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Experimental Studies |
Department of Internal Medicine, University of Ferrara (A.S.), Ferrara; the Division of Endocrinology and Metabolic Diseases, University of Verona (E.B., R.B.), Verona; and the Department of Internal Medicine, University of Catania (P.C.), Catania, Italy; and the Diabetes Division, University of Texas Health Science Center (R.A.D.), San Antonio, Texas 78226
Address all correspondence and requests for reprints to: Anna Solini, M.D., Department of Internal Medicine II, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy; or to: Ralph A. DeFronzo, M.D., Diabetes Division, Department of Internal Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78226.
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Abstract |
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Introduction |
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In recent years the important role of central, especially visceral, adipose tissue in the disturbance of glucose and lipid metabolism has been emphasized by several researchers, including ourselves (3, 5, 14, 15). In contrast, few studies have examined the relationships between body fat distribution and protein metabolism, and their results are conflicting (6, 7, 8).
The aim of the present study was to understand whether the insulin resistance of obesity extends to protein metabolism and, if so, whether this disturbance is related to abnormalities in glucose or lipid metabolism. In addition, we tried to clarify the putative relationship between protein metabolism and the amount of visceral fat.
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Subjects and Methods |
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Twenty nondiabetic paid volunteers were selected for this study after being recruited through newspaper advertising. The purpose was to find 2 groups of 10–12 premenopausal women with a body mass index (BMI) of 27 or less, which was used as a cut-off for obesity according to conventional criteria (16). Eleven obese women (mean age, 36 ± 2 yr; mean BMI, 29 ± 2 kg/m2) were compared to nine lean women (mean age, 37 ± 2 yr; mean BMI, 22 ± 1 kg/m2). None had any evidence of renal, hepatic, cardiovascular, or other major organ system disease by routine history, physical examination, and laboratory screening test. There was no family history of diabetes, and no subject was taking any medication, including oral contraceptives. Menstrual cycles were normal, and there was no clinical evidence suggestive of polycystic ovary syndrome. No subjects were participating in any strenuous exercise or were excessive sedentary.
The purpose, nature, and potential risks of the study were explained to all subjects, and written informed consent was obtained before their participation. The experimental protocol was approved by the institutional review board of the University of Texas Health Science Center, the General Clinical Research Center, and the research and development committees of the V.A. Hospital, and the radiation safety and radioactive drug and research committees of the University of Texas Health Science Center and V.A. Hospital, respectively.
Metabolic studies
Each subject participated in three different studies that were carried out in random order at the Clinical Research Center of the University of Texas Health Science Center. All studies began at 0800 h after a 12-h overnight fast. The studies were separated by 1–2 weeks.
Study 1. In this study, fat mass and fat-free mass (FFM) were estimated by a bolus injection of 80 µCi 3H2O (17, 18), as previously described (5).
Study 2. In this study the euglycemic insulin clamp technique (19) was used in combination with high performance liquid chromatography-purified tritiated glucose infusion (20) and indirect calorimetry (21) to examine glucose and lipid metabolism (total, oxidative, and nonoxidative glucose disposal, and lipid oxidation) in the basal and insulin-stimulated state. Briefly, at 0800 h, a primed-constant infusion of D-[3-3H]glucose (DuPont-New England Nuclear, Boston, MA) was started and continued for 150 min. The tritiated glucose infusion rate was 0.15 µCi/min, and the ratio of the prime to constant infusion was 100:1. During the last 50 min of tracer equilibration, samples were drawn every 10 min for the determination of plasma glucose, insulin, and free fatty acid (FFA) concentrations and plasma glucose radioactivity. At the end of the 150-min tracer equilibration period (time zero), the infusion of tritiated glucose was discontinued, and a euglycemic hyperinsulinemic clamp was started. Insulin was administered as a primed-continuous infusion (20 mU/m2·min), and a glucose infusion was periodically adjusted to maintain the arterialized plasma glucose concentration at the basal level for 240 min. One hundred and twenty minutes after the start of the insulin clamp the 3-[3H]glucose infusion was resumed at the rate of 0.40 µCi/min and continued until the end of the study. Using this approach an excessive dilution of tracer by cold glucose was avoided, and a steady state plateau of plasma glucose specific activity was achieved during the last hour of the study (coefficient of variation, 5.5 ± 0.5%). Blood samples for the determination of plasma glucose specific activity and plasma insulin and FFA concentrations were collected at 180, 190, 200, 210, 220, 230, and 240 min.
Study 3.
In this study, parameters of protein metabolism
were determined by employing the euglycemic insulin clamp in
combination with radiolabeled leucine and indirect calorimetry, as
previously described (22). Briefly, a primed (16- to 22-µCi
bolus)-continuous (0.20 µCi/min) infusion of
[1-14C]leucine (Amersham, Greenfield, IL) was
administered along with a priming dose of
[14C]bicarbonate (4 µCi). After 2 h of isotope
equilibration, blood samples were drawn at 10-min intervals from
120–180 min for the determination of basal leucine and
-ketoisocaproate (-KIC) specific activities and plasma insulin
and substrate concentrations. After that, a prime-continuous infusion
of human insulin was administered at the rate of 20
mU/m2·min for an additional 180 min to raise and maintain
the plasma insulin concentration by 30 µU/mL above baseline for 180
min. Urine was collected separately during the basal and insulin
periods, and the urinary nitrogen concentration was measured.
Indirect calorimetry. In studies 2 and 3, the carbon dioxide and oxygen contents of the expired air were continuously measured by a Deltatrac Metabolic Monitor (Sensormedic, Anaheim, CA) in the last hour of the basal periods and the insulin infusion periods. In study 3, the total 14CO2 output was calculated from the product of the CO2 specific activity (disintegrations per min/mmol) and the carbon dioxide output (millimoles per min), as measured by indirect calorimetry (21).
Analytical determinations
The plasma glucose concentration was determined by the glucose oxidase method. For the determination of glucose specific activity, the plasma was deproteinized according to the Somogyi procedure (23). The plasma insulin concentration was determined by RIA (24), and the plasma FFA concentration was determined by a microfluorimetric method (25). Urinary nitrogen concentration was measured by the Kjeldhal method (26).
The plasma leucine concentration was determined using an amino acid
analyzer (System 6300, Beckman Instruments, Fullerton, CA), as
previously described (22). Plasma -KIC specific activity was
measured using a modification of the method previously described by
Nissen et al. (27). Plasma (1 mL) was loaded in duplicate on
a Dowex 50 G cation exchange resin column (Bio-Rad Laboratories,
Richmond, CA), and the free -ketoacid fraction was eluted with 4 mL
0.01 N HCl in 50-mL culture tubes. Methylene chloride (35
mL) was added, and after shaking vigorously for 1 min, the tube was
centrifuged for 5 min at 2000 rpm to extract the free -ketoacid
fraction from plasma. After decantation of the supernatant, the
-ketoacid was extracted in 350 µL 0.2 mol/L
NaH2PO4 at pH 7. After a brief centrifugation,
200 µL of the supernatant were injected into a high performance
liquid chromatographic system. The absorbance of KIC was monitored at
206 nm. Radioactivity eluting with the KIC peak was measured by
scintillation counting. The intra- and interassay variations for the
determination of [14C]leucine specific activity were
4 ± 2% and 5 ± 2%, respectively. More than 98% of the
radioactivity collected in the amino acid fraction was in the leucine
peak after separation by ion exchange chromatography. The inter- and
intraassay variations for the determination of [14C]KIC
specific activity were 5 ± 2% and 5 ± 4%. The recovery of
[14C]KIC was 69 ± 3%.
Anthropometric measurements
Weight (to the nearest 0.1 kg) and height (to the nearest 0.5 cm) were measured while the subjects were fasting and wearing only their undergarments. BMI was computed as weight divided by height squared. The following circumferences were recorded (to the nearest 0.5 cm) with a plastic tape measure while the subjects were standing: waist (widest diameter between the xiphoid process of the sternum and the iliac crest) and hip (widest diameter over the greater trochanters). The ratio of waist to hip circumference (WHR) was then calculated and used as an index of body fat distribution. A higher WHR was interpreted to represent a predominance of central adiposity, whereas a lower value indicated a predominance of peripheral adiposity.
Subcutaneous abdominal adipose tissue area (SAT) and visceral abdominal adipose tissue area (VAT) were quantitated by nuclear magnetic resonance imaging, as previously described (28), and used as indicators of the amounts of sc and visceral abdominal fat. As reported by Kvist et al. (29), VAT area is strongly correlated with total visceral fat volume (r = >0.95).
Calculations
Glucose metabolism. A steady state plateau of plasma tritiated glucose specific activity was achieved both during the last 50 min of the basal period and during the last hour of insulin clamp in each of the subjects who participated in the study. Therefore, in both basal (-50 to 0 min) and insulin-stimulated (180–240 min) states, the rate of total glucose appearance equals the rate of total glucose disposal (milligrams per min) and was computed according to the equation: tracer infusion rate (disintegrations per min) divided by steady state plasma tritiated glucose specific activity (disintegrations per min/mg). As in the postabsorptive state the only input of glucose into the body is from the liver, the basal rate of the hepatic glucose production (HGP) equals the rate of total glucose appearance. During the insulin/glucose infusion, HGP was computed as the difference between the isotopically determined rate of glucose appearance and exogenous glucose infusion rate (20).
Protein metabolism.
Whole body leucine flux was calculated
with a stochastic model for protein metabolism. The analysis assumes
near-steady state conditions. The validity and assumptions of the model
have been previously discussed in detail by Waterlow et al.
(30) and Golden and Waterlow (31). Briefly, the model generates the
following equations in which total leucine turnover or flux, Q = S
+ C = B + I, where S is the total rate of leucine incorporation
into protein (or nonoxidative leucine disposal), C is the rate of
leucine oxidation (LeuOx), B is the rate of leucine release from
protein (endogenous leucine appearance), and I is the rate of exogenous
leucine input. To calculate rates of leucine turnover and oxidation, we
employed the plasma -KIC (the transaminated product of leucine)
specific activity, because it has been suggested that it may provide a
better estimation of the specific activity in the intracellular mixing
pool (32). The rate of leucine turnover (Q) is calculated as follows:
Q = F/KIC sp act, where F is the infusion rate of
[14C]leucine, and KIC sp act is the specific
radioactivity of -KIC in the plasma compartment under steady state
conditions. The LeuOx rate is calculated as follows: C = O/(K
x KIC sp act), where O is the rate of appearance of
14CO2 in the expired air (disintegrations per
min), and K is a correction factor (0.81) that takes into account the
incomplete recovery of labeled 14CO2 from the
bicarbonate pool. An estimate of the rate of leucine incorporation into
protein (S) can be calculated as follows: S = Q - C. An
estimate of the rate of leucine release into the plasma space from
endogenous protein (B) can be calculated as follows: B = Q -
I. When subjects are in the postabsorptive state, leucine intake (I) =
0, and B = Q. The net leucine balance, which represents the net
flux of leucine into and out of proteins, was calculated as the
nonoxidative leucine disposal minus the endogenous leucine flux.
Statistical analysis
Comparison of data in the basal and insulinized states within a group was performed using Student’s t test for paired data. Comparisons between obese and nonobese women were performed using Student’s t test for unpaired data. Simple (Pearson’s) correlations coefficients were calculated with standard formulas. Stepwise multiple regression analyses were performed to evaluate independent associations among variables. Although a Gaussian distribution has not been demonstrated for many biological parameters assessed in the present study, all values are expressed as the mean ± SE to be consistent and to allow comparison with most previously published data in this field. With this experimental design, we had approximately a 75% chance of detecting a 20% difference at the 0.05 level of significance for the main parameters of leucine metabolism.
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Results |
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Fat mass was 37.3 ± 3.4 kg in obese women and 20.5 ± 1.2 kg in nonobese women (P < 0.001). As expected, the obese group also had a higher FFM (51.2 ± 1.8 vs. 40.8 ± 2.1 kg; P < 0.005). WHR was slightly, although not significantly, higher in obese (0.88 ± 0.02) vs. nonobese women (0.83 ± 0.02). VAT and SAT were higher in obese women ([VAT, 128.9 ± 18.6 vs. 58.7 ± 11.9 cm2 (P < 0.005); SAT, 431 ± 35 vs. 180 ± 10 cm2 (P < 0.001)].
Glucose/lipid metabolism (study 2)
Plasma glucose, insulin, and FFA concentrations in the basal
state and during insulin infusion are reported in Table 1
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. Suppression of HGP during insulin infusion was
slightly, although not significantly, impaired in obese vs.
nonobese women (24.8 ± 9.5 vs. 9.83 ± 9.3
mg/min; P = NS).
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Protein metabolism (study 3)
The total plasma amino acid concentration in the basal state and
during the last hour of insulin infusion are reported in Table 2 together with plasma leucine, tyrosine, and valine
concentrations.
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). LeuOx was similar in nonobese and obese women in the
basal state (0.37 ± 0.04 vs. 0.36 ± 0.05
µmol/min·kg FFM) and remained unchanged during insulin infusion in
both groups (0.34 ± 0.04 vs. 0.39 ± 0.06
µmol/min·kg FFM; Fig. 2). Nonoxidative leucine metabolism (NOLD),
an index of protein synthesis, was not different in the two groups in
the basal state (1.86 ± 0.17 vs. 1.94 ± 0.26
µmol/min·kg FFM) and decreased slightly and similarly during the
clamp (1.72 ± 0.20 vs. 1.71 ± 0.19
µmol/min·kg FFM in nonobese and obese subjects, respectively; Fig. 2). Net leucine balance did not differ in nonobese and obese women in
the postabsorptive state (-0.37 ± 0.04 and -0.36 ± 0.05
µmol/min·kg FFM) and remained unchanged during insulin infusion in
both groups (-0.34 ± 0.04 and -0.39 ± 0.06
µmol/min·kg FFM; Fig. 3).
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When lean and obese subjects were examined collectively, no correlations between any parameter of protein metabolism and total, oxidative, and nonoxidative glucose disposal rates or lipid oxidation rate was observed either in the basal state or during insulin infusion. In nonobese women, we observed a trend to a negative correlation between LeuOx and glucose oxidation during the insulin clamp (r = 0.638; P = 0.064). In this group, LeuOx during the insulin clamp was strongly correlated with lipid oxidation (r = 0.735; P < 0.05). In obese women, basal LeuOx was directly correlated with basal glucose oxidation (r = 0.624; P < 0.05). Protein and lipid oxidation were inversely related in the basal state (r = -0.614; P < 0.05).
Correlations between protein metabolism and total and regional fat
When nonobese and obese women were examined collectively, total fat mass as well as FFM were not significantly correlated with any parameter of protein metabolism. In the whole group, WHR, VAT, and SAT were not correlated to any parameter of protein metabolism (data not shown).
In obese women, we observed inverse relationships between VAT and total, oxidative, and nonoxidative leucine disposal rates during insulin infusion (r = -0.610, P < 0.05; r = -0.409, P = 0.15; and r = -0.624, P < 0.05). In both nonobese and obese women, SAT was not correlated to any parameter of protein metabolism. When the data were analyzed by stepwise regression analysis, in obese women, VAT was inversely related to total leucine disposal during insulin infusion independently of total adiposity, SAT, and basal plasma insulin concentration (F = 5.345; P < 0.05). With the same statistical approach, VAT was inversely related to NOLD during the insulin clamp in obese women (F = 5.753; P < 0.05).
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Discussion |
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With respect to protein metabolism, the few studies that have been published have yielded conflicting results (6, 7, 8, 9, 10, 11, 12, 13). Luzi et al. found an impaired effect of low dose insulin infusion to inhibit endogenous leucine flux and LeuOx in obese subjects (13), a result consistent with those reported by Jensen and Haymond in women with upper body obesity, but at variance with the data of Caballero et al. (12), and Welle et al. (8).
The results of our study support the idea that in the basal, postabsorptive state the rates of endogenous leucine flux (i.e. proteolysis) as well as LeuOx and NOLD are not different in obese and nonobese subjects. When insulin was infused at a rate designed to yield steady state plasma insulin levels similar to those encountered after a meal (35–40 µU/mL), with a superimposable increment above baseline in obese (+30 µU/mL) and nonobese (+27 µU/mL) subjects, we failed to observe any differences in leucine fluxes between the two groups. These data are in agreement with those by Welle and Caballero (8, 12) and suggest that the effect of moderate levels of hyperinsulinemia, similar to those observed in the postprandial situation, on protein metabolism is normal in obesity. In response to the same hyperinsulinemic stimulus, the decreases in endogenous leucine flux (-9% vs. -8%) and NOLD (-12% vs. -8%) were similar in obese and nonobese women, respectively. In contrast, insulin-stimulated glucose disposal rates and insulin-mediated suppression of lipid oxidation and plasma FFA levels were impaired in obese subjects. Thus, a clear dissociation between insulin’s effects on glucose/lipid metabolism and protein metabolism was found in human obesity. These results are similar to those obtained by others and ourselves in insulin-dependent diabetic and noninsulin-dependent diabetic patients (33, 34, 35, 36) as well as in elderly subjects (37).
Our finding that insulin exerted similar effects on leucine metabolism in nonobese and obese women might at first glance appear to be at odds with a recent report by Luzi et al. from the same laboratory (13), who found that the ability of hyperinsulinemia to influence leucine metabolism in obese subjects was impaired. However, it should be noted that the studies of Luzi et al. (13) were carried out with an insulin infusion rate inducing plasma insulin levels only half of those achieved in the present study. Indeed, at an insulin infusion rate twice as high as that used in the present study, Luzi and co-workers did not find any major abnormality in the response of leucine metabolism to insulin in obese subjects (13). Thus, our data are complementary to those from the study performed by Luzi and demonstrate that the abnormalities seen in insulin-mediated leucine metabolism in obese subjects at a low insulin infusion rate (10 mU/m2·min) can be overcome at an insulin infusion rate of 20 mU/m2·min. The combined evidence of our study and that of Luzi et al. (13) points out that the defects in insulin-mediated leucine metabolism observed in obesity are essentially due to a decreased sensitivity of protein metabolism to insulin, with preserved responsiveness.
An interesting finding of the present study is the different pattern of
relationships among glucose, lipid, and leucine metabolism in nonobese
and obese women. In nonobese women, LeuOx tends to be negatively
correlated to glucose oxidation, but positively correlated to lipid
oxidation, whereas in obese women, LeuOx is positively correlated to
glucose oxidation, but negatively to lipid oxidation. These two
patterns are likely to reflect two different metabolic scenarios. In
nonobese women, energy production during hyperinsulinemia relies almost
exclusively (>90%) on glucose, and the two ketoacid dehydrogenases
(pyruvate and branched -ketoacid) are normally dephosphorylated and
thus activated by insulin. Under these circumstances, fuel availability
dictates which substrate, i.e. glucose or leucine, will be
oxidized, and the conditions for a negative correlation between leucine
and glucose oxidation are, therefore, established. In the obese women,
pyruvate dehydrogenase and conceivably -ketoacid dehydrogenase are
resistant to insulin and undergo a less than normal dephosphorylation
in response to hyperinsulinemia. In obese women, glucose accounts for
75% of the energy production, whereas lipids account for a greater
amount (25%) compared to that in lean subjects. Therefore, glucose
is not the only substrate that competes for LeuOx. The amounts of
leucine and glucose oxidized in obese women during hyperinsulinemia
reflect insulin’s ability to activate two closely related enzymes and,
therefore, are positively correlated with each other. In turn,
both of these enzymes exhibit substrate competition with lipids, which
in obese women accounts for a higher proportion (25%) of the energy
production rate during hyperinsulinemia.
Over the last few years, several researchers, including ourselves, have documented that central obesity is associated with a number of abnormalities in glucose and lipid metabolism. All studies except one (38) are concordant in documenting that visceral, rather than subcutaneous adipose tissue, has an adverse effect on glucose and lipid metabolism (5, 14, 15, 39, 40, 41). In contrast, little information is available about the relationships between regional distribution of adipose tissue and protein metabolism. To our knowledge, only three papers have previously addressed this issue. Jensen and Haymond (6) reported that women with upper body obesity have an impaired suppression of leucine turnover after an increase in the plasma insulin concentration of 5 µU/mL. However, the differences, despite being statistically significant, were very small (-3.7% in women with upper body obesity vs. -9.6% in women with lower body obesity), and the absolute values of leucine turnover during insulin infusion were identical in women with upper body vs. lower body obesity. These researchers did not find any relationship between WHR and parameters of basal leucine turnover. Welle et al., using both simple anthropometric measurements (8) and magnetic resonance imaging (7) to characterize body fat distribution, also failed to find any difference in basal or insulin-mediated suppression of leucine turnover between obese subjects with central obesity and those with peripheral obesity.
A major finding of our study is that visceral fat was inversely related to endogenous leucine flux (an index of proteolysis) during hyperinsulinemia. Thus, visceral fat in obese women was associated with a greater sensitivity to the antiproteolytic effect of insulin. This observation may result from interactions between insulin and other glucoregulatory hormones. It is well known that visceral adiposity is associated with subtle changes in the metabolism of cortisol and androgens (42, 43, 44). Insulin suppresses sex hormone-binding globulin production (45). Consequently, obese women with large amounts of visceral fat, who are especially hyperinsulinemic (40, 41), have lower concentrations of sex hormone-binding globulin and higher concentrations of free androgens (46, 47). Furthermore, some evidence suggests that hyperinsulinemia may modulate steroidogenesis, causing an increase in the production of dehydroepiandrosterone and testosterone (48, 49). It is possible that increased levels of anabolic steroid hormones are responsible, therefore, for the enhanced antiproteolytic effect of insulin in women with visceral obesity. Alternatively, it could be hypothesized that the higher levels of FFA (3, 5) and the increased rate of lipid oxidation (5) that are characteristic of individuals with visceral obesity exert a protein-sparing effect, as suggested by previous studies (50, 51, 52). The negative correlation between lipid and LeuOx in obese women is consistent with this hypothesis. A third possibility is that the amount of visceral fat is negatively related to protein metabolism as a result of changes in muscle capillarization and fiber composition in individuals with central obesity (39, 53). Indeed, a correlation between muscle fiber composition and protein turnover has been described (54). All of these hypotheses need to be adequately addressed with specific studies.
Although we have examined only women, so that we cannot a priori extend our results to men, our findings suggest that in human obesity, 1) rates of protein metabolism (proteolysis, protein oxidation, and protein synthesis), both in the basal state and in the range of insulin concentrations encountered after a meal, are normal; 2) protein oxidation is positively correlated with glucose oxidation and negatively related to lipid oxidation; and 3) the amount of visceral adipose tissue is negatively correlated to all parameters of protein metabolism.
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Acknowledgments |
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Footnotes |
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Received January 22, 1997.
Revised April 7, 1997.
Accepted May 13, 1997.
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References |
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-KIC metabolism in
type I diabetes. J Clin Invest. 77:1797–1804.
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