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1 Department of Pediatrics and Center for Human Nutrition, University of Colorado Health Sciences Center, Denver, Colorado 80262; and 2 Exercise and Sport Research Institute, Arizona State University, Tempe, Arizona 85287
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of the present study was to determine the effects of diet composition and exercise on glycerol and glucose appearance rate (Ra) and on nonglycerol gluconeogenesis (Gneo) in vivo. Male Wistar rats were fed a high-starch diet (St, 68% of energy as cornstarch, 12% corn oil) for a 2-wk baseline period and then were randomly assigned to one of four experimental groups: St (n = 7), high-fat (HF; 35% cornstarch, 45% corn oil; n = 8), St with free access to exercise wheels (StEx; n = 7), and HF with free access to exercise wheels (HFEx; n = 7). After 8 wk, glucose Ra when using [3-3H]glucose, glycerol Ra when using [2H5]glycerol (estimate of whole body lipolysis), and [3-13C]alanine incorporation into glucose (estimate of alanine Gneo) were determined. Body weight and fat pad mass were significantly (P < 0.05) decreased in exercise vs. sedentary animals only. The average amount of exercise was not significantly different between StEx (3,212 ± 659 m/day) and HFEx (3,581 ± 765 m/day). The ratio of glucose to alanine enrichment and absolute glycerol Ra (µmol/min) were higher (P < 0.05) in HF and HFEx compared with St and StEx rats. In separate experiments, the ratio of 3H in C-2 to C-6 of glucose from 3H2O (estimate of Gneo from pyruvate) was also higher (P < 0.05) in HF (n = 5) and HFEx (n = 5), compared with St (n = 5) and StEx (n = 5) rats. Voluntary wheel running did not significantly increase estimated alanine or pyruvate Gneo or absolute glycerol Ra. Voluntary wheel running increased (P < 0.05) glycerol Ra when normalized to fat pad mass. These data suggest that a high-fat diet can increase in vivo Gneo from precursors that pass through pyruvate. They also suggest that changes in the absolute rate of glycerol Ra may contribute to the high-fat diet-induced increase in Gneo.
high-fat diet; glucose production; lipolysis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE DEVELOPMENT OF OBESITY and progression into type II diabetes involves both genetic and environmental factors (4). It appears that both obesity and type II diabetes are characterized by an increased contribution of gluconeogenesis to glucose production (4, 18). The factors that lead to changes in gluconeogenesis in obesity and diabetes are poorly understood. Previous studies have demonstrated that diet composition can influence gluconeogenesis. High-sucrose diets increase the capacity for gluconeogenesis in isolated hepatocytes (24) and perfused livers (22). Diets containing saturated fats accelerate gluconeogenesis, compared with diets containing polyunsaturated fats (15, 39). These previous studies have focused either on the effects of the type of fat in the diet and/or have evaluated gluconeogenesis by using in vitro techniques. One aim of the present study was to evaluate the effects of the amount of fat in the diet on gluconeogenesis in vivo.
Lipid delivery can regulate glucose production and gluconeogenesis. Thus increased lipid supply (via exogenous lipid infusion) resulted in a reduction in insulin suppression of glucose appearance (29) and increased gluconeogenesis (8). Decreased lipid supply (via acipimox treatment) reduced gluconeogenesis without altering total glucose appearance (28). These results have lead to the hypothesis that the rate of lipolysis can, in part, determine the contribution of gluconeogenesis to and insulin regulation of glucose production. The implicit assumption of the hypothesis is that gluconeogenesis and insulin regulation of glucose production will respond to changes in total lipolysis, that is, changes in lipid delivery that result from changes in total lipolysis.
High-fat diets, regardless of composition, can increase fat mass (21, 34). Increased fat mass or obesity increases the absolute rate of lipolysis (9). In contrast, chronic exercise reduces fat mass and appears to influence the intrinsic capacity of the fat cell for lipolysis (33). Therefore, the second aim of this study was to investigate in vivo gluconeogenesis by using a rat model in which a high-fat diet or voluntary, chronic exercise was used to alter endogenous lipolysis.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Male Crl:(WI)BR rats (Sasco, Madison, WI) weighing ~150 g on arrival were used in experiments. Rats were housed individually in a temperature-, humidity-, and light- (12:12-h light-dark cycle) controlled environment. Animals had free access to food and water. Housing and treatment of animals met guidelines of the American Association for the Accreditation of Laboratory Animal Care, and the protocol was approved by the University of Colorado Health Sciences Center Animal Care Committee.Diet Protocol
Animals were provided free access to a purified high-starch diet (St; 68% of kcal from cornstarch, 20% protein, 12% corn oil; Table 1) for a 2-wk baseline period. Food intake was measured 3 days/wk, and body weight was measured 1 day/wk. After the baseline period, rats were randomly assigned to one of four experimental groups for an additional 8 wk: St (n = 7), high-fat diet (HF; 35% cornstarch, 20% protein, 45% corn oil; Table 1; n = 8), St with free access to exercise wheels (StEx; n = 7), or HF with free access to exercise wheels (HFEx; n = 7). These rats were used in protocol 1 (defined below). A separate group of animals also underwent a 2-wk baseline period and then were randomly assigned to either St (n = 5), HF (n = 5), StEx (n = 5), or HFEx (n = 5) group for an additional 8 wk. These rats were used in protocol 2 (defined below). All diets were based on the recommendations of the American Institute of Nutrition (30) and were formulated by Research Diets (New Brunswick, NJ).
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Voluntary Exercise Training
Animals in the exercise treatment groups were housed individually in modified plastic cages (~437 cm2 available floor area) with exercise running wheels (1-m circumference) attached to the side of the cages. Sedentary animals were housed individually in hanging plastic cages (~424 cm2 available floor area).Surgery
With rats under general anesthesia (5 mg/kg im acepromazine, 10 mg/kg im xylazine, and 50 mg/kg im ketamine) catheters (PE-50 Intramedic Clay Adams polyethylene tubing) were inserted in the animal's right carotid artery up to the aortic arch and into the left jugular vein up to the vena cava, sutured to the respective vessel, and exteriorized through the back of the neck. The carotid artery catheter was used for blood sampling and the jugular vein cannula for tracer infusions. Animals were allowed 4 days to recover and were at
93% of presurgery body
weight on the day of study. Animals in the voluntary exercise groups
were allowed access to their running wheels on the second and third
days of postsurgery recovery. The amount of running during this period
was equivalent to ~55% of presurgery values.
Experimental Protocol
On the day of the experiment, extensions were added to catheters of 6- to 8-h fasted animals to allow sampling and infusion to occur without disturbing the animals. Animals were then placed in a cage and allowed to rest for ~20 min. In protocol 1, a baseline blood sample was taken, and then primed continuous infusions of HPLC-purified [3-3H]glucose (12 µCi prime, 0.1 µCi/min) and [2H5]glycerol (1.6 µmol/kg prime, 0.1 µmol · kg
1 · min1)
and a continuous infusion of
[3-13C]alanine (1.0 µmol · kg1 · min1)
were initiated. Blood samples were taken at 120, 127.5, 135, 142.5, and
150 min. This study was used to determine the effects of diet
composition and exercise on resting glucose kinetics, glycerol
appearance (used as an estimate of whole body lipolysis), and the
incorporation of alanine into glucose (used as an estimate of
gluconeogenesis from alanine). In protocol
2, a baseline blood sample was taken, an intravenous
bolus of
3H2O
was delivered (0.5 mCi/100 g body wt), followed by a primed, continuous infusion of
[2H5]glycerol
(1.6 µmol/kg prime, 0.1 µmol · kg1 · min1).
Blood samples were taken as noted above. This study was used to
determine the effects of diet composition on glycerol appearance and
gluconeogenesis from all precursors that pass through pyruvate. No more
than 12% of the animals' blood volume was taken (estimated as 8% of
body wt) in any of the experiments. An arterial saline infusion (~5
µl/min) was used to maintain patency in the arterial catheter
throughout the studies (i.e., heparin was not used in any of the experiments).
After the last blood sample, the animal was anesthetized with pentobarbital sodium (50 mg/kg iv), blood was immediately taken from the portal vein, and the following tissues were removed and immediately frozen in liquid nitrogen: liver and gastrocnemius, soleus, and biceps femoris muscles (protocol 1 only). The epididymal, retroperitoneal, and mesenteric fat pads were removed and weighed (protocols 1 and 2).
Analytic Techniques
Plasma radioactivity and enrichment. In protocol 1, plasma samples for analysis of [3H]glucose concentration were deproteinized overnight, centrifuged, and dried to eliminate 3H2O. Radioactivity in reconstituted samples was measured by using a Beckman liquid scintillation counter (Fullerton, CA). Glycerol was converted to its triacetyl derivative, and its 2H5 enrichment was measured by using gas chromatography-mass spectrometry analysis (41). Ions at mass-to-charge ratios (m/z) 145 and 148 were selectively monitored by using a Hewlett-Packard mass spectrometer, model 5970B (17). C-13 enrichment in plasma glucose and alanine was measured by chemical ionization, selected-ion monitoring gas chromatography-mass spectrometry of the pentaacetate (1), and N-acetyl-n-propyl ester (1, 20) derivatives, respectively. For N-acetyl-n-propyl alanine, the protonated molecular ion region comprising m/z 174 and 175 was monitored. The former ion reflects unlabeled alanine, and the latter corresponds to [3-13C]alanine when corrected appropriately for natural abundance.In protocol 2, plasma samples for tritium incorporation into glucose from 3H2O were analyzed as described previously (32). Briefly, tritium associated with C-6 of glucose was determined by periodate oxidation followed by the formation of a dimedone complex with the formaldehyde liberated from C-6 (26). Tritium associated with C-2 of glucose was determined after conversion to glucose-6-phosphate by using phosphoglucose isomerase (32).
Metabolites and hormones. Plasma glucose levels were determined by the glucose oxidase method (13) with the use of a Beckman glucose analyzer (Fullerton, CA). Plasma nonesterified fatty acids were measured by using the Wako NEFA C test kit (Wako Chemicals, Dallas, TX). Plasma alanine and glycerol levels were determined fluorometrically (19). Plasma insulin and glucagon (portal and arterial) levels were measured by radioimmunoassay (Linco Research, St. Charles, MO). The above metabolites and hormones were measured in protocols 1 and 2.
Tissue enzymes. In protocol 1 only, citrate synthase activity was measured in gastrocnemius, soleus, and biceps femoris muscles according to the procedures of Srere (36).
Calculations. Rates of glucose
appearance (Ra) and
disappearance (Rd) were
estimated by isotope dilution as previously described (3). Samples were
collected under steady-state conditions, defined as a change in glucose
specific activity of <0.5%/min. Glycerol
Ra was estimated by using the
isotope-dilution technique, as described for stable isotopes (41). The
ratio of enrichment of glucose to alanine is an estimate of alanine
incorporation into glucose. The terminology used to describe this ratio
is Ala 
Glu. This ratio underestimates the true incorporation
of alanine into glucose due to dilution of alanine enrichment/specific
activity within the hepatocyte oxaloacetate pool (14). Thus the ratio of enrichment of glucose to alanine represents a relative index of
alanine incorporation into glucose and assumes that dilution within the
oxaloacetate pool is equivalent among experimental groups (14).
Importantly, since the true precursor enrichment is not known, an
absolute rate of alanine gluconeogenesis cannot be calculated. The
estimation of gluconeogenesis using tritiated water was determined from
the ratio of tritium bound to C-6 of glucose relative to that bound to
C-2 of glucose (32). This method takes advantage of the binding of
3H from
3H2O
to C-3 of pyruvate that becomes C-6 of glucose in the gluconeogenic process (16, 32). Because the 3H
from
3H2O
bound to C-2 of glucose arises from both gluconeogenesis and glycogenolysis, the amount of 3H
bound to C-6 relative to that bound to C-2 provides a measure of the
fraction of glucose formed via gluconeogenesis (16). This approach is
not limited by dilution of precursor specific activity but excludes the
contribution of glycerol to gluconeogenesis (16, 32). The terminology
used to describe this measurement is Pyr Glu.
Total fat mass was calculated from the regression line that describes the relationship between the sum of the epididymal, retroperitoneal, and mesenteric fat pads and the measured total carcass lipid (r = 0.93, unpublished observations).
Statistical Analyses
Data are reported as means ± SE. Comparisons among groups were performed by using analysis of variance. The Student-Newman-Keuls test was used for post hoc analysis. Statistical significance was accepted at P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Energy-Related Data
In protocol 1, after the 2-wk baseline period, body weight was not significantly different among groups (237 ± 17 g). Energy intake and body weight gain during the 8-wk dietary period were not significantly different between St and HF or between StEx and HFEx groups (Table 2). Similarly, fat pad weights were not significantly different between St and HF or StEx and HFEx groups (Table 3). Body weight gain and fat pad weights were significantly decreased in exercised vs. sedentary rats (Tables 2 and 3). The amount of voluntary exercise was not significantly different between StEx and HFEx animals (Table 2). Body weight, energy intake, and wheel running data from protocol 2 were not significantly different compared with data from protocol 1 (data not shown).
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Muscle Enzymes
Citrate synthase in the soleus, gastrocnemius, or biceps femoris muscles was not significantly different among any of the groups from protocol 1 (Table 4).
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Plasma Metabolites and Hormones
In protocol 1, arterial plasma glucose, nonesterified fatty acids, and glucagon levels were not significantly different among groups (Table 5). Portal vein glucagon levels were not significantly different among groups (Table 5). Arterial plasma insulin levels were significantly increased in HF compared with the other three groups (Table 5). This increase in arterial insulin in HF group was also observed for portal vein insulin concentration (Table 5). Similar results were observed in protocol 2 (data not shown). Plasma alanine and glycerol concentrations were not significantly different among groups or between protocols (Table 6).
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Glucose Kinetics
In protocol 1, Ra and Rd were not significantly different among groups (Table 7).
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Gluconeogenesis
In protocol 1, Ala Glu was
significantly increased in HF and HFEx, compared with St and StEx
(Table 8). Voluntary wheel running did not
significantly affect Ala Glu (Table 8). In protocol 2, Pyr Glu was
significantly increased in HF and HFEx, compared with St and StEx
groups (Table 8). Voluntary wheel running did not significantly affect
Pyr Glu (Table 8).
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Glycerol Appearance
In protocol 1, glycerol appearance, expressed as micromoles per minute or as micromoles per kilogram per minute, was significantly increased in HF compared with St group (Table 9). However, when expressed relative to estimated total fat mass, the difference between HF and St groups was no longer significant (Table 9). In contrast, glycerol appearance was significantly increased in HFEx compared with StEx group, regardless of how the data were expressed (Table 9). Similar data were observed for glycerol appearance in protocol 2 (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, the effects of a high-fat diet and voluntary
exercise on glycerol appearance and on estimated nonglycerol gluconeogenesis (i.e., Ala Glu and Pyr Glu) were
examined. The data suggest that a high-fat diet can increase both the
absolute rate of glycerol appearance (µmol/min) and estimated
nonglycerol gluconeogenesis. The increase in glycerol appearance
appears to be primarily due to a diet-induced increase in fat mass.
Voluntary exercise did not increase the absolute rate of glycerol
appearance or estimated nonglycerol gluconeogenesis. In contrast,
voluntary exercise increased glycerol appearance when expressed
relative to fat mass. These data imply that an increase in the absolute rate of lipolysis may be an important determinant of the overall gluconeogenic rate in vivo.
In the present study, high-fat diet feeding significantly increased
glycerol appearance when expressed as an absolute rate (µmol/min) or
relative to total body weight
(µmol · kg1 · min1)
but not when normalized to fat mass. Thus the increase in glycerol appearance was primarily a consequence of a greater fat mass (~18% increase, relative to the St group). The higher rate of glycerol appearance in HF group occurred in the presence of insulin levels that
were increased approximately twofold compared with the starch controls.
This suggests that the 8-wk high-fat diet feeding period resulted in a
significant reduction in insulin action on lipolysis.
The effects of voluntary wheel running were restricted to the rate of glycerol appearance normalized to total fat mass (St compared with StEx, Table 9). This implies that voluntary wheel running increased the ability of the existing fat mass to mobilize lipid. It is unlikely that this adaptation was due to the previous exercise bout, since animals were removed from wheel access for >36 h before the study (35). Fat cell size is an important determinant of the lipolytic rate (9). However, fat pad mass was actually reduced in exercised compared with sedentary animals; therefore, it is unlikely that starch-fed exercised rats were characterized by increased fat cell size. Because exercise was able to improve insulin action (based on the normalization of fasting insulin levels in the HFEx group), it may be that the exercise-induced adaptation on lipolysis was the result of altered hormone action (5). It should also be noted that the present study measured glycerol appearance; therefore, ascribing all or part of these changes to adipose tissue assumes that release of glycerol from other tissues was negligible.
The high-fat diet increased the contribution of nonglycerol
gluconeogenesis to glucose appearance. This conclusion is based on two
estimates of in vivo gluconeogenesis: incorporation of labeled alanine
into glucose (i.e., Ala Glu) and incorporation of tritiated
water into glucose (i.e., Pyr Glu). To the best of our
knowledge, these are the first data to demonstrate a high-fat diet-induced increase in gluconeogenesis in vivo. That the contribution of nonglycerol gluconeogenesis to glucose appearance was increased by
the high-fat diet can be inferred based on the observation that
increased Ala Glu and increased Pyr Glu occurred
without a significant increase in the
Ra. It is noteworthy that the
apparent increase in the contribution of estimated nonglycerol
gluconeogenesis to glucose appearance occurred in the presence of an
elevated insulin-to-glucagon ratio. This suggests that the high-fat
diet induced selective insulin resistance on gluconeogenesis and/or that intrahepatic adaptations to the diet resulted in increased gluconeogenesis. These data are consistent with previous studies that
have demonstrated diet-induced insulin resistance (21, 23, 37) and a
diet-induced increase in the capacity for glucose production from
gluconeogenic precursors in perfused livers (22).
In humans, endurance training does not appear to significantly affect the Ra or gluconeogenesis at rest (2). In contrast, treadmill training in rats has been reported to have no effect (6) and to increase (38) resting glucose appearance as well as to increase the capacity for gluconeogenesis in perfused livers (7). In the present study, wheel running did not significantly affect glucose appearance or estimated nonglycerol gluconeogenesis. These data suggest that training-induced changes in gluconeogenic capacity (7) are not required or are compensated for in vivo.
Treadmill training produces profound adaptations in skeletal muscle (10). In contrast, voluntary wheel training for 8 wk did not produce statistically significant changes in skeletal muscle citrate synthase activity. Thus the training regimen employed, i.e., treadmill running vs. voluntary wheel running, may explain differences in the gluconeogenic adaptation in rats. Importantly, the lack of a significant training adaptation in skeletal muscle observed in the present study is consistent with previous data (31). In that study, significant skeletal muscle adaptations were only observed in those rats that ran >11 km/day. This is not to say that voluntary wheel running was without effect, since the present study clearly demonstrates an exercise-induced effect on lipolysis and whole body insulin action.
These data are consistent with the notion that lipolysis contributes to the regulation/magnitude of gluconeogenesis. The contribution of lipolysis to the regulation of gluconeogenesis could occur via the provision of glycerol as a carbon source for glucose and/or via the delivery of free fatty acids to the sites of gluconeogenesis, liver and kidney. Although glycerol gluconeogenesis was not measured in the present study, previous data suggest that its contribution to resting gluconeogenesis is small (25, 27) and that provision of glycerol does not result in significant changes in glucose appearance or total gluconeogenesis (12, 29). Previous studies have demonstrated that increased delivery of free fatty acids can increase nonglycerol gluconeogenesis (8) and reduce insulin suppression of glucose production (29). In this context, free fatty acids can promote nonglycerol gluconeogenesis by providing energy (via oxidation) and by inhibiting glycolysis (11). It appears likely that lipolysis may exert a regulatory influence on nonglycerol gluconeogenesis via provision of free fatty acids.
Neither free fatty acid nor glycerol levels were significantly different among any of the groups in the present study. These data imply that increased lipolysis in the high-fat diet-fed rats was matched by increased removal rates of glycerol and free fatty acids. In gluconeogenic tissues (liver and kidney) adaptations that increase removal of free fatty acids would also serve to increase nonglycerol gluconeogenesis. It seems, therefore, that the diet-induced increase in nonglycerol gluconeogenesis involves at least two general adaptations. First, an increased delivery of free fatty acids to gluconeogenic tissues and, second, adaptations within gluconeogenic tissues that facilitate both the uptake of free fatty acids and conversion of gluconeogenic precursors into glucose. Support for such a hypothesis comes from studies that have demonstrated an increased capacity for gluconeogenesis in the liver (22) and increased phosphoenolpyruvate carboxykinase activity after high-fat or high-sucrose diet feeding (23, 40). Future work is required to determine what tissues contribute to increased glycerol removal in this model.
The estimation of gluconeogenesis by using tracers is difficult and subject to a multitude of errors (14). For this reason, two independent techniques were used to estimate nonglycerol gluconeogenesis. The fact that both techniques provided similar qualitative data strengthens the conclusions from the present study. The data also suggest that the majority of gluconeogenic flux in the 6- to 8-h fasted rats is derived from gluconeogenic precursors that pass through pyruvate.
Ad libitum energy intake was not significantly different among rats in the present study. Thus rats in the exercise treatment groups gained less weight during the dietary period. The impact of the reduced weight gain on the parameters measured cannot be determined but should be considered when these data are compared with other studies. The equivalence of energy intake among groups may, in part, be due to 24-h access to the running wheels. That is, most of the wheel activity occurred at night, thus potentially interfering with normal feeding patterns.
In the present study, high-fat diet feeding increased the absolute rate of lipolysis and the contribution of estimated nonglycerol gluconeogenesis to glucose appearance. Voluntary wheel running did not produce significant skeletal muscle training adaptations. However, this form of exercise did result in a significant increase in lipolysis, relative to the existing fat mass and whole body insulin action. Finally, voluntary wheel running did not significantly affect estimated nonglycerol gluconeogenesis.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-47416. D. A. Podolin was supported by a National Institutes of Health Institutional Training Grant (DK-07658). The authors acknowledge the metabolic and gas chromatography cores of the Colorado Clinical Nutrition Research Unit for assistance with insulin and stable-isotope measurements (P30 DK-48520-01).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and correspondence: M. J. Pagliassotti, Arizona State Univ., Dept. of Exercise Science and Physical Education, PO Box 870404, Tempe, AZ 85287-0404 (E-mail: Pagliassotti{at}ASU.edu).
Received 15 June 1998; accepted in final form 22 December 1998.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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