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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 11 5168-5178
Copyright © 2002 by The Endocrine Society

Original Article

Effects of Dietary Macronutrient Content on Glucose Metabolism in Children

Agneta L. Sunehag, Gianna Toffolo, Margarita S. Treuth, Nancy F. Butte, Claudio Cobelli, Dennis M. Bier and Morey W. Haymond

Children’s Nutrition Research Center (A.L.S., M.S.T., N.F.B., D.M.B., M.W.H.), United States Department of Agriculture/Agricultural Research Service, Houston, Texas 77030; and Department of Electronics and Informatics (G.T., C.C.), University of Padua, 35131 Padua, Italy

Address all correspondence and requests for reprints to: Agneta L. Sunehag, M.D., Ph.D., Children’s Nutrition Research Center, 1100 Bates Street, Houston, Texas 77030. E-mail: asunehag{at}bcm.tmc.edu.

Abstract

Effects of carbohydrate, fat, and fructose intake on substrate and hormone concentrations, glucose production, gluconeogenesis, and insulin sensitivity were determined in healthy, nonobese prepubertal children (n = 12) and adolescents (n = 24) using a cross-over design. In one group (12 prepubertal children and 12 adolescents), subjects were studied after 7 d of isocaloric, isonitrogenous diets providing either 60% carbohydrate and 25% fat [high carbohydrate (HCHO)/low fat (LF)] or 30% carbohydrate and 55% fat [low carbohydrate (LCHO)/high fat (HF)], and in a second group (12 adolescents) HCHO/LF diets containing either 40% or 10% fructose was used.

All subjects adapted to changes in carbohydrate and fat intakes primarily by appropriately adjusting their substrate oxidation rates to match the intakes, with only minor changes in parameters of glucose metabolism. Changing from a LCHO/HF to HCHO/LF diet resulted in increased insulin sensitivity (stable labeled iv glucose tolerance test) in adolescents [from 3.2 ± 0.7 x 10-4 to 5.0 ± 1.4 x 10-4 (min-1)/(µU·ml-1) (mean ± SE)] but not in prepubertal children [9.4 ± 2.5 x 10-4 to 9.9 ± 1.5 x 10-4 (min-1)/(µU·ml-1)], whereas ß-cell sensitivity was unaffected in both groups. Insulin sensitivity was higher in prepubertal children than in adolescents (P < 0.05). The dietary fructose content did not affect any measured parameter.

We conclude that in the short term, dramatic changes in fat and carbohydrate intakes (regardless of fructose content) did not adversely affect glucose and lipid metabolism in healthy nonobese children. In the adolescents, the high carbohydrate diet resulted in increased insulin sensitivity, thus facilitating insulin-mediated glucose uptake.

THE PREVALENCE OF obesity [>95th percentile body mass index (BMI)] among children and adolescents has increased dramatically over the past two decades (1). Many factors contribute to the development of obesity in children and adolescents, including parental obesity, total energy intake, relative fat intake, and decreased physical activity (2, 3). Importantly, even in children and adolescents, obesity is associated with the development of type 2 diabetes mellitus (2, 3, 4, 5, 6), and the current rise in the prevalence of childhood obesity has led to a dramatic increase in the incidence of type 2 diabetes in children and adolescents (4). Furthermore, obesity is associated with insulin resistance in children; in addition, childhood obesity is associated with subsequent insulin resistance in young adulthood (7) and with hypertension and adverse alterations in circulating lipids and lipoproteins, which may place these children at increased risk for cardiovascular disease as adults (3, 8, 9). Consequently, early prevention of obesity and deterioration in glucose tolerance are important health care issues in children.

The impact of dietary macronutrient composition on insulin sensitivity, blood lipids, and the development of obesity has been extensively studied in adults. Several studies have demonstrated that a high carbohydrate (HCHO)/low fat (LF) diet improves insulin sensitivity and blood lipids in both young and elderly adults (10, 11, 12, 13), but some studies have also reported that a high carbohydrate intake may increase concentrations of blood lipids in adults, especially when the content of simple sugars, sucrose, and fructose are high (14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Conversely, high fat (HF)/low carbohydrate (LCHO) diets have been associated with increased insulin resistance and increased risk of cardiovascular disease in adults (24, 25, 26); not only is total fat intake important, but the type of dietary fat also exerts an effect (27, 28, 29, 30, 31). Thus, decreasing the proportion of saturated fat while increasing that of monounsaturated fat resulted in increased insulin sensitivity in healthy adults. These effects were, however, limited to a total fat intake up to 37–38% of total energy intake (29, 30).

High dietary fat content has also been directly related to the development of obesity in both adults (32, 33, 34) and children (35, 36). Possible reasons for this are: 1) lipids are more energy dense but less satiating than an equal amount of carbohydrate, which may lead to passive overeating; and 2) a high fat meal induces lower meal-associated thermogenesis than an isocaloric, isonitrogenous high carbohydrate/low fat meal, leaving more energy available for fat storage (34).

Thus, although most nutritional guidelines recommend reducing dietary fat intake to 30% of total intake starting at mid-childhood (10, 37, 38), such reductions necessarily entail an increase in the fraction of dietary energy supplied by carbohydrates to maintain energy balance. In many children and adolescents, a significant portion of the dietary carbohydrate intake is derived from simple sugars, particularly fructose and sucrose (39, 40, 41). This has led some nutritional policy groups to express concern that increased carbohydrate intakes in children and adolescents may adversely affect both blood lipid concentrations and glucose metabolism, leading to the development of insulin resistance and increasing the risk of type 2 diabetes and cardiovascular disease (16, 17, 18, 19, 20, 21, 22, 23).

Despite the extensive amount of adult data, we are not aware of controlled studies addressing the impact of high carbohydrate/low fat vs. low carbohydrate/high fat intakes on glucose and insulin kinetics, lipolytic rates, or triglyceride levels in children. Thus, the purpose of the present studies was to determine the effects of dietary carbohydrate, fat, and fructose contents on parameters of glucose and insulin kinetics and lipid metabolism in healthy nonobese prepubertal children and adolescents. We hypothesized that healthy, nonobese children and adolescents would 1) appropriately adapt to diets with both high fat and high carbohydrate contents by adjusting their substrate oxidation to match the intakes; and 2) respond to a high carbohydrate intake by increasing their insulin sensitivity; and 3) that in these children and adolescents, the fructose content of the diet would not affect parameters of glucose and insulin kinetics or blood triglyceride concentrations.

Subjects and Methods

Experimental subjects

The protocols described below were approved by the Institutional Review Board for Human Subject Research for Baylor College of Medicine and affiliated Hospitals. The subjects (n = 36) were recruited by local advertisement. After written parental consent was given, assent was obtained from all participating children. Each child was in good health as determined by a medical history, a physical examination, and standard blood chemistry analysis. Each subject was selected to have a normal weight for height, BMI less than the 85th percentile for age, and body fat less than 28% determined by dual-energy x-ray absorptiometry (Hologic QDR 2000, Hologic, Inc., Bedford, MA; Refs. 43, 44, 45, 46 ; Table 1Go). Subjects were excluded if they had obese parents (BMI > 28 kg/m2 ) or a first-degree relative with type 1 or type 2 diabetes. Attempts were made to recruit from all ethnic groups. Of the children studied, 19 were European-American, 11 Afro-American, and 6 Hispanic-American.


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  		Table 1. Subject characteristics

 
To determine the impact of the dietary fat and carbohydrate contents on parameters of glucose insulin and lipid metabolism, 12 prepubertal children (Tanner stage I) of equal gender distribution and 12 adolescents (Tanner pubertal stage IV-V), divided equally by gender, were studied on two separate occasions (see Results and Table 1Go). An additional 12 adolescents, 6 boys and 6 girls, were also studied on two occasions to determine the effects of the fructose content on glucose metabolism (see Results and Table 1Go). We previously determined the reproducibility of measurements of plasma concentrations of substrates and hormones and glucose, insulin, and lipid kinetics in prepubertal children and adolescents studied on two separate occasions, each preceded by a 7-d period with identical diets (60% carbohydrate, 25% fat, and 15% protein; Ref. 47). On the basis of the results from that study, 12 subjects in each group would allow us to detect a difference of 10% for substrate oxidation, glucose and C-peptide concentrations, and glucose production rates, and a 25% difference for insulin concentrations, gluconeogenesis, glycerol turnover, insulin secretory indices, insulin sensitivity, and glucose effectiveness (47).

Methods

Tracers. Deuterium oxide (99% 2H), [2H5]glycerol (99% [2H]; 93.5% [2H5]), [1-13C]glucose (99% [13C]); and [6,6-2H2]glucose (99% [2H]; 98% [2H2]) were purchased from Cambridge Isotope Laboratories (Andover, MA). The isotopes were tested for sterility and pyrogenicity by the investigation pharmacy at Texas Children’s Hospital (Houston, TX). The infusates were filtered through a Gelman syringe filter (2 µm; Gelman Laboratories Inc., Ann Arbor, MI) and stored at 4 C for 24–48 h before administration.

Study design. The subjects in protocols 1 and 2 were admitted to the metabolic research unit at the Children’s Nutrition Research Center for two days and two nights on each of two occasions separated by approximately 8 wk. For the 7 d before each study occasion, the subjects received a constant diet of known composition. Thus, the subjects included in protocol 1 were randomly assigned to receive a low carbohydrate/high fat diet (LCHO/HF: 30% carbohydrate, 55% fat, and 15% protein) on one occasion and an isocaloric high carbohydrate/low fat diet (HCHO/LF: 60% carbohydrate, 25% fat, and 15% protein) on the other occasion. In both diets, the fructose content was maintained at 20% of the total carbohydrate content. The subjects studied in protocol 2 randomly received a high carbohydrate/low fat diet (60% carbohydrate, 25% fat, and 15% protein) of which fructose represented either 40% [high fructose (HFruc)] or 10% of the total carbohydrate content [low fructose (LFruc)]. The diets were isocaloric.

Subjects were interviewed by our research dietitian, and food preferences were established from a list of common commercially available foods of known macronutrient content. Diets were then created to achieve the designed macronutrient composition. Three meals and two snacks per day were weighed, prepacked, and sent to the subject’s home by the research kitchen. Nonconsumed food was returned to the kitchen and examined for constituents, and the energy and macronutrient composition of the consumed food was calculated by difference (Tables 2Go and 3Go). A research dietitian was in frequent telephone contact with the families to ensure each child’s compliance with the diet. In every subject, the calorie content was equal on both study occasions (Tables 2Go and 3Go). The total energy intake and distribution of energy from carbohydrate, fat, and protein were analyzed using the Minnesota Database System (version 2.8, MDS, Minneapolis, MN). According to reported values of physical activity, total energy intake for each individual subject was set as a multiple of 1.7–2.0 times basal metabolic rate, predicted from weight and age according to Schofield (48).


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  		Table 2. Protocol 1: Energy intake and expenditure during the HCHO/LF and LCHO/HF diets

 

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  		Table 3. Protocol 2: Energy intake and expenditure during the LFruc and HFruc diets

 
After each 7-d diet period at home, as described above, the subjects were admitted to the metabolic research unit. In the afternoon of the admission day (d 1), the subjects were placed in a room calorimeter to assess 24-h energy expenditure as previously described in detail (47). During the calorimeter tests, the children were fed a diet equivalent to that of the week preceding the calorimetry study, except that total dietary energy content was decreased to 1.4–1.5 times basal metabolic rate to adjust for a lower activity level in the calorimeter (Tables 2Go and 3Go). Net fat and carbohydrate use were computed using 24-h excretion of urinary nitrogen (49). After completion of the calorimetry study on the afternoon of study d 2, subjects were served dinner at 1700 h and a snack at 2000 h. Thereafter, except for water, they were fasted until termination of the inpatient study at 1300 h on d 3.

In the evening of study d 2, two iv catheters were placed under Emla cream analgesia (Astra USA, Inc., Wayne, PA). One was placed in an antecubital vein for infusion, and a second was placed in a contralateral vein for blood sampling.

Administration of tracers. On each study occasion, the subjects included in protocol 1 received the following, stable isotopically labeled tracers as previously described (47).

1. On study d 2 at 1000, 1200, 1400, 1600, and 1800 h, five oral doses of deuterium oxide (a total of 3 g/kg) were administered to measure gluconeogenesis (47).

2. On study d 3, between 0600 and 1300 h, a simultaneous primed-constant rate iv infusion of [1-13C]glucose and [2H5]glycerol was administered to measure glucose production and the plasma turnover of glycerol, an index of lipolysis. The [1-13C]glucose was infused at a rate of 0.66 ± 0 µmol/kg·min (mean ± SE) in prepubertal children and 0.33 ± 0 µmol/kg·min in adolescents, and [2H5]glycerol was infused at 0.29 ± 0.01 µmol/kg·min and 0.14 ± 0 µmol/kg·min in the two groups, respectively (47).

3. At 0900 h on study d 3, after the 0 min blood sample (see below), a bolus injection of glucose, 0.30 ± 0 g/kg containing 10% [6,6-2H2]glucose, was administered over 90–120 sec in all children to measure indices of first and second phase insulin secretion, insulin sensitivity, and glucose effectiveness (47).

The study design of protocol 2 was identical to that of protocol 1, except that the deuterium oxide and [2H5]glycerol were not given.

Blood sampling. To measure substrate and hormone concentrations and tracer isotopic enrichments, 2.5-ml blood samples were obtained at appropriate times, with the sample taken just before the iv glucose bolus designated as time zero. Thus, the first or baseline sample was taken 12 h after the last oral dose of deuterium oxide (t = -180 min), just before the period of continuous isotopic infusion. Subsequent samples were obtained every 10 min during the last half hour of the 3-h glucose and glycerol tracer infusion period (t = -30 to t = 0 min) and then at +2, 3, 4, 5, 8, 10, 18, 20, 28, 32, 40, 60, 120, 180, and 240 min after injection of the iv glucose bolus (47, 50). The substrate natural isotopic abundance values used to calculate isotopic enrichments during the tracer studies were obtained from corresponding values measured in the clinical chemistry blood sample drawn during the recruitment visit.

Analyses. Plasma concentrations of glucose, insulin, and C-peptide were determined as previously described (47). Plasma concentrations of triglycerides and free fatty acids (FFA) were measured using a Cobas Fara II Analyzer (Roche Diagnostic Systems, Inc., Montclair, NJ), and plasma glycerol concentrations were measured by gas chromatography mass spectrometry using a [2-13C]glycerol internal standard and reverse isotope dilution as described previously (47, 51).

Isotopic enrichments were analyzed using gas chromatography mass spectrometry as previously described (47). Gluconeogenesis from pyruvate, estimated from deuterium incorporation at carbon 6 of glucose following ingestion of deuterium oxide, was determined in the hexamethylenetetramine derivative as previously described (47, 52). In the adolescents, total gluconeogenesis was also estimated from the deuterium enrichment at glucose carbon 5 (53). Because the latter method requires large blood sample volumes, we were unable to make this measurement in the prepubertal children (53).

Calculations. Between 2.5 and 3 h of isotope tracer infusion (t = -30 to 0 min), approximate steady states were achieved for both tracer and tracee (coefficients of variation of <= 10%, and slopes not different from zero). Plasma appearance rates of glucose and glycerol were calculated from the average enrichment obtained for [13C1]glucose and [2H3]glycerol during this steady period using conventional tracer dilution techniques (54, 55) as previously described (47). Because the subjects were fasting, the plasma glucose appearance rate is equivalent to the glucose production rate, and plasma glycerol appearance reflects the endogenous glycerol turnover rate, an index of lipolysis.

The fractional contribution of gluconeogenesis from pyruvate to glucose production was calculated from the average incorporation of deuterium at the sixth carbon of glucose (C6) during the steady state measurement period as described previously (47, 52):

In 10 of the adolescents, the total gluconeogenic contribution to glucose production was determined from the average deuterium incorporation at the fifth carbon of glucose (C5) according to Landau et al. (53):

The absolute rate of gluconeogenesis from pyruvate (micromoles per kilogram per minute) was calculated as the percentage of gluconeogenesis from pyruvate x the glucose production rate and, correspondingly, the total gluconeogenic rate (micromoles per kilogram per minute) was calculated as the product of the percentage of total gluconeogenesis and the glucose production rate. In the adolescents, the gluconeogenic contribution from glycerol was calculated as the difference between total gluconeogenic rate and gluconeogenesis from pyruvate. Because of incomplete equilibrium between deuterium in body water and the methyl hydrogens of pyruvate, gluconeogenesis from pyruvate may be underestimated to some degree by the method used (52, 53). Thus, our calculations may slightly overestimate the contribution of glycerol to gluconeogenesis.

As a control experiment to determine whether the [2H5]glycerol tracer infused at the rates used in this study would contribute to the deuterium enrichment at glucose carbons 5 and 6 and, thereby, result in an overestimation of gluconeogenesis, six additional adolescents matched for age, puberty, weight, and body fat were studied on one occasion in the postabsorptive state while receiving an infusion of only [2H5]glycerol at the rate described above. Blood samples were obtained at intervals identical to those detailed above, the hexamethylenetetramine derivative was made, and deuterium incorporation at glucose carbons 5 and 6 was measured. The results demonstrated that the [2H5]glycerol tracer contributed no deuterium enrichment at glucose carbon 5, and only approximately 0.02% of the deuterium enrichment at glucose carbon 6, i.e. infusion of [2H5]glycerol in our studies does not affect estimation of total gluconeogenic rate and, at most, might potentially overestimate the gluconeogenic rate from pyruvate by 5%.

Insulin sensitivity (SI*; the sensitivity of glucose disposition to insulin) and glucose effectiveness (SG*; the effect of glucose per se on its own disposition at basal insulin concentrations) were calculated using the labeled minimal model (56) based on the [6,6-2H2]glucose enrichments in plasma and insulin data, respectively, in the samples obtained after the glucose bolus (47). Insulin secretory indices ({Phi}1 and {Phi}2) were calculated using the C-peptide data obtained during the iv glucose tolerance test (IVGTT; Refs. 47 and 57). The results of these calculations presented below represent the data from 11 subjects (5 boys and 6 girls). In one adolescent boy, the model parameters on insulin sensitivity and glucose effectiveness provided by the minimal model had a very high degree of uncertainty, and the data were, therefore, excluded.

Statistical methods. Data are presented as mean ± SE. In both studies, differences between values obtained at the two study occasions were tested by paired, two-tailed t test or Wilcoxon’s nonparametric test. Differences between groups (boys vs. girls and prepubertal children vs. adolescents) were tested by one-way ANOVA followed by Fisher’s least significant difference test. A P value of no more than 0.05 was used to define statistical significance.

Results

Subject characteristics are depicted in Table 1Go. As expected, adolescent girls had a higher percentage of body fat than adolescent boys (P < 0.01), whereas there was no gender difference in body fat in the prepubertal children. In subsequent comparisons, percentage of body fat did not correlate with any parameter of glucose or lipid metabolism.

Protocol 1: effects of low carbohydrate/high fat (LCHO/HF) intake vs. high carbohydrate/low fat intake (HCHO/LF) on parameters of glucose and lipid metabolism

Energy intake. Table 2Go demonstrates that the achieved energy intakes and dietary macronutrient distributions were in good agreement with the intended values according to the study designs.

Energy expenditure. In both adolescents and prepubertal children, total energy expenditure and macronutrient substrate oxidation matched the respective dietary intakes during both the LCHO/HF and HCHO/LF diets (Table 2Go) and included the corresponding appropriate changes in nonprotein respiratory quotients (NPRQ; adolescents, LCHO/HF diet, 0.83 ± 0.01; HCHO/LF diet, 0.89 ± 0.01; P < 0.0001; prepubertal children, LCHO/HF diet, 0.82 ± 0.01; HCHO/LF diet, 0.88 ± 0.01; P < 0.0001). Additional detailed results from calorimetric studies are presented in Ref. 57A .

Baseline substrate and hormone concentrations (Table 4Go). Plasma concentrations of glucose, glycerol, triglycerides, and FFA were within normal range and were unaffected by age, gender, or dietary macronutrient content (Table 4Go). Although all insulin values were within the normal range, plasma insulin concentrations were marginally higher during the HCHO/LF diet than the LCHO/HF diet in both prepubertal children (P < 0.01) and adolescents (P = 0.05; Table 4Go). Independent of dietary macronutrient content, plasma insulin concentrations were higher in the adolescents than in the prepubertal children (P < 0.001) and higher in adolescent girls than adolescent boys (P < 0.01; Table 4Go). There were no gender differences in plasma insulin in the prepubertal children.


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  		Table 4. Substrate and hormone concentrations: protocol 1

 
C-peptide concentrations were also within the normal range and were affected by dietary macronutrient content only in prepubertal children (HCHO/LF > LCHO/HF; P < 0.01; Table 4Go). As was seen with plasma insulin levels, adolescents had higher plasma C-peptide concentrations than prepubertal children (P < 0.0001), independent of dietary composition. In prepubertal children, gender did not affect C-peptide response to diet composition. Adolescent boys and girls had similar C-peptide responses during the LCHO/HF diet (P = 0.28), and girls had marginally higher C-peptide levels during the HCHO/LF diet (P = 0.05; Table 4Go).

Kinetic measurements

Glucose production. In adolescents, glucose production rose slightly during consumption of the HCHO/LF diet compared with the rate found on the LCHO/HF diet (13.1 ± 0.5 and 12.5 ± 0.4 µmol/kg·min, respectively; P < 0.01). There was no diet effect on glucose production rates in prepubertal children (HCHO/LF, 21.2 ± 1.4 µmol/kg·min; LCHO/HF, 19.4 ± 0.6 µmol/kg·min; P = 0.11), although the glucose production rate was significantly higher in prepubertal children compared with adolescents during both diet periods (P < 0.001). Gender had no influence on glucose production in any of the study groups.

Lipolysis. Plasma glycerol appearance rate was not affected by diet composition, age, or gender. In adolescents, the plasma glycerol appearance rate was 4.4 ± 0.5 µmol/kg·min during both diets and was 3.9 ± 0.5 and 4.8 ± 0.4 µmol/kg·min [not significant (ns)] during the HCHO/LF and LCHO/HF diets, respectively, in prepubertal children.

Gluconeogenesis. Gender did not affect absolute gluconeogenic rates in prepubertal children or adolescents. In prepubertal children, gluconeogenesis from pyruvate was higher than that found in adolescents during both diet periods (P < 0.01; Fig. 1AGo). Furthermore, prepubertal children responded to the LCHO/HF diet with higher gluconeogenic rates (11.0 ± 0.6 µmol/kg·min) than those found during the HCHO/LF diet (9.2 ± 0.7 µmol/kg·min; P < 0.01; Fig. 1AGo), whereas in adolescents neither gluconeogenesis from pyruvate (LCHO/HF, 7.3 ± 0.2 µmol/kg·min, vs. HCHO/LF, 6.8 ± 0.3 µmol/kg·min) nor total gluconeogenesis (LCHO/HF, 8.7 ± 0.3 µmol/kg·min, vs. HCHO/LF, 8.4 ± 0.6 µmol/kg·min) was affected by diet (Fig. 1AGo). Thus, gluconeogenesis from pyruvate in prepubertal children on the LCHO/HF diet accounted for 57 ± 3% of glucose production, an increase from the 43 ± 2% found on the HCHO/LF diet (P < 0.001; Fig. 1BGo), and the gluconeogenic contribution of pyruvate to glucose production in adolescents was marginally higher in response to the same change in dietary composition, 59 ± 2 vs. 52 ± 2% of glucose production, respectively (P < 0.05; Fig. 1BGo). In adolescents, the contribution of glycerol to glucose production averaged 11 ± 2% on both diets, and the total gluconeogenic substrate contribution to glucose production was unaffected by diet, averaging 69 ± 2% and 64 ± 4% during the LCHO/HF and HCHO/LF diets, respectively (Fig. 1BGo).



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  		Figure 1. A, Impact of low carbohydrate/high fat ({blacksquare}) and high carbohydrate/low fat ({square}) diets on rates of gluconeogenesis from pyruvate (measured by the deuterium oxide glucose carbon 6 method) in prepubertal children and adolescents and on total gluconeogenesis (measured by the deuterium oxide glucose carbon 5 method) in adolescents. Adolescents vs. prepubertal children, **, P < 0.01; #, P < 0.001. B, Impact of low carbohydrate/high fat ({blacksquare}) and high carbohydrate/low fat ({square}) diets on fractional gluconeogenesis from pyruvate (measured by the deuterium oxide glucose carbon 6 method) in prepubertal children and adolescents and on total gluconeogenesis (measured by the deuterium oxide glucose carbon 5 method) in adolescents. Adolescents vs. prepubertal children, **, P < 0.01.

 
Insulin sensitivity, glucose effectiveness, and indices of insulin secretion

Insulin sensitivity. There was no significant gender difference in insulin sensitivity in prepubertal children or adolescents consuming either diet, but insulin sensitivity was higher (P < 0.05) in the prepubertal children independent of diet (Fig. 2AGo). Although consumption of the HCHO/LF diet did not affect insulin sensitivity in prepubertal children (9.9 ± 1.5 x 10-4 and 9.4 ± 2.5 x 10-4 (min-1)/(µU·ml-1) during the HCHO/LF and LCHO/HF diets, respectively, insulin sensitivity increased in adolescents consuming the HCHO/LF diet [5.0 ± 1.4 x 10-4 (min-1)/(µU·ml-1)], compared with the value of 3.2 ± 0.7 x 10-4 (min-1)/(µU·ml-1) (P < 0.01) found during the LCHO/HF diet period (Fig. 2AGo).



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  		Figure 2. A, Impact of low carbohydrate/high fat ({blacksquare}) and high carbohydrate/low fat ({square}) diets on insulin sensitivity (Si*) and glucose effectiveness (Sg*) in prepubertal children and adolescents. Adolescents vs. prepubertal children, *, P < 0.05; #, P < 0.001. B, Impact of low carbohydrate/high fat ({blacksquare}) and high carbohydrate/low fat ({square}) diets on first phase ({phi}1) and second phase ({phi}2) insulin secretory indices in prepubertal children and adolescents. Adolescents vs. prepubertal children, *, P < 0.05; #, P < 0.001.

 
Glucose effectiveness. Glucose effectiveness was not affected by the diet but was higher in prepubertal children, independent of dietary macronutrient content and gender (P < 0.001; Fig. 2AGo).

Insulin secretory indices. First phase ({phi}1) and second phase ({phi}2) insulin secretory indices were unaffected by diet, regardless of age or gender (Fig. 2BGo), but were higher ({phi}1, P < 0.05; and {phi}2, P < 0.001) in adolescents than in prepubertal children, independent of dietary macronutrient content (Fig. 2BGo).

Protocol 2: effects of fructose intake on substrate and hormone concentrations and on glucose and insulin kinetics

The fructose intakes achieved during consumption of the HFruc and LFruc diets were in good agreement with the designed intakes, and we did not observe any effects of dietary fructose content on 24-h energy expenditure, use of carbohydrate, fat, and protein, or NPRQ regardless of gender (Table 3Go). The 4-fold increase in dietary fructose contribution to total dietary carbohydrate intake had no significant effect on the plasma concentrations of glucose, triglycerides, insulin, or C-peptide, or on glucose production rates, insulin sensitivity, glucose effectiveness, or insulin secretory indices (Table 5Go).


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  		Table 5. Effects of increasing dietary fructose intake on parameters of glucose and insulin kinetics in adolescents

 
The macronutrient contents of both protocol 2 diets were the same as the macronutrient contents of the HCHO/LF diet used in protocol 1, except for the contribution of fructose to total carbohydrate and energy intakes (Table 5Go). Thus, fructose accounted for 10% of dietary carbohydrate in the LFruc diet consumed in protocol 2, 20% of carbohydrate intake in the HCHO/LF diet used in protocol 1, and 40% of carbohydrate intake in the HFruc diet eaten in protocol 2, contributing 6%, 12%, and 24%, respectively, of dietary energy intakes. Combining the data from protocols 1 and 2 (Table 5Go) demonstrates clearly that increasing the fructose content of dietary carbohydrates from 10–40%, representing increments of fructose contribution to dietary energy intake from 6–24%, had no significant effects on plasma glucose, insulin, C- peptide, or triglyceride concentrations or on glucose production, insulin sensitivity, glucose effectiveness, or indices of insulin secretion (Table 5Go).

As we had observed in protocol 1, in protocol 2 girls had higher insulin concentrations than boys (LFruc, 10.1 ± 1.3 and 5.8 ± 0.7 µU/ml, respectively; P < 0.05; HFruc, 10.0 ± 1.0 and 5.2 ± 0.8 µU/ml, respectively; P < 0.01) irrespective of dietary fructose content. Likewise, C-peptide concentrations were higher in girls (P < 0.05) during the LFruc diet (2.0 ± 0.1 vs. 1.5 ± 0.2 ng/ml; P < 0.05) but not during the HFruc diet (2.0 ± 0.1 vs. 1.7 ± 0.2 ng/ml; P = 0.23). Marginal gender differences were observed for glucose concentrations during the HFruc diet (girls, 5.6 ± 0.2 mM, vs. boys, 5.0 ± 0.1 mM; p < 0.05), but not during the LFruc diet (girls, 5.3 ± 0.1 mM, vs. boys, 5.0 ± 0.1 mM; p = 0.19), and for glucose production rates during the LFruc diet (girls, 13.8 ± 0.6 µmol/kg·min, vs. boys, 11.6 ± 0.4 µmol/kg·min; P < 0.01), although these differences are unlikely to be of clinical significance because all are well within the normal range. There were no gender differences in glucose production during consumption of the HFruc diet (girls, 13.1 ± 0.8 µmol/kg·min, vs. boys, 12.2 ± 1.0 µmol/kg·min; P = 0.50).

Discussion

The present study demonstrates that healthy nonobese prepubertal children and adolescents adapt rapidly to large changes in carbohydrate and fat intakes primarily by appropriately adjusting carbohydrate and fat oxidation, respectively. Thus, both prepubertal children and adolescents almost completely match an approximate doubling of dietary carbohydrate and fat intakes with corresponding substrate oxidation. In addition, this agreement between the macronutrient distribution of the intakes and substrate oxidation indicates that a 7-d diet period was sufficient for complete adaptation and supports the robust nature of the "pack out" dietary program used.

Furthermore, in agreement with most adult data (10, 11, 12, 13), consumption of a high carbohydrate diet did not adversely affect insulin sensitivity in either age group, remaining unchanged in prepubertal children and increasing in adolescents. The fact that a high carbohydrate diet increased insulin sensitivity in adolescents could potentially have implications on preservation of optimal glucose metabolism during puberty, when insulin sensitivity tends to fall. Similarly, high carbohydrate intake did not appear to place additional demands on pancreatic ß-cell secretory function because first and second phase indices of insulin secretion were unaltered both in adolescents and in prepubertal children. That the pancreatic ß-cell and peripheral insulin sensitivity responses were sufficient is clearly demonstrated by the fact that carbohydrate fuel oxidation matched dietary intake.

The high fat diet has the potential of both providing gluconeogenic substrate (glycerol) and reducing equivalents (via FFA oxidation) to drive the gluconeogenic process. Thus, we might have anticipated that the high fat diet would increase gluconeogenesis, an expectation that was satisfied in part by our observations showing that the fraction of glucose production derived via gluconeogenesis from pyruvate was significantly higher during the high fat diet, both in adolescents and in prepubertal children. Only in prepubertal children, however, did the high fat diet augment the absolute rate of gluconeogenesis from pyruvate and, likewise in adolescents, neither the absolute total rate of gluconeogenesis nor the rates of gluconeogenesis from pyruvate were affected by changes in dietary composition.

Previous reports from studies in adults have indicated that high fructose or high sucrose intakes may adversely affect plasma triglyceride concentrations (16, 17, 18, 19, 20, 21, 22, 23). In the present study, increasing dietary fructose intake from 6–24% of energy intake did not affect either plasma concentrations of glucose, triglycerides, fatty acids, insulin, and C-peptide, or glucose production rates, insulin secretory indices, insulin sensitivity, and glucose effectiveness, at least during the short, 7-d duration of the present studies. Thus, despite the wide range of carbohydrate, fat, and fructose intakes provided by the study diets, the effects on glucose and lipid metabolism were minimal in the healthy, nonobese prepubertal children and adolescents studied.

In contrast, substantial differences were observed between prepubertal children and adolescents. In agreement with our previous reports (47, 58), when expressed on a body weight basis, rates of glucose production were higher in prepubertal children than in adolescents. This difference is explained by the greater brain to body weight ratio in prepubertal children compared with adolescents (~4% and 2%, respectively) and the fact that the brain consumes about 20 times more glucose than fat and muscle tissue per 100 g tissue (59, 60, 61). For this same reason, rates of gluconeogenesis were higher in the prepubertal children, independent of diet. Additionally, baseline insulin concentrations and insulin secretion were lower, and insulin sensitivity and glucose effectiveness were higher in prepubertal children regardless of diet.

Insulin sensitivity has been determined using the glucose clamp technique (62, 63, 64) and by unlabeled and labeled IVGTTs with frequent blood sampling (56, 57, 65). In contrast to the clamp technique, the labeled IVGTT can distinguish between the ability of glucose to stimulate its own uptake at baseline insulin concentrations (glucose effectiveness) and the effect of insulin on hepatic and peripheral glucose uptake (insulin sensitivity; Ref. 47); in addition, in our experience, the data obtained by the labeled model are more reproducible than those obtained by the unlabeled model (47). To our knowledge, there are only two published reports on insulin sensitivity and glucose effectiveness in children using the labeled model (66, 67). These reports addressed the impact of obesity (66) and pubertal stage and gender (67) on insulin sensitivity and glucose effectiveness but do not report the effects of dietary macronutrient content on these variables. In contrast to our findings, as well as to the results of others using the clamp technique (68) or the unlabeled IVGTT (69, 70, 71), Hoffman et al. (67) failed to demonstrate any effects of pubertal stage on insulin sensitivity. These authors speculate that this inconsistency might be due to the small number of children studied or to the fact that the study was longitudinal and not cross-sectional.

There were no gender differences for any parameter of glucose or lipid metabolism among the prepubertal children. In adolescents, baseline insulin concentrations were higher in girls than in boys, but insulin secretory response and insulin sensitivity were unaffected by gender. Hoffman et al. (67) demonstrated that girls, independent of pubertal stage, had lower peripheral insulin sensitivity and compensated for this by increased insulin secretion to preserve normoglycemia. Our failure to demonstrate similar gender differences may be the result of the small number of subjects of each gender studied.

Obesity and body fat, particularly intra-abdominal fat, have been directly related to insulin sensitivity in both adults (72, 73) and children (66, 74). In the present study, adolescent girls had a higher percentage of body fat than boys, but we did not find any relationship between insulin sensitivity and body fat. This may be because all subjects were nonobese with body fat contents within a narrow normal range.

In summary, we demonstrate that, at least in the short term, healthy nonobese prepubertal children and adolescents adapt very well to large changes in dietary carbohydrate and fat intakes, mainly by appropriately adjusting their substrate oxidation rates to match the macronutrient intakes. In addition, insulin sensitivity was not affected adversely by consumption of a high carbohydrate intake. Furthermore, in neither prepubertal children nor in adolescents did dietary macronutrient content adversely affect indices of insulin secretion. Thus, normal blood glucose concentrations were maintained during both high carbohydrate and high fat diets without apparent increase in the demand on pancreatic ß-cell secretory function. Finally, the fructose content of the diet did not affect substrate and hormone concentrations or adversely alter measured parameters of glucose and insulin kinetics.

We conclude that, at least in the short term, dramatic changes in dietary fat and carbohydrate intakes, irrespective of dietary fructose content, would not adversely affect glucose and lipid metabolism in healthy, nonobese children. In fact, in the adolescents, the high carbohydrate diet resulted in increased insulin sensitivity, thus, facilitating insulin-mediated glucose uptake.

Therefore, issues other than dietary macronutrient distribution must be considered as the major risk factors for carbohydrate intolerance and insulin resistance.

Acknowledgments

This work is a publication of the U.S. Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement from the U.S. government.

We thank our research nurse Andrea Dotting Jones, our dietitian Sandy Kattner, and the staff of the Metabolic Research Unit at the Children’s Nutrition Research Center for their help in conducting these studies. We also thank Kathryn Louie, Cindy Clarke, Shaji Chacko, Dan Donaldson, Anne Adolph, Maurice Puyau, Firoz Vohra, and Nitesh Mehta for excellent technical assistance, and Elena Breda (Department of Electronics and Informatics, University of Padua, Padua, Italy) for excellent assistance in performing the minimal model calculations.

Footnotes

This project was supported by grants from Mars, Inc., and U.S. Department of Agriculture Cooperative Agreement 58-6250-6-001.

Present address for M.S.T.: Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205.

Abbreviations: {Phi}1, First phase insulin secretory index; {Phi}2, second phase insulin secretory index; BMI, body mass index; FFA, free fatty acids; HCHO, high carbohydrate; HF, high fat; HFruc, high fructose; IVGTT, iv glucose tolerance test; LCHO, low carbohydrate; LF, low fat; LFruc, low fructose; NPRQ, nonprotein respiratory quotients; ns, not significant; SG*, glucose effectiveness; *SI*, insulin sensitivity.

Received May 1, 2002.

Accepted July 25, 2002.

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