Biomedical subjects

C Bogardus

Publications and source records attributed to C Bogardus.

At least 37 records · Page 2Linked to original sources

PubMed2001

Analysis of linkage disequilibrium between polymorphisms in the KCNJ9 gene with type 2 diabetes mellitus in Pima Indians.

The KCNJ9 gene encodes a G-protein-coupled inwardly rectifying potassium channel and is located within a region on human chromosome 1 that has been linked with type 2 diabetes mellitus in Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within KCNJ9 to diabetes susceptibility in the Pimas, we have genotyped 11 single nucleotide polymorphisms (SNPs) in 50 Pimas with diabetes and 50 Pimas over the age of 45 without diabetes and in 51 sib pairs, discordant for the disease, who were characterized by decreased allele sharing at the chromosomal location of the maximum LOD score. We detected three SNP clusters exhibiting distinct linkage disequilibria. Polymorphisms in intron 2, exon 3, and the 3'-UTR were in statistically significant linkage disequilibrium with diabetes in the case-control group (P = 0.006), but not the sibling pairs (P = 0.097). A weak association with diabetes was also found in the original linkage set comprising 1150 Pimas (odds ratio = 0.64/P = 0.079 for a dominant model and OR = 0.67/P = 0.005 for a recessive model). However, no effect on linkage was detected following adjustment for one of the most strongly associated SNPs in the entire original linkage set. Our results indicate that variants in KCNJ9 are associated with diabetes in Pimas but do not account for the linkage of 1q with diabetes in this population.

Adult↗

PubMed2001

Reduced skeletal muscle calpain-10 transcript level is due to a cumulative decrease in major isoforms.

The DNA polymorphism SNP-43 in the calpain-10 gene is associated with insulin resistance and reduced skeletal muscle transcript in Pima Indians. Alternative splicing generates transcript isoforms calpain-10a to -10h. We determined the contribution of calpain-10 mRNA isoforms to the decreased total skeletal muscle calpain-10 mRNA levels observed in the G/G homozygotes. The expression levels of the major isoforms, calpain-10a and -10f, were positively correlated with the total calpain-10 mRNA levels, indicating a cumulative effect.

Calpain↗

PubMed2001

Analysis of the lamin A/C gene as a candidate for type II diabetes susceptibility in Pima Indians.

AIMS/HYPOTHESIS: Lamin A/C (LMNA) is located within a region on chromosome 1q that has been linked with Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. Rare mutations in exon 8 of LMNA underlie Dunnigan-Type familial partial lipodystrophy, a disease characterized by regional adipocyte degeneration and frequently accompanied by insulin resistance, glucose intolerance, and diabetes. A more common variant in exon 10 (3408C/T) has recently been associated with obesity in non-diabetic aboriginal Canadian subjects. Because obesity is a strongly predisposing factor for Type II diabetes, we hypothesized that the LMNA 3408C/T variant could be associated with diabetes and body mass index in Pima Indians. METHODS: To determine whether the LMNA 3408C/T variant contributes to Type II diabetes susceptibility, we genotyped the polymorphism in 1,338 Pimas using allelic discrimination technology. The locus was screened for additional variants in 20 diabetic Pima Indians and non-diabetic Pima Indians using denaturing high performance liquid chromatography and dideoxy sequencing. RESULTS: We found no evidence for association of 3408C/T with diabetes, body mass index, total cholesterol, HDL cholesterol, triglycerides, leptin concentrations, or indices of insulin sensitivity and secretion. Subsequent screening of the remaining LMNA exons and flanking sequences revealed only rare variants in intron 4 and the 3'UTR, showing no frequency differences between diabetic and non-diabetic Pima Indians. We reassessed the linkage with diabetes following adjustment for the LMNA 3408C/T variant; adjustment for the effects of LMNA did not substantially modify the evidence for linkage. CONCLUSION/INTERPRETATION: We conclude that the LMNA 3408C/T variant probably does not play a role in susceptibility to diabetes or obesity in Pima Indians.

Alleles↗

PubMed2001

Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion.

OBJECTIVE: Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Fasting plasma IL-6 concentrations (enzyme-linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). RESULTS: Fasting plasma IL-6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = -0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL-6 was not related to M (partial r = -0.23, p = 0.089). DISCUSSION: Fasting plasma IL-6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL-6 and insulin action seems to be mediated through adiposity.

Adipose Tissue↗

PubMed2001

Exaggerated pancreatic polypeptide secretion in Pima Indians: can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans?

Vagally-mediated hyperinsulinemia is a common abnormality in various rodent models of genetic and hypothalamic obesity that have a high propensity for type 2 diabetes. We hypothesized that Pima Indians, a population with a high prevalence of hyperinsulinemia, obesity, and type 2 diabetes also have an increased parasympathetic drive to the pancreas. To test this, we measured plasma concentrations of insulin and pancreatic polypeptide (PP), a surrogate marker of pancreatic vagal tone, in lean and obese Pima Indian and Caucasian children (n = 43, 26P/17C, 7 +/- 1 y) and adults (n = 92, 61P/31C, 31 +/- 5 y). Pima Indian children had approximately 2-fold higher fasting insulin and 57% higher fasting PP concentrations than age- and sex-matched Caucasian children (P < .05). Although there was no difference in fasting PP concentration between Pima Indian and Caucasian adults, in response to a mixed meal, Pima Indians had a 51% higher early (30 minutes) PP concentration and 2-fold higher early insulin concentration than Caucasians (P < .05). PP concentrations at 60 minutes and 120 minutes after the meal were also markedly higher in both lean and obese Pima Indians compared with lean and obese Caucasians. These results suggest that Pima Indians may have an increased parasympathetic drive to the pancreas, which could lead to a primary hypersecretion of insulin and contribute to their high propensity for obesity and diabetes, as is the case in various rodent models of obesity.

Adult↗

PubMed2001

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.

Adult↗

PubMed2001

Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes.

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among those whose mothers were diabetic during pregnancy. To define the metabolic abnormalities predisposing individuals in these high-risk groups to diabetes, we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subjects, acute insulin secretory response (AIR) to a 25-g intravenous glucose challenge correlated with the age at onset of diabetes in the mother (r = 0.23, P = 0.03) and, in multiple regression analyses, the age at onset of diabetes in the father (P = 0.02), after adjusting for maternal age at onset and after allowing for an interaction between these terms. In contrast, insulin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabetes in the parents affected insulin secretion in the offspring across a range of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compared with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% CI] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lower in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the birth of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant offspring of people with early onset type 2 diabetes. This impairment may be worsened by exposure to a diabetic environment in utero.

Adipose Tissue↗

PubMed2001

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.

Absorptiometry, Photon↗

PubMed2000

Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies.

The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures of insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1,731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained during an oral glucose tolerance test. Fasting serum insulin concentration and the insulin sensitivity index (10(4)/(I0 x G0)) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemic-euglycemic clamp (absolute value r approximately 0.60). They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups approximately 3.0). Corrected insulin response (I120/(G120 x (G120 - 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35). Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be reasonable surrogates for more sophisticated measures in epidemiologic studies.

Adult↗

PubMed2000

Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians.

The PEA15 gene encoding a protein kinase C substrate is widely expressed, and its overexpression may contribute to impairment of glucose uptake. PEA15 is located within a region on human 1q linked with type 2 diabetes in both Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within this locus to disease susceptibility in the Pimas, we have investigated its genomic sequences. The PEA15 locus is composed of four exons spanning approximately 10.2kb of genomic DNA, flanked upstream by an potentially expressed Alu element, downstream by the H326 gene, and is located within 250kb of KCNJ9. We also sequenced over 2kb of the promoter region and identified various motifs analogous to known transcription factor binding sites. By analysis of 22 Pimas, including 13 diabetic subjects, we detected four single nucleotide polymorphisms (SNPs) in the non-coding regions of PEA15, including three frequent variants that were in allelic disequilibrium, and one variant found only in a single Pima. The three SNPs were not associated with type 2 diabetes mellitus in 50 affected and 50 control Pimas (p=0.12-0.17), and we conclude that mutations in this gene probably do not contribute significantly to disease susceptibility in this Native American tribe. However, knowledge of the genomic structure of PEA15 provides the basis for similar systematic examinations of this candidate locus in relation to type 2 diabetes and other metabolic disorders in other populations.

Alleles↗

PubMed2000

Long-term changes in insulin action and insulin secretion associated with gain, loss, regain and maintenance of body weight.

AIMS/HYPOTHESIS: We aimed to quantify changes in insulin action and insulin secretion associated with long-term gain, loss, regain, and maintenance of body weight in subjects with normal (NGT) or impaired (IGT) glucose tolerance. METHODS: Insulin action (hyperinsulinaemic clamp) and insulin secretion (intravenous glucose challenge) were measured longitudinally in 209 Pima Indians body weight 94.4 +/- 22.8 kg (means +/- SD) 89 women/120 men, 151 NGT/58 IGT[, who either lost (n = 110) or gained (n = 99) weight (-23% to +29%) over 2.6 +/- 2.0 years. Insulin action and insulin secretion were reassessed on a third occasion in 33 subjects who lost at least 5% body weight over 1.5 +/- 0.8 years and then either regained or maintained weight over the subsequent 1.8 +/- 1.1 years. RESULTS: There was a linear negative relation between changes in body weight and changes in insulin-stimulated glucose disposal in subjects with normal glucose tolerance (r = -0.51, p < 0.0001) and impaired glucose tolerance (r = -0.54, p < 0.0001). In contrast, changes in the acute insulin response were positively related to weight changes in subjects with normal glucose tolerance (r = +0.26, p < 0.005) but negatively in those with impaired glucose tolerance (r = -0.51, p < 0.0001). Improvements in insulin action after an average of 10% weight loss were lost with weight regain but largely preserved with weight maintenance. CONCLUSION/INTERPRETATION: Improvements in insulin action are proportional to the amount of weight loss, similar in magnitude to the impairment in insulin action with weight gain, preserved with long-term weight maintenance and similar between subjects with normal and with impaired glucose tolerance. Weight gain could, however, have more detrimental effects in people with impaired glucose tolerance, in whom insulin secretion decreases rather than increases to compensate for the decreased insulin action.

Adult↗

PubMed2000

Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance.

AIMS/HYPOTHESIS: Cross-sectional studies indicate that enlarged subcutaneous abdominal adipocyte size is associated with hyperinsulinaemia, insulin resistance and glucose intolerance. To further explore the pathophysiological significance of these associations, we examined prospectively whether enlarged subcutaneous abdominal adipocyte size predicts Type II (non-insulin-dependent) diabetes mellitus. METHODS: Body composition (hydrodensitometry), mean subcutaneous abdominal adipocyte size (fat biopsy), insulin sensitivity (hyperinsulinaemic clamp) and the acute insulin secretory response (25-g i.v. GTT) were assessed in 280 Pima Indians with either normal (NGT), impaired (IGT) or diabetic glucose tolerance (75-g OGTT). Subjects with NGT were then followed prospectively. RESULTS: After adjusting for age, sex and per cent body fat, mean subcutaneous abdominal adipocyte size was 19% and 11% higher in subjects with diabetes and IGT, compared with those with NGT (p < 0.001). Insulin sensitivity was inversely correlated with mean subcutaneous abdominal adipocyte size (r = -0.53, p < 0.0001), even after adjusting for per cent body fat (r = -0.31, p < 0.001). In 108 NGT subjects followed over 9.3 +/- 4.1 years (33 of whom developed diabetes), enlarged mean subcutaneous abdominal adipocyte size but not high per cent body fat, was an independent predictor of diabetes, in addition to a low insulin sensitivity and acute insulin secretory response [relative hazard 10th vs 90th centile (95% CI): 5.8 (1.7-19.6), p < 0.005]. In 28 NGT subjects with a 9% weight gain over 2.7 +/- 1.3 years, changes in insulin sensitivity were inversely and independently related to changes in mean subcutaneous abdominal adipocyte size and per cent body fat. CONCLUSION/INTERPRETATION: Although enlarged mean subcutaneous abdominal adipocyte size is associated with insulin resistance cross-sectionally, prospectively, both abnormalities are independent and additive predictors of Type II diabetes.

Abdomen↗

PubMed2000

Energy balance and weight regulation: genetics versus environment.

The prevalence of obesity is reaching epidemic proportions in many industrialized countries. There is growing evidence that, even if the trigger of this epidemic is found in changes in the environment, genes are interacting with the environment to cause weight gain. Studies of twins reared apart indicate that approximately two-thirds of the variability in BMI is attributed to genetic factors. From prospective studies in Pima Indians we can ascribe 12% of the variability in BMI to metabolic rate, 5% to fat oxidation, and another probable 10% to the level of spontaneous physical activity. These data indicate that at least 40% of the variability in BMI is related to genetic factors involved in the regulation of food intake and/or volitional activity. This indicates that the most likely successful therapy for obesity may target pathways of the regulation of food intake. Similarly, an environment favouring engagement in physical activity should be promoted.

Body Composition↗

PubMed2000

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

Adult↗

PubMed2000

Association of dopamine D2 receptor polymorphisms Ser311Cys and TaqIA with obesity or type 2 diabetes mellitus in Pima Indians.

OBJECTIVES: To investigate whether (a) variants within the dopamine D2 receptor gene (DRD2) are associated with obesity and type 2 diabetes in Pima Indians, and (b) whether variation in this gene could be responsible for previously observed linkage to these phenotypes, at chromosome location 11q23-24, in this population. DESIGN: Two single nucleotide polymorphisms (SNPs), Ser311Cys and TaqIA, within the DRD2 gene were genotyped by allelic discrimination PCR in subjects who had provided evidence of linkage to diabetes and obesity in an autosome-wide scan. SUBJECTS: A total of 1,187 subjects were genotyped, including 947 full heritage Pima Indians (80%). Descriptive statistics for all subjects analyzed, for whom clinical data were available, were (mean+/-s.d.): age at time of last exam = 41 +/- 15 y; birth year=1950 +/- 14; age-sex-adjusted body mass index (BMI; adjusted to a mean age of 35y)=36 +/- 8kg/m2; male = 44%; diabetic = 57%. For full heritage Pimas only: age = 43 +/- 15 y; birth year = 1948 +/- 14; sex- age-adjusted BMI = 36 +/- 8 kg/m2; male = 43%; diabetic = 59%. RESULTS: Neither polymorphism was significantly associated with diabetes in full heritage Pimas. Individuals with a 'CG' genotype at the Ser311Cys SNP had a higher BMI than those with a 'CC' genotype (36.7 vs 35.5 kg/m2, P= 0.04). Linkage analysis of BMI, adjusted for either polymorphism, resulted in LOD scores that were similar to those obtained without adjustment. CONCLUSION: Heterozygotes at the Ser311Cys DRD2 polymorphism had a slightly higher BMI than homozygotes, however neither the Ser311Cys nor the TaqIA polymorphism accounted for the linkage with BMI on chromosome 11 in Pima Indians.

Adult↗

PubMed2000

Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects.

Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 microM palmitate in cultured myoblasts correlated with the fasting glucose (r = 0.71, P = 0.001), log fasting insulin (r = 0.52, P = 0.03), and insulin-mediated glucose storage rate (r = -0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 microM palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 microM palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor.

Adult↗

PubMed2000

A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance.

Previous linkage studies in Mexican-Americans localized a major susceptibility locus for type 2 diabetes, NIDDM1, to chromosome 2q. This evidence for linkage to type 2 diabetes was recently found to be associated with a common G-->A polymorphism (UCSNP-43) within the CAPN10 gene. The at-risk genotype was homozygous for the UCSNP-43 G allele. In the present study among Pima Indians, the UCSNP-43 G/G genotype was not associated with an increased prevalence of type 2 diabetes. However, Pima Indians with normal glucose tolerance, who have a G/G genotype at UCSNP-43, were found to have decreased rates of postabsorptive and insulin-stimulated glucose turnover that appear to result from decreased rates of glucose oxidation. In addition, G/G homozygotes were found to have reduced CAPN10 mRNA expression in their skeletal muscle. A decreased rate of insulin-mediated glucose turnover, or insulin resistance, is one mechanism by which the polymorphism in CAPN10 may increase susceptibility to type 2 diabetes mellitus in older persons.

Adolescent↗

PubMed2000

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.

Adaptation, Physiological↗