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Epicardial Adipose Tissue and Insulin Resistance in Obese Subjects

Endocrinology, Department of Clinical Sciences, La Sapienza University, 00161 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Gianluca Iacobellis, Dipartimento di Scienze Cliniche, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy. E-mail: gianluca.iaco{at}tin.it.

	Abstract

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Context: Epicardial adipose tissue has been recently recognized as a source of bioactive molecules as well as free fatty acids, adiponectin, and inflammatory cytokines. Epicardial fat reflects intraabdominal visceral fat, and the echocardiographic assessment of this tissue is an easy and reliable marker of visceral adiposity.

Objective: In this study we evaluated whether epicardial adipose tissue is related to insulin sensitivity and glucose metabolism in obese subjects.

Patients: Thirty obese subjects (20 women and 10 men; mean age, 40.8 ± 11.5 yr; body mass index, 43 ± 9.1 kg/m²) were included in this study. No subject was taking drugs or had a history or evidence of metabolic, cardiovascular, respiratory, or hepatic disease.

Main Outcome Measures: Each subject underwent a transthoracic echocardiogram to evaluate epicardial adipose tissue thickness, a euglycemic hyperinsulinemic clamp to estimate insulin sensitivity, and an oral glucose tolerance test to evaluate glucose tolerance.

Results: The thickness of the epicardial adipose tissue on the right ventricle varied between 4 and 17.4 mm. Echocardiographic epicardial adipose tissue was significantly correlated with whole-body glucose uptake index from the clamp and with all indices of insulin resistance and glucose intolerance measured, except the 120-min plasma glucose level after an oral glucose tolerance test.

Conclusions: Our study showed that the epicardial fat is significantly related to obesity-related insulin resistance. This finding could be of potential interest in clinical practice and research of obesity-related risk stratification.

	Introduction

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EMERGING EVIDENCE SUGGESTS that epicardial adipose tissue could play a role as a cardiac risk marker as well as a potentially active player in the development of an unfavorable metabolic risk profile (1, 2, 3, 4). We previously reported that epicardial adipose mass reflects intraabdominal visceral fat, and the echocardiographic assessment of this tissue is an easy and reliable marker of visceral adiposity (5, 6). Moreover, we showed that epicardial adipose tissue is clinically related to left ventricular mass (7) and other features of the metabolic syndrome, such as fasting insulin, adiponectin, low-density lipoprotein cholesterol, and arterial blood pressure (1).

Obesity is frequently associated with insulin resistance and abnormalities in glucose metabolism. A body of evidence indicates that both sc and visceral fat accumulation play important roles in the development of insulin resistance (8, 9, 10, 11). Although sc fat in the trunk is known to be correlated with insulin sensitivity in both diabetic and nondiabetic subjects (9, 10, 11), extraabdominal visceral fat depots, including mediastinal and epicardial adipose tissues, have only recently been considered (1, 2, 3, 4, 5, 6, 7, 12). The relationship between epicardial fat and obesity-related insulin resistance is still unexplored. Hence, in this study we evaluated whether epicardial adipose tissue is related to insulin sensitivity and glucose metabolism in obese subjects.

	Subjects and Methods

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We selected 30 obese subjects [20 women and 10 men; mean age, 40.8 ± 11.5 yr; body mass index (BMI), 43 ± 9.1 kg/m²] from 120 obese subjects who were referred to our day hospital for obesity. Obese subjects selected for the study met the following inclusion criteria: no clinically significant abnormalities on physical examination; no lipid-lowering, hypoglycemic, or antihypertensive drugs or hormone replacement therapy; normal thyroid function; and no history or evidence of metabolic, cardiovascular, respiratory, or hepatic disease. Eighteen obese women were premenopausal, and two were postmenopausal. Among premenopausal women, menstrual cycles were normal, and there was no clinical evidence suggestive of polycystic ovary syndrome.

Each subject underwent transthoracic echocardiogram to calculate epicardial adipose tissue, a euglycemic hyperinsulinemic clamp to estimate insulin sensitivity, and an oral glucose tolerance test (OGTT) to evaluate glucose tolerance. This study was conducted in accordance with the guidelines proposed in the Declaration of Helsinki and was approved by the review committee of La Sapienza University. All subjects gave their written informed consent before the study began.

Echocardiographic study

Echocardiograms were performed with a Toshiba instrument (Toshiba American Medical Systems, Tustin, CA) using standard techniques with subjects in the left lateral decubitus position.

We measured epicardial fat thickness on the free wall of the right ventricle from both parasternal long- and short-axis views, as previously described (5). Measurement of epicardial fat in this region provides a size measure (millimeters) of maximal epicardial fat thickness. We used imaging constraints to ensure that epicardial fat thickness was not measured obliquely. Measurements on M-mode strips obtained from both two-dimensional views with longitudinal cursor beam orientation in each view were also performed. The maximum fat thickness at any site was measured, and the average value was considered. Very good reliability of epicardial fat thickness measurements from different views occurred (intraclass correlation coefficient, 0.92). Epicardial adipose tissue appears as an echo-free or hyperechoic space if it is massive. The measurement of epicardial fat on the right ventricle was chosen for two reasons: 1) this point is recognized as the highest absolute epicardial fat layer thickness; and 2) parasternal long- and short-axis views allow the most accurate measurement of epicardial adipose tissue on the right ventricle, with optimal cursor beam orientation in each view.

Clamp study

A euglycemic hyperinsulinemic clamp was performed according to methods previously described (13). Insulin was continuously infused at a rate of 4.0 mU·kg^–1·min^–1 for 5 min, 2.0 mU·kg^–1·min^–1 for 5 min, and 1.0 mU·kg^–1·min^–1 for 110 min. The plasma glucose concentration was measured every 5 min after the start of the insulin infusion, and a variable infusion of 20% glucose was adjusted, based on the negative feedback principle, to maintain the plasma glucose level at a fasting plasma glucose level with a coefficient of variation less than 5%. The steady state of the test was considered to be the interval between 60 and 120 min. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin. Whole-body glucose uptake (M), expressed in milligrams per kilogram of body weight per minute, was calculated from the infusion rate of exogenous glucose during the second hour of the insulin clamp period, after correction for changes in glucose levels in a distribution volume of 250 ml/kg.

OGTT

For the OGTT, 75 g glucose was ingested over 5 min, and venous blood was sampled at 30-min intervals for 2 h for plasma glucose and insulin measurements (fasting and at 120 min). The insulin sensitivity index (ISI) was determined from the OGTT according to a published formula (14). The areas under the curve (AUCs) for insulin and glucose after the OGTT were also calculated using the trapezoid rule (15) .

Triglycerides, high-density lipoprotein cholesterol, and fasting and OGTT glucose and insulin levels were measured as previously described (1).

Statistical analysis

Data in the text and tables are expressed as the mean ± SD and as the median for skewed variables. An unpaired t test with 95% confidence interval was applied to evaluate the differences between men and women. The correlation between parameters was tested with Spearman correlation coefficients. A two-tailed value of P < 0.05 indicated statistical significance. We used InStat software (GraphPad, Inc., San Diego, CA) for statistical analysis

	Results

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The clinical and metabolic characteristics of obese subjects are summarized in Table 1. Twenty obese subjects had normal glucose tolerance, three presented with impaired fasting glucose, and seven showed impaired glucose tolerance (16, 17). The obese subjects included in this study showed a wide range of obesity degree (BMI range, 32.5–61 kg/m²) and insulin sensitivity (fasting insulin range, 6.1–84 µU/ml; 120-min insulin, 31–200 µU/ml; ISI, 1.03–8.4; M index, 2.5–9 mg·kg^–1·min^–1).

Echocardiographic epicardial adipose tissue was significantly correlated with M index (r = –0.70; P = 0.01; Fig. 1), waist circumference (r = 0.65; P = 0.01), fasting insulin (r = 0.59; P = 0.01), BMI (r = 0.53; P = 0.02), 120-min insulin (r = 0.45; P = 0.03), ISI (r = –0.42; P = 0.03), fasting glucose (r = 0.40; P = 0.03), and AUC for insulin (r = 0.38; P = 0.03). The correlation between epicardial fat thickness and M was substantially unchanged after adjusting for BMI (r = –0.69; P = 0.01) and waist circumference (r = –0.68; P = 0.01).

View larger version (12K): [in this window] [in a new window]   FIG. 1. Relationship between M and epicardial fat thickness. Echocardiographic epicardial fat thickness was significantly correlated with M (r = –0.70; P = 0.01) obtained from euglycemic hyperinsulinemic clamp. •, Women; , men.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study showed that the size of epicardial fat is significantly related to obesity-related insulin resistance. This is the first report showing a clinical correlation between a relatively small fat depot, such as epicardial adipose tissue, and impaired insulin sensitivity. We also found a significant, although weak, association of epicardial fat with fasting glucose. This finding could be linked to the relationship between insulin resistance and epicardial adipose tissue and needs to be evaluated in a larger group of diabetic patients.

The biochemical and endocrine properties of epicardial adipose tissue could explain its correlation with insulin resistance. In young adult guinea pigs, the rate of free fatty acid synthesis, release, and breakdown by the rather small amount of epicardial adipose tissue in response to catecholamines was markedly higher than that in other adipose depots, whereas the oxidative capacity was significantly weaker (18). Data from monkeys showed that the maximum capacity of glucose utilization in the epicardial fat is lower than that of other abundant fat depots (18). Human epicardial adipose tissue has been recently recognized as a metabolically active organ that generates a variety of bioactive molecules as well as free fatty acids (18), adiponectin (2), and inflammatory cytokines, including ILs and TNF- (3). We found that adiponectin expression was significantly lower in epicardial fat isolated from patients with coronary artery disease (2). Clinically, we showed that increased epicardial fat is associated with obesity-related parameters such as low-density lipoprotein cholesterol, fasting insulin, adiponectin, arterial blood pressure (1), and left ventricular mass (7).

Consistent with our previous studies (1, 5), epicardial fat was related more to regional fat distribution than to BMI, although waist circumference can be confounded by large amounts of sc fat, particularly in severely obese subjects. In contrast, the echocardiographic measurement of this small visceral fat depot may provide a more sensitive and specific measure of true visceral fat content, avoiding the possible confounding effect of increased sc abdominal fat thickness. Echocardiographic measure of epicardial fat thickness may be a marker for increased truncal fat or intraabdominal fat.

Finally, our study suggests that the echocardiographic assessment of epicardial fat may be a simple and practical tool for the management of obese subjects. The fact that echocardiography is routinely performed in obese subjects could mean that this objective measure may be readily available at no extra cost. In addition, echocardiographic assessment of epicardial visceral fat would provide data on cardiac parameters that can be useful in the clinical management of obese subjects. Our finding could be of potential interest in clinical practice and for research of obesity-related risk stratification.

Limitations of the study

In this study we explored the clinical correlation between echocardiographic measurement of epicardial adipose tissue and insulin resistance indices; therefore, no conclusions about the mechanisms of this relationship can be drawn. Because we did not use tracer methodology to estimate hepatic glucose production, our index of insulin resistance obtained from the clamp is probably underestimated, especially because our constant dose of insulin (milligrams per kilogram per minute) was highly unlikely to have completely suppressed hepatic glucose production. Clearly, additional studies in a larger population of epicardial adipose tissue and its relationship to insulin resistance and glucose metabolism as well as its use as a marker of metabolic and cardiovascular risk are warranted.

	Footnotes

 
First Published Online August 9, 2005

Abbreviations: AUC, Area under the curve; BMI, body mass index; ISI, insulin sensitivity index; M, whole-body glucose uptake; OGTT, oral glucose tolerance test.

Received May 16, 2005.

Accepted August 2, 2005.

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