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Plasma Adiponectin Concentrations in Children: Relationships with Obesity and Insulinemia

Clinical Diabetes and Nutrition Section (N.S., J.C.B., A.D.S., P.A.T.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016; and Department of Internal Medicine and Molecular Science (T.F., Y.M.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

Address all correspondence to: Norbert Stefan, M.D., Clinical Diabetes and Nutrition Section, National Institutes of Health, 4212 North 16th Street, Room 5-41, Phoenix, Arizona 85016. E-mail: nstefan{at}mail.nih.gov.

Abstract

Adiponectin, a novel adipokine with anti-inflammatory and insulin-sensitizing properties, has been found to have independent negative associations with obesity and hyperinsulinemia/insulin resistance in adults. We measured fasting plasma adiponectin and insulin concentrations and body composition (dual-energy x-ray absorptiometry or doubly labeled water) in 30 5-yr-old (11 boys and 19 girls) and 53 10-yr-old (17 boys and 36 girls) Pima Indian children. A subgroup of 20 children (5 boys and 15 girls) had all measurements at both 5 and 10 yr of age. Cross-sectionally, plasma adiponectin concentrations were negatively correlated with percentage body fat and fasting plasma insulin concentrations at both 5 yr (r = -0.35, P = 0.06, r = -0.42, P = 0.02) and 10 yr (r = -0.46, P = 0.001, r = -0.38, P = 0.005) of age. At age 10 yr, percentage body fat (P = 0.03) but not fasting plasma insulin (P = 0.59) was independently associated with fasting plasma adiponectin concentrations. Longitudinally, plasma adiponectin concentrations decreased with increasing adiposity. In summary, these results confirm our previously reported findings in adults of an inverse relationship between plasma adiponectin concentrations and adiposity in children. Longitudinal analyses indicated that hypoadiponectinemia is a consequence of the development of obesity in childhood. We did not find evidence that adiponectin is an early mediator of obesity-induced insulin resistance, a preliminary observation that needs to be confirmed in studies using a more direct measurement of insulin action than the one used in this investigation.

CHILDHOOD OBESITY IS epidemic in industrialized countries (1). Presently in the United States, 8% of children 4–5 yr of age are overweight (2). Childhood obesity is associated with chronic disease risk factors such as high blood pressure, hyperlipidemia, or hyperinsulinemia (3). Moreover, with the increasing prevalence of overweight in children, the incidence of type 2 diabetes is on the rise (4). To develop effective prevention strategies, it is important to understand the causes of weight gain and its pathophysiological consequences. The novel adipokine, adiponectin, has been shown to have an important role in glucose metabolism. Adiponectin is the most abundant adipose-specific protein and is exclusively expressed and secreted from adipose tissue (5, 6). There have been several recent reports from animal studies suggesting that adiponectin plays a role in modulating glucose tolerance and insulin sensitivity (7, 8, 9). Plasma adiponectin concentrations are decreased in individuals with obesity and type 2 diabetes (10, 11, 12). Longitudinally, plasma adiponectin concentrations increased after weight reduction in obese nondiabetic and diabetic subjects (11) as well as in severely obese subjects who underwent bariatric surgery (13). Single-nucleotide polymorphisms in the adiponectin gene that are associated with low plasma adiponectin concentrations and type 2 diabetes have been identified (14).

The Pima Indians of Arizona are highly prone to developing obesity (15) and as a result have the highest reported prevalence of type 2 diabetes in the world (16). Adult Pima Indians have lower plasma adiponectin concentrations, compared with Caucasians (12), and in Pima Indian adults low plasma adiponectin concentrations predict a decrease in whole-body insulin sensitivity (17). Pima Indian children are hyperinsulinemic (18) and prone to developing obesity (15, 19). Because plasma adiponectin concentrations are closely associated with adiposity in adults, we investigated whether similar relationships apply to children. First, we examined whether plasma adiponectin concentrations are associated with adiposity in prepubertal children and whether plasma adiponectin concentrations decrease with increasing adiposity. Second, we examined whether plasma adiponectin concentrations are as closely correlated with fasting plasma insulin concentrations as shown for adults. Third, we investigated whether low plasma adiponectin concentrations in children at baseline are predictive of changes in adiposity or plasma insulin concentrations 5 yr later.

Subjects and Methods

Subjects

Children were selected from among participants in an ongoing study on the risk factors for childhood obesity in Pima Indians (20, 21). Data in 5-yr-old children (n = 30) were collected during the summer months of 1995–1996. Data in the 10-yr-old children (n = 53) were collected during the summer months of 2000 or 2001. A subgroup of 20 children had measurements at both visits (baseline and follow-up). Briefly, children were studied at the NIH field clinic located in the Gila River Indian Community in Sacaton, Arizona, about 40 miles southeast of Phoenix. Pima Indian children were of full Indian and at least 75% Pima-Papago heritage. Children arrived at the clinic at 0800 h in the fasting state, accompanied by one of their parents, and their health status was determined by medical history and physical examination. Before participation, volunteers and their parents were fully informed of the nature and purpose of the study, and written informed consent/assent was obtained. The experimental protocol was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases and the Tribal Council of the Gila River Indian Community.

Methods

Anthropometrics. Anthropometric measurements on all 5-yr-old children and 46 10-yr-old children were performed during two clinic admissions, 1 wk apart, and results represent the means of the two measurements. Height was measured without shoes. Body weight was measured while the children were wearing light summer clothing. Body mass index (BMI) was calculated as ratio of body weight and squared height. Body water, calculated from ¹⁸O dilution spaces, was used to assess body composition in all 5-yr-old children and seven 10-yr-old children with the assumption that water is 75% of the fat-free mass in girls and 74% in boys (22). At follow-up, body composition was measured by ¹⁸O dilution in seven of the 10-yr-old children; in the 46 remaining children, body composition was determined using dual-energy x-ray absorptiometry (DEXA) as described previously (23). A regression equation was used to convert percentage body fat measured by DEXA to percentage fat measured by ¹⁸O (percentage body fat ¹⁸O = 0.835 · percentage body fat DEXA + 9.13; R2 = 0.95, SE of the estimate = 2.1%, P < 0.0001). This equation was developed using the percentage body fat values of 64 10-yr-old children who had both DEXA and ¹⁸O measurements (21).

Analytical procedures. Blood samples were drawn for the determination of fasting plasma glucose, insulin, and adiponectin concentrations. Plasma insulin concentrations were determined by an automated immunoassay (Access; Beckman Instruments, Fullerton, CA). Blood samples for the measurement of fasting plasma adiponectin concentrations were drawn and transferred into prechilled EDTA tubes and immediately placed on ice. All tubes were cold-centrifuged (+4 C) and stored at -70 C until assayed at the Department of Internal Medicine and Molecular Sciences, Osaka University, Japan. Fasting plasma adiponectin concentrations were determined using a validated sandwich ELISA using an adiponectin-specific antibody (intraassay and interassay coefficients of variation were 3.3% and 7.4%, respectively) as described previously (10).

Statistical methods. All statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, NC). Throughout the text, the data are expressed as means ± SD. Fasting plasma insulin and adiponectin concentrations were log transformed (log10) to approximate a normal distribution.

Cross-sectional analyses. Pearson correlation coefficients were used to quantify the relationships among the variables of interest. Relationships between fasting plasma insulin concentrations and plasma adiponectin concentrations were examined after adjustment for gender and percentage body fat in general linear models.

Prospective analyses. Differences in anthropometric and metabolic characteristics at 5 and 10 yr of age were assessed by t test. General linear models were used to assess the predictive effect of baseline plasma adiponectin concentrations on change in percentage body fat or insulin levels after adjustment for gender, percentage body fat, and plasma insulin concentrations at 5 yr of age. The predictive effect of percentage body fat at 5 yr of age on change in plasma adiponectin concentrations was examined after adjustment for gender and plasma adiponectin concentrations at 5 yr of age.

Results

Cross-sectional analyses at age 5 yr

At 5 yr of age, the mean BMI was at the 64th percentile in boys and 71st percentile in girls, compared with the average population of children in the United States (24). Because no gender differences were noted in any of the body composition variables or fasting plasma concentrations of glucose, insulin and adiponectin at age 5 yr (Table 1), data from boys and girls were analyzed together. Plasma adiponectin concentrations were negatively correlated with percentage body fat (r = -0.35, P = 0.06), BMI (r = -0.41, P = 0.02), and fasting plasma insulin concentrations (r = -0.42, P = 0.02, Fig. 1). In general linear regression models, none of the independent variables (gender, BMI, percentage body fat, and fasting plasma insulin concentrations) were independent determinants of plasma adiponectin concentrations.

View larger version (19K): [in this window] [in a new window]   Figure 1. Associations of percentage body fat and fasting plasma insulin with adiponectin concentrations in 5- and 10-yr-old children.

At 10 yr of age, the mean BMI was at the 93rd percentile in boys and 91st percentile in girls. Girls had higher fasting plasma insulin concentrations than boys (P < 0.01). There were no other significant gender differences for the 10-yr-old group (Table 1). Using data from boys and girls analyzed together, plasma adiponectin concentrations were negatively correlated with percentage body fat (r = -0.46, P = 0.001), BMI (r = -0.35, P = 0.01), and plasma insulin concentrations (r = -0.38, P = 0.005, Fig. 1). All associations were also significant when boys and girls were analyzed separately. In a general linear regression model, percentage body fat (P = 0.03), but not gender (P = 0.36) or fasting plasma insulin concentrations (P = 0.56), was an independent determinant of plasma adiponectin concentrations.

Longitudinal and prospective analyses

A subset of children (n = 20; 5 boys and 15 girls) with measurements at both 5 and 10 yr of age was included in these analyses. Longitudinally, the change in plasma adiponectin concentrations was negatively correlated with changes in percentage body fat (r = -0.37, P = 0.11) and BMI (r = -0.44, P = 0.05). Prospectively, plasma adiponectin concentrations at 5 yr of age were not predictive of a change in percentage body fat adjusted for gender. Plasma adiponectin concentrations at 5 yr of age were not predictive of a change in plasma insulin concentrations independent of change in percentage body fat or gender.

Discussion

We have previously reported that plasma adiponectin concentrations are associated with adiposity in adult Pima Indians and Caucasians. Moreover, in that study, low plasma adiponectin concentrations were more closely related to hyperinsulinemia and insulin resistance than adiposity (12). In the present analyses, we confirm the cross-sectional associations between plasma adiponectin concentrations and obesity and hyperinsulinemia, in 5- and 10-yr-old children. The association between plasma adiponectin concentrations and hyperinsulinemia that was independent of adiposity in adults, however, was not apparent in children of these ages. Nevertheless, we have shown that longitudinally plasma adiponectin concentrations decreased with increasing adiposity in children.

The most important observation in the present study is the lack of a cross-sectional association between fasting plasma adiponectin and fasting plasma insulin concentrations independent of adiposity. Although the small sample size of this cohort of children may have had an effect, this finding was unexpected, and an explanation is not immediately obvious. It has been hypothesized that the negative association between plasma adiponectin concentrations and hyperinsulinemia, independent of adiposity in adults, reflects the potential insulin-sensitizing effect of adiponectin that has been documented in animals (7, 8, 9). Consistent with this, we found that low plasma adiponectin concentrations at baseline were associated with a decrease in insulin sensitivity, independent of change in adiposity in adults (17).

The lack of such an association in children suggests, but does not prove, that adiponectin plays a less important role in whole-body insulin sensitivity in children. It is especially important to emphasize that our preliminary conclusion is based on very indirect measurements of insulin action. Therefore, the effect of adiponectin on insulin sensitivity in children needs to be confirmed in studies using more direct measurements such as the euglycemic-hyperinsulinemic clamp. However, the pubertal increase in fasting plasma insulin concentration and insulin resistance that occurs during progression from Tanner stages I–III must also be considered (25, 26, 27). The same as-yet-unidentified mechanisms for this physiological event (e.g. hormones) may override any independent relationship that adiponectin may have with plasma insulin concentrations during this time. Although there are no available Tanner staging data on this group of children, it is not unreasonable to assume that many of these 10-yr-old children, particularly the girls, were in Tanner II or III at the time of measurement (28).

Examples for hormones that increase in plasma during puberty and may affect adiponectin secretion from adipose tissue emerge from recent findings in vitro. Adiponectin gene expression has been shown to be decreased by insulin, dexamethasone, and TNF- (29, 30). Although data on the effects of insulin on adiponectin gene expression are not consistent (29), it has been shown that IGF-I increases adiponectin gene expression (29, 31). Assuming these associations hold true for human metabolism, it may be speculated that in prepubertal/pubertal children, factors like glucocorticoids and TNF- may not be as effective in decreasing adiponectin gene expression. On the other hand, IGF-I, which has been shown to increase in puberty (32), may prevent such a decrease.

Notwithstanding the contradictory results regarding insulinemia, plasma adiponectin concentrations in children decreased with increasing adiposity. This suggests that the same mechanisms that are active in adults also decrease adiponectin transcription and secretion in children. However, mean plasma adiponectin concentrations in Pima Indian children at 10 yr of age were found to be similar to those from impaired glucose-tolerant and diabetic Pima Indian adults (12). This unexpected finding may suggest that, because Pima Indian children are already more obese than their parents were at a comparable age (33), their plasma adiponectin concentrations may be even lower when they reach adulthood.

In animals, administration of adiponectin prevented high-carbohydrate/high-fat diet-induced obesity (7). This was not associated with a reduction in food intake but with an increase in lipid oxidation in muscle. We, therefore, tested whether low plasma adiponectin concentrations at baseline would predict an increase in adiposity 5 yr later. There was no association between change in adiposity and plasma adiponectin concentrations at baseline. Clearly this issue must be reinvestigated when adiponectin is available for human administration.

A possible limitation of our study is that body composition measurements at follow-up were obtained using two different methods. Although this reduces somewhat the confidence in our prospective analysis and warrants confirmation from independent studies, it is important to point out that we have recently described a similar lack of effect of adiponectin on weight gain in adults (34).

In summary, these results confirm our previously reported data in adults of an inverse relationship between plasma adiponectin concentrations and adiposity and fasting insulin levels in children. Prospective and longitudinal analyses suggest that hypoadiponectinemia is a consequence of the development of obesity in childhood. We did not find evidence that adiponectin is an early mediator of obesity-induced insulin resistance, a preliminary observation that needs to be confirmed in studies using a more direct measurement of insulin action than the one used in this investigation.

Acknowledgments

We gratefully acknowledge the help of the nursing and dietary staffs of the NIH metabolic unit for the care of the volunteers. We also thank the technical staff of the NIH Clinical Diabetes and Nutrition Section in Phoenix and of the Department of Internal Medicine and Molecular Sciences, Osaka University, Japan for assisting in the laboratory analyses. We are grateful to the members and leaders of the Gila River Indian Community for their continuing cooperation in our studies. Most of all, we thank the children and their families for the participation in this study.

Footnotes

Abbreviations: BMI, Body mass index; DEXA, dual-energy x-ray absorptiometry.

Received May 3, 2002.

Accepted July 1, 2002.

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