert, 63009 Clermont-Ferrand Cedex 1, France. E-mail: boirie{at}clermont.inra.fr.
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Abstract |
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Introduction |
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During aging, a progressive impairment of in vivo insulin action on glucose metabolism has been described (13, 14). Indeed, it is usually reported that peripheral glucose utilization mediated by insulin is reduced in elderly humans (13, 15, 16), with normal suppression of hepatic glucose production (13, 14, 17). Nevertheless, age-related changes in insulin action on body protein homeostasis have been less well documented. A previous study determined whether the age-related defect in insulin action on glucose metabolism extends to amino acid metabolism (18). The researchers concluded that there was actually a lower glucose disposal rate in elderly subjects, but a normal reduction of whole body PB under different insulin infusion rates. Noticeably, plasma insulin levels were higher in the elderly than in the young group during the clamps. Thus, the effect of insulin on PB observed in elderly subjects was obtained with higher insulin concentrations than in young subjects. Moreover, plasma amino acid concentrations were not maintained at their basal levels during insulin infusion. A later study (7) examined the effect of age on the response of protein metabolism to physiological increases in insulin, in healthy young and elderly subjects, with maintenance of basal plasma amino acid concentrations. A lesser insulin dose-dependent reduction of PB was documented in the aging population compared with that in the young group. Thus, the response of whole body PB to a physiological increase in insulin levels appeared to be affected by aging. Because amino acids can potentiate insulin-mediated inhibition of PB (9, 10), amino acid concentrations also have to be considered in the action of insulin on protein metabolism. For instance, during the fed state, a situation where insulin and amino acid are increased, a lesser inhibition of PB has been reported in elderly subjects despite a normal increase in the amino acid concentration (19, 20). Therefore, the combined effects of insulin and amino acids at postprandial concentrations on protein metabolism should be investigated in elderly subjects.
Hence, in the present study the response of whole body PB to insulin was investigated with either basal or high plasma amino acid concentrations in healthy young and elderly subjects. For this purpose, we used two euglycemic hyperinsulinemic clamps differing by amino acid infusion levels: euaminoacidemic (EuAA) and hyperaminoacidemic (HyperAA). The data indicate that in elderly subjects, whole body PB is resistant to insulin action, but amino acids are still able to inhibit PB in this population.
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Subjects and Methods |
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The study group consisted of 14 young (mean ± SEM, 24.4 ± 0.8 yr; body mass index, 22.1 ± 0.6 kg/m2) and 24 healthy elderly (70.2 ± 0.7 yr; 25.4 ± 0.5 kg/m2) male subjects. All volunteers had normal physical examinations without any medical history of digestive, renal, cardiovascular, endocrine, or chronic diseases. The physical characteristics of the subjects are indicated in Table 1
. Body composition was assessed by dual energy x-ray absorptiometry (QDR-4500A, Hologic, Inc., Waltham, MA).
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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 Cambridge Isotope Laboratories, Inc. (Andover, MA). The isotopic and chemical purities of glucose and 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. Throughout each experiment, tracers were membrane-filtered through 0.22-µm pore size filters. Human insulin (Actrapid, Novo-Nordisk Pharmaceutique, Copenhagen, Denmark) was diluted in sterile saline just before the infusion. A 20% glucose solution (Braun Medical, Boulogne, France) was used to maintain blood glucose at the baseline level as previously described (7). Amino acid mixtures (5% and 10% Primene) were purchased from Clintec Parenteral (Montargis, France).
Experimental protocol
All subjects were studied in the postabsorptive state after a 10-h overnight fast. On the day of the experiment, two venous tracts were laid on the arms. One catheter was retrogradely inserted into a dorsal vein of the left arm and was used for blood sampling. The hand of the subject was introduced into a ventilated box heated to 60 C to obtain arterialized blood. A second catheter was inserted into the contralateral arm and was used for tracer, insulin, and amino acid infusions. A third catheter was inserted into the same arm for the administration of a 20% glucose solution at rates adjusted for periodic plasma glucose measurements. After a prime dose of [13C]bicarbonate (6 mg/5 ml within 1 min), a primed [EuAA, 5.9 µmol/kg fat-free mass (FFM); HyperAA, 8.4 µmol/kg FFM] continuous (EuAA, 0.098 µmol/kg FFM·min; HyperAA, 0.14 µmol/kg FFM·min) infusion of L-[1-13C]leucine in combination with a primed (EuAA, 1.8 mg/kg; HyperAA, 3 mg/kg) continuous (EuAA, 0.03 mg/kg·min; HyperAA, 0.05 mg/kg·min) infusion of D-[6,6-2H2]glucose were performed for 8 h. The L-[1-13C]leucine infusion rate was increased (0.21 µmol/kg FFM·min) during the HyperAA insulinemic clamp to account for the higher dilution rate of the tracer by exogenous amino acids. After a 4-h basal period, the EuAA or HyperAA, euglycemic, hyperinsulinemic clamps were performed in young (EuAA, n = 6; HyperAA, n = 8) and elderly (EuAA, n = 12; HyperAA, n = 12; Fig. 1) male subjects. Subjects undergoing the EuAA clamp were from a previous study (7). However, because a gender effect was observed, only data from men were considered in the present study. For the two clamps, a continuous infusion of insulin was administered at a rate of 0.7 mIU/kg FFM·min. The plasma glucose concentration was determined every 5 min using a glucose oxidase method (glucose analyzer 2, Beckman Coulter, Fullerton, CA) and was maintained constant by a periodic adjustment of the 20% glucose infusion according to the negative feedback principle.
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Blood and breath samples were taken before any infusions, then at 20-min intervals during the last hour of each period. From the whole blood, the plasma supernatant was separated, an internal standard was added, and the sample was kept at –20 C until additional analysis. Breath samples were kept in 10-ml Vacutainers (BD Biosciences, Grenoble, France). Total carbon dioxide production rates were measured during the last hour of the two periods by open circuit indirect calorimetry (Deltatrac, Datex, Geneva, Switzerland) to determine leucine oxidation.
Insulin sensitivity assessment
Insulin resistance was not considered for glucose and protein metabolism together in all previous studies. Because the response of PB to insulin seemed to be altered in insulin-resistant elderly subjects (7), the question was raised of how to know whether this response was related to various degrees of insulin sensitivity for glucose metabolism. The influence of insulin resistance on protein metabolism regulation by insulin and amino acid was thus explored in elderly subjects, who were divided a posteriori into two groups: insulin sensitive (IS-E) or insulin resistant (IR-E).
The differentiation between IS-E (n = 12) and IR-E (n = 12) elderly subjects, with six IS-E and six IR-E subjects per clamp, was determined on the basis of both insulin clamp data [whole body glucose disposal (GDR)/insulinemia] (21) and a classical index of clamp-derived insulin sensitivity [glucose infusion rate/(glycemia x (insulinemia during clamp – insulinemia during basal state)] (22). Both indexes indicated the same value to separate the two populations (first index mean (21): IS-E, 0.18; IR-E, 0.11; second index mean (22): IS-E, 0.17; IR-E, 0.09). Mean indexes for IR-E and IS-E were significantly different (P < 0.05). Elderly subjects were considered to be insulin resistant when the insulin sensitivity index value was lower than the insulin sensitivity index (0.15) determined at similar insulin infusion rate by Bergman et al. (23).
Analytical methods
Plasma [2H2]glucose, [13C]leucine, and ketoisocaproate (KIC) enrichments and concentrations were measured by gas chromatography-mass spectrometry (5971A, Hewlett-Packard, Palo Alto, CA) as previously described (7, 20). 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 ELISA (BioSource Europe, Nivelles, Belgium).
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 (24). The glucose disposal rate was obtained by calculating total glucose flux considering the time changes in concentrations and enrichment of plasma glucose. 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 (25). Those parameters were normalized for FFM to consider the differences in body composition between young and elderly subjects. The total leucine rate of appearance (Ra; micromoles per kilogram of FFM per minute) was calculated from plasma isotopic dilution of [13C]KIC. This flux includes the tracer infusion and unlabeled leucine infused with other amino acids to maintain amino acid concentrations at the basal level (EuAA) or to elevate those concentrations 2- to 3-fold above the basal level (HyperAA). From this equation, whole body PB (Endo Leu Ra; micromoles per kilogram of FFM per minute) 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 kilogram of FFM per minute) was then calculated by measuring 13CO2 production as the product of CO2 production and 13CO2 enrichment divided by [13C]KIC enrichment, because KIC is the immediate precursor of irreversible leucine decarboxylation in cells. 13CO2 enrichment was corrected for incomplete recovery by a factor of 0.70 in the basal state and 0.84 during the clamp according to previous clamp studies (26). The contribution of natural enrichment of the infused glucose and amino acid solutions to 13CO2 production was determined in three additional subjects receiving these solutions during 4 h at rates similar to those used previously. This infusion increased the 13CO2 enrichment in the expired air (+2 delta per thousand). This contribution has been corrected for the subsequent calculation of leucine oxidation (Fig. 2). Nonoxidative leucine disposal (micromoles per kilogram of FFM per minute), an index of whole body protein synthesis, is the difference between total leucine Ra and leucine oxidation. Finally, leucine balance is the difference between total leucine intake (from tracer and amino acid infusions) and leucine oxidation.
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Statistical analysis
Results are expressed as the mean ± SEM. Body composition and biological data between the groups were compared using a one-way ANOVA (StatView 5.0, Abacus Concepts, Inc., Berkeley, CA). Glucose and leucine parameters were compared between the groups by two-way ANOVA for repeated measurements, with age and insulin sensitivity as the classifying factors. For all parameters in which significant differences were detected in the basal state ([13C]leucine, [13C]KIC, and [2H2]glucose enrichments; [13C]leucine infusion rate; plasma branched chain, essential, nonessential, and total amino acid concentrations; plasma insulin concentrations; endogenous leucine Ra; leucine oxidation; nonoxidative leucine disposal; and leucine balance), an analysis of covariance model was applied using the basal values as covariates. However, the statistical outcomes were not affected by such analysis. The ratios between the change over basal in the whole body glucose disposal rate or PB and the change over basal in the plasma insulin concentration were also analyzed by two-way factorial ANOVA. When a significant effect was detected, differences among individual means were assessed with Fisher’s protected least significant difference post hoc test to determine pairwise differences. The level of significant difference was set at P < 0.05 for all statistical tests.
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Results |
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Body mass index (BMI) was higher in elderly subjects than in young subjects (P < 0.05; Table 1
). FFM was not statistically different between young and elderly individuals [P = not significant (NS)] in absolute value, but was significantly lower in elderly subjects in proportion to body weight (young, 80.5 ± 1.4%; elderly, 74.7 ± 1.5%; P < 0.05, elderly vs. young). The contribution of fat mass to body weight was greater in elderly subjects than in young subjects (P < 0.05), whereas there was no difference in body weight in either groups. Fasting glucose was slightly higher, but not significantly so, in elderly compared with young individuals, but none had fasting hyperglycemia.
BMI, body weight, FFM, fat mass, and fasting glucose were not statistically different between IS-E and IR-E subjects (P = NS), except for IR-E, who had higher BMIs than IS-E subjects during the HyperAA clamp (Table 2).
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[13C]Leucine and [13C]KIC enrichments (Table 3) remained constant when amino acid infusion enabled maintenance of the basal plasma leucine concentration and were diminished during the infusion of high amount of leucine with amino acid infusion (P < 0.05). The [13C]leucine enrichments were higher during the clamp in elderly subjects than in young subjects regardless of the plasma amino acid level (Table 3).
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; P < 0.05). During insulin infusion, these enrichments were higher during the HyperAA clamp in elderly than in young subjects. The insulin infusion induced an increase in expired 13CO2 production in both conditions (P < 0.05; Table 3). However, this parameter was higher during the HyperAA clamp (P < 0.05). Plasma insulin concentration
Plasma insulin concentrations (see Table 5) were systematically higher in the elderly compared with the young subjects (P < 0.05). The basal plasma insulin level was not different between groups, except for IR-E subjects in HyperAA conditions, in whom it was significantly higher than in other groups (Table 2). During the HyperAA clamp, IR-E subjects had higher plasma insulin concentrations than during the EuAA clamp (Table 2).
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Plasma amino acid concentrations (Table 4) were not different during the EuAA clamp in young and elderly subjects. During the HyperAA clamp, plasma amino acid concentrations were increased in both groups, but in elderly subjects, branched chain, essential, and total amino acid levels were higher than those in young subjects (P < 0.05).
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As indicated in Table 5, the basal glucose disposal rate was not different between young and elderly subjects during the two clamps. However, the insulin-mediated increase in glucose disposal, represented by the ratio between the change over the basal glucose disposal rate and the change over the basal plasma insulin concentration (Fig. 3A), was lower in elderly than in young subjects during both the EuAA clamp (elderly vs. young, 0.10 ± 0.02 vs. 0.20 ± 0.03 mg/ml·µU/kg FFM·min; P < 0.05) and the HyperAA clamp (elderly vs. young, 0.05 ± 0.01 vs. 0.13 ± 0.02 mg/ml·µU/kg FFM·min; P < 0.05). The utilization of glucose was lower after HyperAA clamp than after EuAA clamp only in young subjects (P < 0.05). Endogenous glucose production was not different between groups in the basal state. This parameter was reduced by insulin similarly in young and elderly subjects in both conditions (P = NS).
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). Leucine metabolism
As indicated in Table 5, basal total leucine flux normalized for FFM was similar in young and elderly subjects during both clamps (P = NS). During the HyperAA clamp, total leucine Ra was stimulated in both young and elderly subjects (P < 0.0001). In the postabsorptive state, PB was not different between groups. After insulin infusion, rates of PB, in absolute values (Table 5), were lower in HyperAA than in EuAA groups (P < 0.05). When the differences in insulin concentration between the groups were considered (Fig. 3B), the ratio between the change over basal PB and the change over basal insulin concentration was statistically lower in elderly subjects than in young subjects in both conditions [EuAA, –0.014 ± 0.002 vs. –0.024 ± 0.003 µmol/ml·µU/kg FFM·min (elderly vs. young, P < 0.05); HyperAA, –0.022 ± 0.002 vs. –0.036 ± 0.003 µmol/ml·µU/kg FFM·min (elderly vs. young, P < 0.05)]. The insulin-mediated PB inhibition was greater after HyperAA clamp than after EuAA clamp (P < 0.05) regardless of the age of the subjects.
When the insulin sensitivity of elderly subjects was considered, the inhibition of PB was similar in IS-E and IR-E individuals (Table 2). Nevertheless, addition of amino acids to the insulin infusion increased the inhibition of PB only in IS-E subjects (P < 0.05, HyperAA vs. EuAA).
Leucine oxidation (Table 5) remained stable during the EuAA clamp and was increased during the HyperAA clamp (P < 0.05) regardless of the age of the subjects. Nonoxidative leucine disposal (Table 5), an index of protein synthesis, increased during the HyperAA clamp (P < 0.05), but was not changed compared with the basal value during the EuAA clamp. Leucine balance (Table 5) was less negative after the EuAA (P < 0.05) clamp and became strongly positive during the HyperAA clamp (P < 0.05), similarly in young and elderly subjects.
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Discussion |
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As previously described, we noticed a reduced insulin action not only on glucose utilization (7, 13, 14, 15, 16, 17, 18), but also on PB in the aged population (7). Only a few studies have shown that the insulin sensitivities of glucose and protein metabolism may be differently affected during aging (9, 18, 27). This is also the case in other circumstances, such as diabetes (28) or obesity (29). In all of these studies, proteolysis inhibition was calculated without consideration of the plasma insulin levels of the subjects. Indeed, plasma insulin concentrations were significantly increased in obese (29) and noninsulin-dependent diabetes mellitus (28) subjects in the fasted state and during the insulin clamp. Insulin levels were higher during the clamp in elderly subjects than in young subjects (18), suggesting reduced insulin clearance with age, as previously reported (30). Because higher plasma insulin levels were required in the elderly to obtain the same result as in young, the insulin action on PB may be interpreted as defective in elderly individuals. This aspect was demonstrated previously (7) and in our present study. Actually, during both clamps, a lesser inhibition of PB mediated by insulin was found in elderly subjects despite a greater insulinemia than in young subjects. Therefore, the inhibition of PB should be evaluated according to the individual insulinemia to compare protein metabolism in individuals differing in plasma insulin levels. The effect of amino acid infusion on protein metabolism was also investigated in our experiment. Indeed, proteolysis may be inhibited by amino acids alone (8, 11) or in conjunction with insulin (9, 10). Amino acids induced a greater inhibition of PB in both young and elderly subjects, but PB inhibition was still less in the elderly. Thus, amino acid infusion could not compensate for the decreased response of proteolysis to the inhibitory effect of insulin in elderly subjects. This observation is consistent with the concept of a relative resistance to the anabolic action of insulin and amino acids during aging, because it has been shown previously for protein synthesis (3, 31, 32). It seems that in elderly population, the alteration in the anabolic process involves resistance not only to the stimulatory action of amino acids and nutrients on protein synthesis, but also to the inhibitory effect of insulin on PB. This defective response to nutritional factors could contribute to the age-related loss of protein mass or to a redistribution of protein metabolism from the muscle to the splanchnic tissues (20, 33). Therefore, leucine balance may not reflect what is happening at the muscle level. Indeed, metabolic alterations can reduce protein deposition in the postprandial state, which may not compensate for protein lost during the postabsorptive phase. Nevertheless, recent studies have shown an improvement of protein retention in elderly subjects by increasing amino acid availability (34, 35). One possibility would be to modulate the distribution of daily protein intake; when 80% of protein intake was consumed at one meal (a pulse pattern feeding), the increase in nitrogen balance was higher than when the same intake was distributed over four meals (a spread pattern) in elderly women (34). The inverse tendency was found in young women (a better nitrogen balance with the spread pattern) (36). The protein digestion rate of proteins, i.e. the slow and fast protein concept (37) could also increase amino acid availability. A fast absorbed protein included in a mixed meal induced a better protein balance than a slow one in elderly subjects, contrary to what was observed in young subjects (35). In so far as the pulse feeding condition could be assimilated to the administration of a fast protein, these studies clearly demonstrated the major relevance of amino acid availability in combination with a postprandial increase in insulin to improve protein retention and thus to prevent sarcopenia in the aged population.
In the present study the influence of hyperaminoacidemia on glucose metabolism was also investigated in young and elderly individuals. The modulation of insulin action on glucose disposal by amino acids has been previously documented in young subjects (38, 39, 40, 41, 42), but not in the elderly. Infusion of a mixture of amino acids decreased the rate of infusion of exogenous glucose required to maintain euglycemia during a hyperinsulinemic clamp (38, 42), suggesting a reduction in whole body glucose utilization (40). The mechanism involved in skeletal muscle insulin resistance induced by plasma amino acids may be an inhibition of glucose transport/phosphorylation, resulting in a marked reduction of glycogen synthesis (43). In addition, amino acids could decrease glucose oxidation (44, 45) by substrate competition at the mitochondrial level, such as for glucose/lipid competition, or by interaction with early steps of insulin signaling (46). The whole body glucose disposal rate, in this study, is reduced after the infusion of high amino acid levels in young subjects only. Actually, the resistance to insulin action on glucose metabolism already existed in elderly subjects. Thus, the effect of amino acid administration on the glucose metabolism response to insulin may not be effective in the elderly. Therefore, considering previous observations in young subjects, we could hypothesize that insulin resistance in the elderly occurred at the glucose transport or phosphorylation level.
To a lesser extent, the sensitivity of insulin for glucose and protein metabolism has been evaluated in the elderly population under euglycemic hyperinsulinemic conditions. Two groups were distinguished on the basis of glucose disposal rate: IR-E and IS-E. Because insulin resistance and glucose intolerance develop with aging, previous studies have been designed to determine the impact of diet or physical exercise on improvement in insulin sensitivity in aged individuals (47, 48, 49). However, the relationship between insulin sensitivity for glucose and protein metabolism was poorly documented. In our study the increase in glucose disposal mediated by insulin was greater in the IS-E group than in the IR-E group, but insulin action was similarly reduced on PB in both elderly groups. Despite a better response of glucose metabolism to insulin in the IS-E group, it seemed to have more difficulty acting on PB.
In conclusion, this study showed that 1) elderly subjects developed resistance to insulin action for both glucose utilization and PB; 2) hyperaminoacidemia enhanced insulin-mediated PB inhibition; and 3) the sensitivity of glucose metabolism is dissociated from the sensitivity of protein metabolism to insulin. The results of this study support the concept that aminoacidemia appears to be as important as insulinemia in the regulation of protein metabolism in young and elderly individuals.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; EuAA, euaminoacidemia; FFM, fat-free mass; GDR, whole body glucose disposal; HyperAA, hyperaminoacidemia; IS-E, insulin-sensitive elderly; IS-R, insulin-resistant elderly; KIC, ketoisocaproate; MPE, molar percent excess; NS, not significant; PB, protein breakdown; Ra, rate of appearance.
Received August 14, 2003.
Accepted September 2, 2004.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-ketoacids on the metabolism of isolated rat liver cells. III. Interactions with pyruvate dehydrogenase. J Biol Chem 255:413–418This article has been cited by other articles:
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) and elderly (
) subjects during EuAA and HyperAA, euglycemic, hyperinsulinemic clamps. *, P < 0.05 for age effect; 
, P < 0.05 for amino acid effect.