Comparison of plasma insulin levels after a mixed-meal challenge in children with and without intrauterine exposure to diabetes.

BACKGROUND: The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring. OBJECTIVE: We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest. DESIGN: After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point. RESULTS: After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01). CONCLUSION: A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children.

An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.

The intestinal fatty acid binding protein locus (FABP2) was investigated as a possible genetic factor in determining insulin action in the Pima Indian population. A polymorphism at codon 54 of FABP2 was identified that results in an alanine-encoding allele (frequency 0.71) and a threonine-encoding allele (frequency 0.29). Pimas who were homozygous or heterozygous for the threonine-encoding allele were found to have a higher mean fasting plasma insulin concentration, a lower mean insulin-stimulated glucose uptake rate, a higher mean insulin response to oral glucose and a mixed meal, and a higher mean fat oxidation rate compared with Pimas who were homozygous for the alanine-encoding allele. Since the FABP2 threonine-encoding allele was found to be associated with insulin resistance and increased fat oxidation in vivo, we further analyzed the FABP2 gene products for potential functional differences. Titration microcalorimetry studies with purified recombinant protein showed that the threonine-containing protein had a twofold greater affinity for long-chain fatty acids than the alanine-containing protein. We conclude that the threonine-containing protein may increase absorption and/or processing of dietary fatty acids by the intestine and thereby increase fat oxidation, which has been shown to reduce insulin action.

Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans.

Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans.

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 +/- 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 +/- 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genome-wide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated.

Circulating ghrelin levels are decreased in human obesity.

Ghrelin is a novel endogenous natural ligand for the growth hormone (GH) secretagogue receptor that has recently been isolated from the rat stomach. Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents. To investigate the possible involvement of ghrelin in the pathogenesis of human obesity, we measured body composition (by dual X-ray absorption) as well as fasting plasma ghrelin concentrations (radioimmunoassay) in 15 Caucasians (8 men and 7 women, 31+/-9 years of age, 92+/-24 kg body wt, and 29+/-10% body fat, mean +/- SD) and 15 Pima Indians (8 men and 7 women, 33+/-5 years of age, 97+/-29 kg body wt, and 30+/-8% body fat). Fasting plasma ghrelin was negatively correlated with percent body fat (r = -0.45; P = 0.01), fasting insulin (r = -0.45; P = 0.01) and leptin (r = -0.38; P = 0.03) concentrations. Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians (P < 0.01). Also, fasting plasma ghrelin was lower in Pima Indians, a population with a very high prevalence of obesity, compared with Caucasians (87+/-28 vs. 129+/-34 fmol/ml; P < 0.01). This result did not change after adjustment for fasting plasma insulin concentration. There was no correlation between fasting plasma ghrelin and height. Prospective clinical studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity.

A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure.

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.

Differential brain responses to satiation in obese and lean men.

Knowledge of how the brain contributes to the regulation of food intake in humans is limited. We used positron emission tomography and measures of regional cerebral blood flow (rCBF) (a marker of neuronal activity) to describe the functional anatomy of satiation (i.e., the response to a liquid meal) in the context of extreme hunger (36-h fast) in 11 obese (BMI > or =35 kg/m2, age 27+/-5 years, weight 115+/-11 kg, 38+/-7% body fat; mean +/- SD) and 11 lean (BMI < or =25 kg/m2, age 35+/-8 years, weight 73+/-9 kg, 19+/-6% body fat) men. As in lean men, satiation in obese men produced significant increases in rCBF in the vicinity of the ventromedial and dorsolateral prefrontal cortex and significant decreases in rCBF in the vicinity of the limbic/paralimbic areas (i.e., hippocampal formation, temporal pole), striatum (i.e., caudate, putamen), precuneus, and cerebellum. However, rCBF increases in the prefrontal cortex were significantly greater in obese men than in lean men (P < 0.005). rCBF decreases in limbic/paralimbic areas, temporal and occipital cortex, and cerebellum were also significantly greater in obese men than in lean men (P < 0.005), whereas rCBF decreases in the hypothalamus and thalamus were attenuated in obese men compared with lean men (P < 0.05). This study raises the possibility that the brain responses to a meal in the prefrontal areas (which may be involved in the inhibition of inappropriate response tendencies) and limbic/paralimbic areas (commonly associated with the regulation of emotion) may be different in obese and lean men. Additional studies are required to investigate how these differential responses are related to the pathophysiology of obesity.

Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration.

OBJECTIVE: An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions. RESEARCH DESIGN AND METHODS: Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test). RESULTS: Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin. CONCLUSIONS: In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.

Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development.

OBJECTIVE: Although prospective studies indicate that insulin resistance and insulin secretory dysfunction predict type 2 diabetes, they provide limited information on the relative contributions of both abnormalities to worsening glucose tolerance at different developmental stages of the disease. We therefore assessed the predictive effect of insulin resistance and insulin secretory dysfunction separately for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and from IGT to diabetes. RESEARCH DESIGN AND METHODS: Insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp), acute insulin secretory response (AIR) (25-g intravenous glucose tolerance test), and body composition (hydrodensitometry or dual-energy X-ray absorptiometry) were measured in 254 Pima Indians with NGT and in 145 Pima Indians with IGT, who were then followed for 0.5-13 years. RESULTS: After follow-ups of 4.4 +/- 3.1 and 5.5 +/- 3.4 years, 79 (31%) of the subjects with initial NGT had developed IGT, and 64 (44%) of the subjects with initial IGT had developed diabetes. In proportional-hazards analyses with adjustment for age, sex, and percent body fat, low M and low AIR were independent predictors of both the progression from NGT to IGT (relative hazards [95% CI] for 10th vs. 90th percentile: M 2.4 [1.2-4.7], P < 0.02; AIR 2.1 [1.1-4.1], P < 0.04) and from IGT to diabetes (M 2.5 [1.3-5.0], P < 0.01; AIR 1.8 [0.99-3.3], P = 0.055). CONCLUSIONS: During each stage of the development of type 2 diabetes, insulin resistance and insulin secretory dysfunction are independent predictors of worsening glucose tolerance and are, therefore, both targets for the primary prevention of the disease.

Respiratory quotient is inversely associated with muscle sympathetic nerve activity.

The relative amounts of the macronutrients oxidized by an individual are reflected in the respiratory quotient (RQ), which varies inversely with lipid oxidation. A high RQ, indicating a relatively low lipid oxidation, and a low activity of the sympathetic nervous system have both been identified as risk factors for body weight gain. The stimulatory effect of norepinephrine on lipid oxidation suggests that low lipid oxidation may contribute to the relationship between low sympathetic nervous activity and body weight gain. The purpose of the present study was to determine whether low basal muscle sympathetic nerve activity (MSNA), a direct measure of sympathetic nervous outflow, is independently associated with low lipid oxidation. Intraneural recordings of basal MSNA were performed in 39 healthy, nondiabetic males, 19 Caucasians (mean +/-SD, 33 +/- 9 yr, 91 +/- 23 kg, and 28 +/- 11% body fat) and 20 Pima Indians (30 +/- 5 yr, 94 +/- 25 kg, and 35 +/- 8% fat) immediately after measurement of 24-h RQ in a respiratory chamber. Basal MSNA, energy balance, and age were independent determinants of 24-h RQ, together explaining 45% of its variability. Accordingly, 24-h RQ adjusted for energy balance and age was inversely related to MSNA (r = -0.41; P = 0.01). Race, percent body fat, and fasting plasma insulin were not independent determinants of 24-h RQ. Although MSNA explained only a limited part of the variability in 24-h RQ, the results support the hypothesis that an effect on lipid oxidation contributes to the demonstrated relationship between low activity of the sympathetic nervous system and body weight gain.

Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males.

The sympathetic nervous system controls cardiovascular homeostasis and regulates energy metabolism. Pima Indians, a population with a low prevalence of hypertension and a high prevalence of obesity, have low sympathetic nervous activity, compared with Caucasians. Preliminary findings suggest that they may also have a low beta-adrenergic sensitivity. We studied beta-adrenergic sensitivity in 87 nondiabetic normotensive individuals [52 Pima Indians (35 males/17 females) and 35 Caucasians (24 males/11 females)], matched for age and body weight. Chronotropic sensitivity to beta-adrenergic stimulation was assessed by the dose of isoproterenol necessary to increase heart rate by 25 beats per minute [chronotropic dose-25 (CD25)]. Despite a similar basal heart rate and arterial blood pressure, Pimas tended to have lower beta-adrenergic sensitivity than Caucasians (CD25 = 2.37 +/- 2.27 vs. 1.57 +/- 1.38 microg, P = 0.07; mean +/- SD). This difference was significant in males (CD25 = 3.03 +/- 2.39 vs. 1.85 +/- 1.56 microg, P = 0.02) but not in females (CD25 = 1.01 +/- 1.17 vs. 0.96 +/- 0.61 microg, P = 0.99). In males only, CD25 was positively correlated to percent body fat (r = 0.36, P < 0.01). After adjustment for percent body fat, beta-adrenergic sensitivity was still significantly lower in Pima than in Caucasian males (CD25 = 3.44 +/- 2.24 vs. 2.57 +/- 1.60 microg, P = 0.05). In conclusion, our data suggest that increased adiposity is accompanied by decreased beta-adrenergic sensitivity in males only. However, at each level of adiposity, Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males. In combination with a low sympathetic nervous system activity, a reduced beta-adrenergic sensitivity may contribute to the low prevalence of hypertension and the high prevalence of obesity observed in Pima Indians.

Energy expenditure, fat oxidation, and body weight regulation: a study of metabolic adaptation to long-term weight change.

Relatively low rates of energy expenditure and fat oxidation predict body weight gain. Weight gain, in turn, is associated with increases in energy expenditure and fat oxidation that may oppose further weight change. In response to experimental weight gain induced by overfeeding, increases in energy expenditure and fat oxidation are overcompensatory, i.e. greater than predicted for the change in body composition. To determine whether such metabolic adaptation occurs in response to spontaneous long term weight change, we conducted a longitudinal study in which 24-h energy expenditure (24-EE) and 24-h respiratory quotient (24-RQ; i.e. fat to carbohydrate oxidation) were repeatedly measured in 102 Pima Indians at baseline and after a mean follow-up of 3.6 +/- 2.7 yr, during which changes in body weight varied widely (-21 to +28 kg). We found that changes in 24-EE and 24-RQ in response to weight change were related to the amount of weight change, even after adjustment for body composition (partial r = 0.23 and -0.30, respectively; both P < 0.05). For a 15-kg weight gain, the increases in 24-EE (+244 Cal/day) and 24-h fat oxidation (+152 Cal/day) were 33 and 53 Cal/day greater than predicted from the cross-sectional relationship between both measures and body weight. Changes in 24-EE and 24-RQ varied substantially among individuals. Thus, on the average, spontaneous long term weight changes are accompanied by small metabolic adaptations in both energy expenditure and fat oxidation. The metabolic responses to weight changes are highly variable among individuals, however.

Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.

Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.

Body mass index as a measure of adiposity in children and adolescents: relationship to adiposity by dual energy x-ray absorptiometry and to cardiovascular risk factors.

Body mass index is widely used as a measure of adiposity in adults, but its use in children and adolescents is controversial. We assessed body mass index as a measure of adiposity in children and adolescents between the ages of 5 and 20 yr examined as part of the NIH survey of health in the Pima Indian population. Body mass index (measured in 985 subjects and analyzed in 3 age groups: 5-9, 10-14, and 15-19 yr, in both sexes) was compared cross-sectionally to percent fat and fat mass derived from dual energy x-ray absorptiometry and to fasting and 2-h plasma glucose, systolic and diastolic blood pressures, cholesterol, high density lipoprotein cholesterol, fasting insulin, and triglycerides. Body mass index was strongly correlated in all age groups to both percent fat (r = 0.83-0.94; for each group, P < 0.0001) and fat mass (r = 0.96-0.98; P < 0.0001). The relationship of body mass index to percent fat was different in males and females; differences were more marked in older age groups. Body mass index, percent fat, and fat mass showed similar degrees of correlation to metabolic measures in childhood. Body mass index is strongly associated with measures of adiposity derived from dual energy x-ray absorptiometry. Both measures show similar associations with cardiovascular risk factors in Pima Indian children.

Functional neuroimaging: a new generation of human brain studies in obesity research.

Obesity is predominantly caused by overeating, an abnormal behaviour for which there is no unequivocal neurophysiological explanation. Functional neuroimaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have recently emerged as new tools to search for regions of the brain that are involved in the regulation of eating behaviours and those that are involved in the pathophysiology of obesity. Using these techniques, a limited number of studies have provided the first in vivo images of the human hypothalamic response to nutritional stimuli and revealed the complexity of the human brain response to hunger, taste, and satiation. Selective differences have been reported in the functional architecture of the brain of obese and lean individuals. We discuss current use and possible future developments of functional neuroimaging applied to obesity research. We conclude that functional neuroimaging provides an increasingly important tool for investigating how different regions of the brain work in concert to orchestrate normal eating behaviours and how they conspire to produce obesity and other eating disorders.

Use of dual-energy X-ray absorptiometry in obese individuals.

Dual-energy X-ray absorptiometry (DXA) provides precise measurements of body composition in humans. Because its use in obese subjects is limited by the size of the scanning area, we explored the possibility of estimating whole-body composition from DXA half-body scans. Body composition of 183 subjects with a wide range of body sizes [body mass index (BMI; in kg/m2) of 17.7 - 52.8] was assessed by DXA and hydrodensitometry. Subjects fitting in the DXA scanning area (group A, n = 156) were scanned once whereas subjects exceeding it (group B, n = 27) were scanned twice, once for each side of the body. When body-composition results for the right and left sides were compared, only minimal differences between the two sides of the body were found in both groups. Least-squares-regression analysis of whole-body composition by hydrodensitometry on DXA gave the following results: percent body fat, r2 = 0.89 (SEE = 4.1%); fat-free mass, r2 = 0.89 (SEE = 3.72 kg); and fat mass, r2 = 0.95 (SEE = 3.57 kg). Similar r2 values and SEEs were obtained for percent body fat when only results from DXA half-body scans of all subjects were considered: right side, r2 = 0.90 (SEE = 4.1%); and left side, r2 = 0.89 (SEE = 4.2%). The error in predicting body composition by hydrodensitometry from DXA whole- or half-body scans was not affected by the subject's body size and/or scanning technique. In conclusion, our results indicate that half-body scan values by DXA accurately predict whole-body composition.

Thermic effect of food in humans: methods and results from use of a respiratory chamber.

During the past two decades, many investigators have measured the thermic effect of food (TEF) in humans and have speculated on its role in the development of obesity. In this study we compared different ways of computing TEF from daily energy expenditure measurements in a respiratory chamber, evaluated the determinants of TEF, and more importantly assessed for the first time the relation between TEF and change in body weight. In 471 subjects, TEF was 1697 +/- 857 kJ/d (mean +/- SD), ie, 18 +/- 9% of energy intake. In 114 subjects studied more than once, intraindividual TEF variability was very high (CV = 48%). TEF correlated positively with the level of spontaneous physical activity (SPA) and negatively with fasting plasma glucose and insulin concentrations. TEF correlated inversely with age (males only) and body weight, percent body fat, and waist-to-hip ratio (females only). The level of SPA and fasting plasma glucose concentration were the only significant determinants of TEF, explaining 15% of its variance. In 137 subjects in whom body weight was measured > or = 6 mo after TEF measurement (mean follow-up duration of 2.9 +/- 1.7 y), a low TEF was not predictive of body weight gain. We conclude that, despite the low reproducibility of TEF from use of a respiratory chamber, data in a large number of subjects suggest that TEF is increased by higher SPAs and that insulin resistance is associated with a low TEF. More important, longitudinal data indicate that the variability in TEF is not associated with changes in body weight.

Ad libitum food intake on a "cafeteria diet" in Native American women: relations with body composition and 24-h energy expenditure.

Epidemiologic studies consistently report associations between obesity and dietary fat but not total energy intake. We measured ad libitum food intake in a laboratory setting and evaluated its relation to body weight and composition, energy expenditure, and macronutrient utilization in 28 women of Pima-Papago heritage (aged 27 +/- 7 y, 85.3 +/- 19.0 kg, 44 +/- 6% body fat; means +/- SD). All women were studied during the follicular phase of the menstrual cycle. After a 4-d weight-maintenance period, the volunteers selected their food for 5 d from computerized vending machines offering a variety of familiar and preferred foods, ie, a "cafeteria diet". Twenty-four-hour energy expenditure and substrate oxidation were measured in a respiratory chamber on the 4th d o weight maintenance and the 5th d of ad libitum intake. Average ad libitum intake was 13,732 +/- 4238 kJ/d (11 +/- 1% protein, 40 +/- 1% fat, 49 +/- 4% carbohydrate), ie, moderate overeating by 27 +/- 37% above weight maintenance requirements (range: -27% to 124%). Percent body fat correlated with daily energy intake (r = 0.53, P < 0.01), the degree of overeating (r = 0.41, P < 0.05), and the selection of a diet higher in fat and lower in carbohydrate (r = 0.70 and r = -0.63, respectively, P < 0.001). Excess carbohydrate intake caused an increase in carbohydrate oxidation (r = 0.51, P < 0.01), whereas excess fat intake resulted in a decrease in fat oxidation (r = -0.53, P < 0.01) and thus a positive fat balance of 85 +/- 65 g/d. The positive relations among degrees of obesity, dietary fat intake and overeating, and the fact that dietary fat does not induce fat oxidation, support the hypothesis that dietary fat promotes obesity in women.

Ad libitum food intake in humans after manipulation of glycogen stores.

It is controversial whether food intake in humans is under day-to-day regulation to maintain constant body glycogen stores. In eight white males with a mean (+/-SD) age of 30 +/- 4 y, body weight of 82 +/- 20 kg, and percentage body fat of 22 +/- 5%, exercise and diets were used to produce either high (HG) or low glycogen (LG) stores in a randomized crossover design. After each treatment a vastus lateralis muscle biopsy was obtained. Subsequent ad libitum food intake was measured with an automated food-selection system during 2 d in a respiratory chamber. Despite a 46 +/- 21% difference in muscle glycogen between the two treatments, ad libitum 2-d food intakes (energy, weight, or macronutrients) were similar between treatments (HG: 23.80 +/- 4.67 MJ/d; LG: 21.20 +/- 6.73 MJ/d). However, energy intake on the second day of ad libitum feeding was negatively correlated with carbohydrate balance on the first day, adjusted for the effect of total energy intake and treatment. Adjusted carbohydrate balance on day 1 only explained 9% of the variance in energy intake on day 2. The 24-h respiratory quotient on the first day after treatment was higher after the HG than after the LG treatment: 0.94 +/- 0.04 and 0.88 +/- 0.07 (P < 0.001). The findings suggest that 1) body glycogen stores play at most a minor role in short-term food intake regulation, and 2) in the short term, imbalances in glycogen stores are corrected by adjustments of macronutrient oxidation rates.

Lower daily energy expenditure as measured by a respiratory chamber in subjects with spinal cord injury compared with control subjects.

BACKGROUND: This study was designed to determine the effect of chronic spinal cord injury on daily energy expenditure. OBJECTIVE: We hypothesized that both resting and total energy expenditure would be lower in spinal cord-injured (SCI) subjects than in control subjects because of lower sympathetic nervous system activity and reduced levels of physical activity in SCI subjects. DESIGN: Twenty-four-hour energy expenditure (24-h EE), resting metabolic rate (RMR), sleeping metabolic rate, spontaneous physical activity, the thermic effect of food (TEF), and 24-h respiratory quotient were measured by using a respiratory chamber in 10 male SCI subjects (injury ranged from level C6 to L3) and 59 age-matched, noninjured, male control subjects. RESULTS: The 24-h EE was lower in SCI than in control subjects (7824 +/- 305 compared with 9941 +/- 188 kJ, P < 0.01). After adjustment for fat-free mass, fat mass, and age, 24-h EE was still lower (-753 kJ/d, P < 0.01) in SCI than in control subjects. Spontaneous physical activity measured by a radar system was also significantly lower (4.6 +/- 0.6% compared with 6.5 +/- 0.3% of time, P < 0.01) in SCI than in control subjects. In absolute value (7347 +/- 268 compared with 9251 +/- 1326 kJ/d, P < 0.01) or after adjustment for fat-free mass, fat mass, and age (-678 kJ/d, P < 0.01), RMR was also lower in SCI than in control subjects. TEF was significantly lower in SCI than in control subjects (987 +/- 142 compared with 1544 +/- 213 kJ/d, representing 12.9% and 15.9% of total energy intake, respectively, P < 0.05). The sleeping metabolic rate and 24-h respiratory quotient did not differ significantly between groups. CONCLUSIONS: The 24-h EE was significantly lower in SCI than in control subjects. This difference can be explained by the lower levels of physical activity, and lower RMR and TEF values, in SCI subjects.