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Adiponectin in Youth

Relationship to visceral adiposity, insulin sensitivity, and ß-cell function

From the Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Silva A. Arslanian, MD, Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213. E-mail: silva.arslanian{at}chp.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
OBJECTIVE—Adiponectin is an adipose tissue protein that enhances insulin sensitivity and has antiatherogenic properties. The present study investigated the relationship of adiponectin levels in adolescents to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X.

RESEARCH DESIGN AND METHODS—Twenty-three normal-weight and 26 obese adolescents had fasting adiponectin, lipid profile, and proinsulin measurements performed. Hepatic and peripheral insulin sensitivity were assessed with constant-rate [6,6-²H₂]glucose infusion and a 3-h hyperinsulinemic-euglycemic clamp, respectively. Body composition was evaluated by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) and subcutaneous adipose tissue were measured by computed tomography scan at the L₄-L₅ level.

RESULTS—Obese adolescents had 50% lower adiponectin than normal-weight adolescents. Moreover, obese adolescents with high (111.8 ± 9.3 cm²) versus low (55.4 ± 2.1 cm²) VAT had lower adiponectin levels (6.2 ± 0.9 vs. 9.0 ± 1.0 µg/ml, P = 0.05). Plasma adiponectin correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P < 0.001 and r = 0.54, P < 0.001, respectively) and HDL (r = 0.52, P < 0.001) and negatively with fasting proinsulin and the proinsulin-to-insulin ratio (r = -0.64, P < 0.001 and r = -0.43, P = 0.003, respectively). In a multiple regression analysis, adiponectin, independently and together with BMI, explained 73% (R² = 0.73, P < 0.001) of the variance in insulin sensitivity. Adiponectin, but not adiposity, was the significant independent determinant of the proinsulin-to-insulin ratio (R² = 0.18, P = 0.008) and of HDL (R² = 0.45, P < 0.001).

CONCLUSIONS—In summary, hypoadiponectinemia in youth is a strong and independent correlate of insulin resistance, ß-cell dysfunction, visceral adiposity, and syndrome X. The antidiabetogenic and antiatherogenic properties of adiponectin are evident early in life and compromised in youth-onset obesity.

Abbreviations: DEXA, dual-energy X-ray absorptiometry • HGP, hepatic glucose production • SAT, subcutaneous adipose tissue • VAT, visceral adipose tissue

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Adiponectin is an adipocytokine that is exclusively expressed and secreted from adipose tissue (1,2). Its levels are low in obesity (3,4) and increase after weight loss (5). Its role as a protective adipokine is suggested by low levels in states of insulin resistance, cardiovascular disease, and type 2 diabetes (4). In addition, it is believed to have anti-inflammatory and antiatherogenic properties (6). These studies imply that adiponectin has an important role in the regulation of glucose metabolism and insulin resistance and that it might be involved in the pathogenesis of other components of syndrome X, including dyslipidemia and elevated blood pressure.

Given the increasing rates of obesity and its comorbidities in children (7), we hypothesized that the negative impact of low adiponectin levels on insulin sensitivity and the components of syndrome X could be a marker of youth-onset obesity. Therefore, the present study examined the relationship of adiponectin to 1) obesity and body fat distribution and 2) insulin sensitivity and the components of syndrome X in adolescents.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Twenty-three normal-weight and 26 obese but otherwise healthy white adolescents were studied, some of whom have been previously reported (8). The studies were approved by the Human Rights Committee of the Children’s Hospital of Pittsburgh. Study participants were recruited through newspaper advertisements. Parental informed consent and child assent were obtained after a detailed explanation of the study was provided. Clinical characteristics of the study subjects are summarized in Table 1. All subjects were at Tanner stage II to V of puberty, as assessed by physical examination and confirmed by measurement of plasma testosterone in males, estradiol in females, and dehydroepiandrosterone sulfate in all (Table 1).

Body composition
Body composition was determined by dual-energy X-ray absorptiometry (DEXA). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were examined by a single-slice computed tomography scan at intervertebral space L₄-L₅, as we have previously described (10). Blood pressure was measured between 10:00 to 11:00 P.M. and 6:00 to 7:00 A.M., when, as before, the subjects were resting in the supine position in bed (9).

Biochemical measurements
Adiponectin (µg/ml) was measured using a commercially available radioimmunoassay kit (Linco Research). The intra- and interassay coefficients of variation were 3.6 and 9.3% for low and 1.8 and 9.3%, respectively, for high serum concentrations.

Plasma glucose was measured by the glucose oxidase method (Yellow Springs Instrument, Yellow Springs, OH), and the insulin concentration was determined by radioimmunoassay (10). HbA_1c was measured by high-performance liquid chromatography (A1c 2.2 Plus Glycohemoglobin Analyzer; Tosoh Medics). Plasma lipid levels were measured using the standards of the Centers for Disease Control and Prevention (9). Deuterium enrichment of glucose in the plasma was determined on a Hewlett-Packard 5971 mass spectrometer (Hewlett-Packard, Palo Alto, CA) coupled with a 5890 series II gas chromatograph, as reported (9,10).

Fasting HGP was calculated during the last 30 min of the fasting 2-h isotope infusion period according to steady-state tracer dilution equations previously reported by us (9,10). In the fasting state, an index of hepatic insulin sensitivity was calculated as the inverse of the product of HGP and the fasting plasma insulin concentration (1,000/HGP x fasting plasma insulin), as described by Miyazaki et al. (11). Insulin-stimulated glucose disposal was calculated, during the last 30 min of the euglycemic clamp, to be equal to the rate of exogenous glucose infusion. Peripheral insulin sensitivity was calculated by dividing the glucose disposal rate by the steady-state clamp insulin level, as reported previously (9,12).

Statistical analyses
Statistical analyses were performed using Student’s t test for two-group comparisons. Pearson or Spearman correlation analysis was used when applicable to examine bivariate relationships. To evaluate multivariate relationships, multiple regression analysis was applied. All statistical assumptions were met. Data are presented as means ± SE. P value 0.05 was considered statistically significant. Data on visceral adiposity were missing in two obese subjects, one male and one female, and DEXA measurements were not possible in five subjects (four males and one female) with severe obesity whose weight exceeded the DEXA limit of 250 lbs.

	RESULTS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
The normal-weight and obese adolescents had similar age and pubertal stage distribution. The obese group had significantly higher BMI, fat mass, percent body fat, and abdominal adipose tissue (Table 1).

Fasting metabolic data and blood pressure
Both normal-weight and obese adolescents had normal fasting glucose and HbA_1c levels (5.14 ± 0.08 vs 5.03 ± 0.09%). However, obese adolescents had significantly higher fasting insulin, proinsulin-to-insulin ratio, cholesterol, triglycerides, LDL, cholesterol-to-HDL ratio, and blood pressure and significantly lower HDL. HGP was lower in obese adolescents in the presence of higher fasting insulin levels (Table 2). Thus, hepatic insulin sensitivity was significantly lower. Adiponectin level was 50% lower in obese adolescents (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1— Fasting adiponectin concentrations in normal-weight (NW) and obese (OB) adolescents (left panel) and obese adolescents with low versus high VAT (right panel).

Peripheral insulin sensitivity
Plasma glucose during the last 30 min of the hyperinsulinemic-euglycemic clamp was similar in normal-weight and obese adolescents (5.6 ± 0.02 vs. 5.6 ± 0.03 mmol/l, respectively), while insulin concentration was higher in obese (638.7 ± 35.3 vs. 1,744.7 ± 93.9 pmol/l, P < 0.001). The rates of glucose disposal and insulin sensitivity were lower in obese adolescents (51.7 ± 3.9 vs. 32.7 ± 2.5 mmol · kg^-1 · min^-1, P < 0.001 and 8.8 ± 0.8 vs. 2.1 ± 0.2 µmol · kg^-1 · min^-1 per pmol/l, P < 0.001, respectively). In the obese group, insulin sensitivity was lower in the high- than low-VAT group (1.5 ± 0.1 vs. 2.6 ± 0.5 µmol · kg^-1 · min^-1 per pmol/l, P = 0.03).

Relationship of adiponectin to the components of syndrome X
Adiponectin levels correlated inversely with BMI (r = -0.70, P < 0.001), fat mass (r = -0.73, P < 0.001), percent body fat (r = -0.66, P < 0.001), VAT (r = -0.67, P < 0.001), and SAT (r = -0.69, P < 0.001). Adiponectin levels correlated positively with peripheral and hepatic insulin sensitivity (r = 0.67, P < 0.001 and r = 0.54, P < 0.001, respectively) and negatively with fasting insulin (r = -0.66, P < 0.001), proinsulin (r = -0.64, P < 0.001), and the proinsulin-to-insulin ratio (r = -0.43, P = 0.003) (Fig. 2). The positive relationship between adiponectin and peripheral insulin sensitivity persisted after controlling for percent body fat (r = 0.48, P = 0.002) and reached significance for hepatic insulin sensitivity (r = 0.27, P = 0.098). The inverse relationship between adiponectin and the proinsulin-to-insulin ratio persisted after controlling for percent body fat (r = -0.33, P = 0.04).

View larger version (34K): [in this window] [in a new window]   Figure 2— The relationship between adiponectin concentration and peripheral insulin sensitivity (upper left panel), hepatic insulin sensitivity (upper right panel), fasting proinsulin level (lower left panel), and proinsulin-to-insulin ratio (lower right panel) in normal-weight (NW) and obese (OB) adolescents.

In a multiple regression analysis, with peripheral insulin sensitivity as the dependent variable, adiponectin independently (partial correlation 0.43, P = 0.004), and together with BMI, explained 73% of the variance in insulin sensitivity (R² = 0.73, P < 0.001 for both BMI and adiponectin in the model, and R² = 0.67, P < 0.001 for only BMI in the model). For hepatic insulin sensitivity, adiponectin (P = 0.088) and BMI (P = 0.003) together explained 44% (R² = 0.44, P < 0.001) of the variance. Adiponectin, but not BMI, was the significant independent determinant of the proinsulin-to-insulin ratio (R² = 0.18, P = 0.008) and HDL (R² = 0.45, P < 0.001). Adiponectin did not have a significant independent contribution to the variance in cholesterol, VLDL, or blood pressure. BMI and not adiponectin was a significant independent determinant of LDL (R² = 0.19, P = 0.03) and systolic (R² = 0.39, P < 0.001) and diastolic (R² = 0.16, P = 0.049) blood pressure.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
Adiponectin is an adipocyte-specific plasma protein that modulates insulin resistance, dyslipidemia, and cardiovascular disease (13,14). The present study advances previous observations by demonstrating that 1) not only obesity, but particularly visceral adiposity, is associated with low adiponectin levels, 2) adiponectin is an important determinant of insulin sensitivity and HDL levels in children, and 3) adiponectin concentrations have an inverse relationship to the proinsulin-to-insulin ratio, a marker of ß-cell failure, an observation that has not been investigated in the past.

In the adult literature, adiponectin levels have been reported to correlate inversely with BMI (3,13) and percent body fat (4,14) and to increase with weight loss (5). In Pima Indian children, plasma adiponectin concentrations inversely correlated with BMI and percent body fat and decreased with increasing adiposity over time (15). Similarly, in Hispanic and Asian-American children, adiponectin correlated inversely with BMI and fat mass (16). In a study of obese and nonobese adolescents, adiponectin levels were inversely related to percent body fat and muscle lipid content (17). The present study extends these findings by demonstrating that not only total body adiposity but also body fat topography is related to alterations in adiponectin levels in youth. More specifically, our results demonstrate that in obese adolescents, visceral adiposity is associated with further decline in adiponectin levels. This is consistent with findings in adults showing an inverse relation between plasma adiponectin and waist-to-hip ratio (4,13,18). In agreement with these studies, in vitro data demonstrate that adiponectin secretion from human omental adipose cells correlates negatively with the subjects’ BMI (19). Our results of lower adiponectin levels in viscerally obese adolescents differ from a prior publication where the authors found no correlation between adiponectin and visceral fat (17). This could be related to statistical power because our study has almost twice as many obese adolescents. Moreover, our study grouped the obese adolescents according to low and high VAT, whereas the prior study assessed correlations (17).

Our data also demonstrate that adiponectin is a strong and independent predictor of in vivo insulin sensitivity. Previous studies in Pima Indian, Hispanic, and Asian-American children demonstrated that plasma adiponectin levels correlate inversely with fasting insulin levels (15,16). Also, adiponectin levels were positively related to insulin-stimulated glucose metabolism in adolescents (17). In our study, adiponectin levels correlated directly with both peripheral and hepatic insulin sensitivity. Moreover, in a multiple regression analysis, adiponectin independent of adiposity contributed to the variability in insulin sensitivity. This is consistent with the Pima Indian data showing that hypoadiponectinemia precedes the decline in insulin sensitivity independent of changes in percent body fat (14).

The observed inverse relationship between adiponectin and proinsulin-to-insulin ratio in the current study has not been previously reported in adult or pediatric subjects. Elevated proinsulin-to-insulin ratio is found in patients with type 2 diabetes (20) or impaired glucose tolerance (21) and correlates with the degree of islet cell dysfunction (22). Furthermore, increased proinsulin level is a marker of the future development of type 2 diabetes (23–25). Therefore, we postulate that hypoadiponectinemia may be used as a surrogate marker of ß-cell dysfunction. In favor of such a postulate is the observation that in a prospective nested case-control study, low concentrations of adiponectin were associated with the future development of type 2 diabetes (26). Thus, hypoadiponectinemia may not only be a marker of insulin resistance but also ß-cell dysfunction, both of which contribute to the pathophysiology of type 2 diabetes.

Adiponectin also has anti-inflammatory and antiatherogenic properties (6,27). Consistent with this, adiponectin levels are lower in patients with coronary artery disease (6,28). In diabetic and nondiabetic adults, as well as in children, adiponectin concentrations correlated inversely with triglycerides and positively with HDL levels (13,16,17,29). In our study, adiponectin levels correlated positively with HDL and inversely with triglycerides, VLDL, and cholesterol-to-HDL ratio. However, after controlling for adiposity, adiponectin remained to be a significant determinant of only HDL, one of the components of syndrome X.

In summary, the present study demonstrates that hypoadiponectinemia in youth is associated with 1) obesity, particularly visceral adiposity, 2) insulin resistance independent of adiposity, 3) ß-cell dysfunction, reflected in elevated proinsulin-to-insulin ratio, and 4) some of the components of syndrome X. The low adiponectin levels observed in white adolescents with youth-onset obesity and insulin resistance translates to an early loss of the antidiabetogenic and antiatherogenic benefits of adiponectin. Thus, adiponectin may constitute an early biomarker to identify obese youth at high risk for the future development of diabetes and atherosclerosis.

	Acknowledgments

 
This work was supported by U.S. Public Health Service Grants RO1 HD27503, K24 HD01357, and MO1-RR00084, the General Clinical Research Center, and Eli Lilly.

We thank the nurses of the General Clinical Research Center for their expert nursing assistance and Pat Antonio for secretarial assistance. These studies would not have been possible without the recruitment efforts of Lynnette Orlansky and Sandy Stange, the laboratory expertise of Resa Brna, and, most importantly, the commitment of the volunteer children and their parents.

Received for publication July 17, 2003. Accepted for publication November 7, 2003.

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				F. Bacha, R. Saad, N. Gungor, and S. A. Arslanian Are Obesity-Related Metabolic Risk Factors Modulated by the Degree of Insulin Resistance in Adolescents? Diabetes Care, July 1, 2006; 29(7): 1599 - 1604. [Abstract] [Full Text] [PDF]

				Z. Punthakee, E. E. Delvin, J. O'Loughlin, G. Paradis, E. Levy, R. W. Platt, and M. Lambert Adiponectin, Adiposity, and Insulin Resistance in Children and Adolescents J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2119 - 2125. [Abstract] [Full Text] [PDF]

				B. Buemann, A. Astrup, O. Pedersen, E. Black, C. Holst, S. Toubro, S. Echwald, J. J. Holst, C. Rasmussen, and T. I. A. Sorensen Possible Role of Adiponectin and Insulin Sensitivity in Mediating the Favorable Effects of Lower Body Fat Mass on Blood Lipids J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1698 - 1704. [Abstract] [Full Text] [PDF]

				K. K. Ong, J. Frystyk, A. Flyvbjerg, C. J. Petry, the Avon Longitudinal Study of Parents and Childre, A. Ness, and D. B. Dunger Sex-Discordant Associations With Adiponectin Levels and Lipid Profiles in Children. Diabetes, May 1, 2006; 55(5): 1337 - 1341. [Abstract] [Full Text] [PDF]

				J.-P. Despres Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk Eur. Heart J. Suppl., May 1, 2006; 8(suppl_B): B4 - B12. [Abstract] [Full Text] [PDF]

				S. Lee, F. Bacha, N. Gungor, and S. A. Arslanian Racial Differences in Adiponectin in Youth: Relationship to visceral fat and insulin sensitivityv Diabetes Care, January 1, 2006; 29(1): 51 - 56. [Abstract] [Full Text] [PDF]

				K. Staiger, N. Stefan, H. Staiger, M. D. Brendel, D. Brandhorst, R. G. Bretzel, F. Machicao, M. Kellerer, M. Stumvoll, A. Fritsche, et al. Adiponectin Is Functionally Active in Human Islets but Does Not Affect Insulin Secretory Function or {beta}-Cell Lipoapoptosis J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6707 - 6713. [Abstract] [Full Text] [PDF]

				P. Balagopal, D. George, H. Yarandi, V. Funanage, and E. Bayne Reversal of Obesity-Related Hypoadiponectinemia by Lifestyle Intervention: A Controlled, Randomized Study in Obese Adolescents J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6192 - 6197. [Abstract] [Full Text] [PDF]

				M. Banning Obesity: pathophysiology and treatment The Journal of the Royal Society for the Promotion of Health, July 1, 2005; 125(4): 163 - 167. [Abstract] [PDF]

				J. Verhaeghe, R. van Bree, E. van Herck, and W. Coopmans Exogenous Corticosteroids and in Utero Oxygenation Modulate Indices of Fetal Insulin Secretion J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3449 - 3453. [Abstract] [Full Text] [PDF]

				N. Gungor, T. Thompson, K. Sutton-Tyrrell, J. Janosky, and S. Arslanian Early Signs of Cardiovascular Disease in Youth With Obesity and Type 2 Diabetes Diabetes Care, May 1, 2005; 28(5): 1219 - 1221. [Full Text] [PDF]

				F. Bacha and S. A. Arslanian Ghrelin Suppression in Overweight Children: A Manifestation of Insulin Resistance? J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2725 - 2730. [Abstract] [Full Text] [PDF]

				N. Gungor, F. Bacha, R. Saad, J. Janosky, and S. Arslanian Youth Type 2 Diabetes: Insulin resistance, {beta}-cell failure, or both? Diabetes Care, March 1, 2005; 28(3): 638 - 644. [Abstract] [Full Text] [PDF]

				S. A. Arslanian, F. Bacha, R. Saad, and N. Gungor Family History of Type 2 Diabetes Is Associated With Decreased Insulin Sensitivity and an Impaired Balance Between Insulin Sensitivity and Insulin Secretion in White Youth Diabetes Care, January 1, 2005; 28(1): 115 - 119. [Abstract] [Full Text] [PDF]

N. Stefan, M. Stumvoll, H.-U. Haring, and A. Fritsche Adiponectin in Youth: Response to Bacha et al. Diabetes Care, June 1, 2004; 27(6): 1519 - 1520.