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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 744-749
Copyright © 2001 by The Endocrine Society

Original Studies

Relationship between Abdominal Fat Compartments and Glucose and Lipid Metabolism in Early Postmenopausal Women1

M. Rendell, U. L. Hulthén, C. Törnquist, L. Groop and I. Mattiasson

Departments of Vascular Diseases (M.R., I.M.), Endocrinology (U.L.H., L.G.), and Radiology (C.T.), Lund University, Malmö University Hospital, S20502 Malmö, Sweden

Address correspondence and requests for reprints to: Dr. Ingrid Mattiasson, Associate Professor, Department of Vascular Diseases, Malmö University Hospital, Ing.41, S20502 Malmö, Sweden. E-mail: ingrid.mattiasson{at}medforsk.mas.lu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The relationships between abdominal and pelvic fat compartments and glucose and lipid metabolism were investigated in early postmenopausal women. Fifty-five healthy, postmenopausal women aged 52–53 yr participated in the study. Fat distribution (intra-abdominal and sc abdominal fat, and intrapelvic and sc pelvic fat) was estimated by computed tomography. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. In a multiple regression analysis, the size of the intra-abdominal fat compartment was the only significant predictor of insulin sensitivity (r2 = 24%; P = 0.0002). Plasma triglycerides were closely related to the size of the intra-abdominal fat compartment (r2 = 26%; P < 0.0001), whereas plasma free fatty acid concentrations only correlated to the size of the sc abdominal fat compartment (r2 = 18.5%, P = 0.001).

In early postmenopausal women the amount of the intra-abdominal fat strongly influences insulin sensitivity and plasma triglyceride levels, whereas plasma free fatty acids are closely related to the amount of the sc abdominal fat. Accordingly, from a metabolic standpoint it seems most essential to reduce intra-abdominal fat in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MENOPAUSE IS ASSOCIATED with an increased risk for cardiovascular morbidity and mortality in women (1, 2, 3, 4). This has been attributed to estrogen deficiency, which leads to increased levels of low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a) and decreased levels of high-density lipoprotein (HDL) cholesterol (5, 6, 7, 8, 9, 10, 11). Menopause may also be associated with reduced insulin secretion and a progressive decrease in insulin sensitivity (12, 13, 14). Postmenopausal women generally gain weight and achieve a fat distribution that is more similar to men (android adiposity) than to premenopausal women (gynoid adiposity). It has been postulated that this is due to diminished oestrogen secretion (15, 16).

Abdominal obesity seems to increase the risk of coronary heart disease by adversely influencing lipid and glucose metabolism as well as blood pressure (15, 17, 18). In these studies, waist to hip ratio (WHR) was used as a measure of central obesity. However, WHR does not differentiate between intra- and extra-abdominal fat compartments. In recent years, more specific methods for the measurement of abdominal fat compartments, such as computed tomography (CT) and magnetic resonance imaging, have been introduced (19, 20, 21).

The aim of the present study was to investigate the relationship between the size of the intra- and extra-abdominal fat compartments estimated by CT and glucose and lipid metabolism in early postmenopausal women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study group

Women living in the city of Malmö (born in 1942 and 1943 and aged 52–53 yr at the start of the study) were extracted from the National Birth Registry and were sent a questionnaire (April through September 1995) concerning weight, height, date of last menstruation, and former and present medication, including use of estrogens. Of the 1936 women contacted, 1278 returned the questionnaire.

Exclusion criteria were: spontaneous menstruation during the last year (n = 206); current estrogen use or estrogen terminated less than 6 months earlier (n = 582); current medication, with the exception of T4 and pulmonary inhalation aerosols (n = 116); cancer of the breast, uterus, or other malignancies (n = 26); and a body mass index (BMI) of 24 or less (n = 133).

Two hundred fifteen women were included. One hundred forty-one of them declined to participate, 74 eligible women came to the screening visit, and 55 of them accepted to participate (40 were born in 1942, and 15 were born in 1943). Nine women had been on earlier estrogen treatment; in seven of them the treatment was stopped more than 1 yr before inclusion in the study. Twenty-five women were smokers. None of them used inhalation steroids. One woman used ipratropiumbromide and one used salbutamol intermittently for inhalation.

All participants gave their informed consent to the study, which was approved by the Ethics Committee of the University of Lund.

Body composition measurement

BMI was calculated as weight (kg) divided by height2 (m). The WHR was calculated by dividing waist circumference with hip circumference from measurements made at the level of the umbilicus and iliac crest, respectively, with the subject standing erect. Waist circumference corrected for height was calculated as waist circumference (m) divided by height (m).

Bioelectrical impedance (BIA) was used to estimate fat free mass. The BIA is based on the principle that conductance (impedance) through body fluids of an electrical current (800 µA, 50 Hz) is detected as resistance to this electrical current. The different compartments of the body have varying ability to conduct electricity. Resistance was measured with the subject in the supine position, with tetrapolar electrodes on the left side, as described by Lukaski et al. (22), with BIA-101 (RJL System, Detroit, MI).

CT of the abdomen

The total abdominal and pelvic fat mass and its distribution in sc and intra-abdominal/intrapelvic fat was estimated by area measurements on two slices of CT. All women were investigated with the same CT scanner (Tomoscan SR 7000; Philips, Best, The Netherlands). No contrast media were used. To obtain comparable conditions, each woman emptied her bladder immediately before the CT and then a scoutview of the lower abdomen was obtained. Using this, careful positioning of two CT slices (10-mm thick, 120 kV, 300 mAs) was performed at the cranial edge of the iliac crest (abdominal slice) and major trochanter (pelvic slice), respectively (Fig. 1Go). A maximum field of view (48 cm) was used, and the matrix was 512 x 512 pixels. Tissue with attenuation values in the interval of -30 to -190 Hounsfield units was considered to be fat (20). Using a standard function of the CT scanner, regions of interest were manually defined with a cursor; first, the entire slices at the two levels and, second, the intra-abdominal/intrapelvic areas at the same two levels (Fig. 1Go, B and C). In the "level detection" function (also a standard function of CT scanner) the computer was then given the selected Hounsfield unit interval for fat, and it displayed all pixels within that interval in white and those areas were then given in mm2 by the computer. Parts of fecal material in the colon or rectum were frequently displayed as fat. These fat areas within the bowels were then calculated and subtracted from the previous measurements of total and intra-abdominal/intrapelvic fat. Thus, the abdominal slice was divided into intra-abdominal fat and sc abdominal fat, and the pelvic slice was divided into intrapelvic fat and sc pelvic fat.



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  		Figure 1. CT of the abdomen. A, Scoutview showing the levels of measurement. B, Abdominal slice at the level of the iliac crest. C, Pelvic slice at the level of the major trochanter. At both levels, the white cursor line, positioned along the muscular and bony walls of the abdominal cavity, defines the border between the intra- and extra-abdominal compartments. The typical low density of fat at CT is easily appreciated in the vast amount of sc fat at both levels as well as in the intra-abdominal compartments.

 
Euglycemic hyperinsulinemic clamp

Insulin sensitivity was evaluated with the euglycemic hyperinsulinemic clamp technique (23). Before the investigation, all subjects were instructed to adhere to their normal daily lifestyle and to avoid changes in food intake and exercise. The subjects fasted overnight and were asked not to smoke before the investigation. Polyethylene catheters (BOC Ohmeda AB, Helsinborg, Sweden) were inserted into one cubital vein and a vein on the dorsoradial side of the wrist, both on the same side. From 1000–1200 h the euglycemic hyperinsulinemic clamp was performed. Insulin (Actrapid; Novo Nordisk, Copenhagen, Denmark) was infused using an infusion pump (Perfusor Secura FT; Braun, Melsungen, Germany) at a rate of 45 mU/m2 body surface area per minute. Measurement of arterialized blood glucose concentration was performed with a glucose dehydrogenase method (HemoCue AB, Ängelholm, Sweden), every 5 min with a target level of 5.0 mmol/L. Arterialized blood samples for measurement of insulin concentration were collected at 0, +60, and +120 min. The glucose disposal rate (M) was calculated as the amount of glucose infused during the second hour of the clamp and was expressed as milligrams per kg body weight per minute. The reproducibility of the euglycemic clamp method was investigated in 24 subjects by repeating the test 6 months later, which showed an almost identical mean glucose disposal rate on the two occasions (r = 0.74; P < 0.0001; Ref. 24).

Oral glucose tolerance test (OGTT) and exercise test

An OGTT was performed according to WHO criteria (75 g glucose). Blood glucose was measured at 0, +60, +90, and +120 min with HemoCue. Seven patients had glucose concentration at 120 min (Glu 120) more than 7.8 mmol/L. The insulin concentration at 120 min (INS120), was taken as a measure of insulin secretory capacity.

Immediately after the OGTT a submaximal exercise test with continuous heart rate monitoring was carried out on a bicycle ergometer using work intensities of 75 or 100 W depending on the weight and reported physical activity of the subject. The mean heart rate during the last 2 min of cycling (steady state, >=120 beats/min) was used in calculating the maximal oxygen uptake and the duration of the test varied between 6 and 12 min. The workload was chosen according to standard nomogram (25). A comparison between this indirect measure of maximal oxygen uptake and direct measurement of maximal oxygen uptake made in 15 middle-aged, normotensive, normoglycemic men and 13 normotensive men with impaired glucose tolerance showed the same mean value, with a coefficient of variation less than 10% (26, 27).

Assays

All blood samples were taken after 10 h of fasting. Serum concentrations of cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, insulin, T3, TSH, FSH, LH, and estradiol were analyzed by routine methods at the Department of Clinical Chemistry, University Hospital (Malmö, Sweden). Leptin was analyzed by a double-antibody RIA using rabbit antihuman leptin antibodies, 125I-labeled human leptin as a tracer, and human leptin as a standard (Human Leptin RIA Kit, catalog no. HL-81K; Linco Research, St. Charles, MO). Free fatty acids (FFAs) were quantified with an enzymatic colorimetric method using the Wako NEFA C kit (Wako Chemicals Gmbh, Neuss, Germany). The intra-assay variation was 4.6% (mean value, 1.42), and the inter-assay variation was 6.5% (mean value, 1.46).

Statistics

Values are given as means ± 1 SD. Because serum insulin and serum triglycerides were not normally distributed, they were log transformed before being used in calculations. The relationships between variables were analyzed by Pearson correlation coefficients and stepwise multiple regression analyses. Because correction according to Bonferroni for multiple tests was judged to be less suitable because of supposed interrelations between the parameters, the level of significance was taken as P less than 0.01.

All statistical analyses were performed using a Statview program (Abacus Concepts Inc., Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of the study group are given in Table 1Go. The median time after last menstruation was 38 months (range, 6–165). All women had low serum estradiol (75.6 ± 20 pmol/L) and elevated serum LH (21.8 ± 6.7 IU/L) and FSH (55.8 ± 12.8 IU/L) concentrations, confirming a postmenopausal status.


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  		Table 1. Characteristics of the study group

 
Correlations between fat compartments and insulin sensitivity and insulin secretory capacity

Only the intra-abdominal fat compartment was significantly inversely related to insulin-stimulated glucose uptake (M) (r = -0.49, P = 0.0002; Table 2Go). In a stepwise regression analysis with M as the dependent variable and all fat compartments as independent variables, the intra-abdominal fat compartment was the only significant predictor of insulin sensitivity (r2 = 24%, P = 0.0002).


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  		Table 2. Correlation coefficients between insulin sensitivity and postchallenge insulin, on the one hand, and the fat compartments, metabolic measurements, as well as leptin and maximal oxygen uptake, on the other hand

 
In a stepwise regression analysis with M as the dependent variable and intra-abdominal fat compartment, triglycerides, leptin, FFA, and maximal oxygen uptake as independent variables, only the intra-abdominal fat compartment was significantly related to M (r2 = 24%; P = 0.0002; slope, -2.706E-4; SEM, -6.876E-5). The slope decreased when corrected for triglycerides, FFA, leptin, and oxygen uptake. To evaluate the influence of the estradiol level, it was tested together with intra-abdominal fat in a stepwise regression model. This fat compartment was the only variable significantly correlated to M.

INS 120 was directly related to the intra-abdominal fat (r = 0.43, P = 0.0009). In a stepwise regression analysis including INS 120 as the dependent variable and all fat compartments as well as FFA as independent variables, only the intra-abdominal fat compartment was correlated with INS 120 (r2 = 18.5%; P = 0.0009).

Correlations between fat compartments and lipids, FFA, and leptin

Triglycerides were closely related to intra-abdominal fat (r = 0.51; P < 0.0001) and to intrapelvic fat (r = 0.42, P = 0.001), but not to the sc fat compartments (Table 3Go). The intra-abdominal fat explained 26% of the variance in triglyceride levels. In contrast, FFAs were significantly related only to sc abdominal fat (r = 0.43; P = 0.001), which explained 18.5% of the variance in FFA levels. These relationships were not influenced by the level of estradiol. Total cholesterol, HDL-cholesterol, and LDL-cholesterol did not correlate with any of the fat compartments (data not shown).


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  		Table 3. Correlation coefficients between triglycerides and FFA concentrations, on the one hand, and the fat compartment, on the other hand

 
Leptin showed the strongest relationship with abdominal sc fat (r = 0.63; P < 0.0001), but also sc pelvic (r = 0.53, P < 0.0001), intra-abdominal (r = 0.55, P < 0.0001), and intrapelvic (r = 0.42, P = 0.001) fat compartments were significantly correlated with leptin. In a stepwise regression analysis, abdominal sc fat explained 39.7% and intra-abdominal fat 6.2% of the variance in leptin concentrations.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Several studies have emphasized the importance of abdominal fat accumulation for insulin sensitivity (28, 29, 30, 31, 32, 33, 34). Intra-abdominal fat measured with the CT scanning technique has earlier been suggested to be a major determinant of glucose and lipid metabolism (35, 36, 37, 38, 39). To our knowledge, no previous study has evaluated the relationship between abdominal fat distribution assessed by CT and insulin sensitivity, measured by euglycemic hyperinsulinemic clamp, in postmenopausal women.

Several new pieces of information may be extracted from the current study. Although serum triglycerides were closely related to intra-abdominal fat, FFA concentrations were tightly related to sc abdominal fat. Intra-abdominal fat was a strong predictor of insulin-stimulated glucose uptake as opposed to FFA levels. At first glance, these data seem to be at variance with studies demonstrating a close correlation between FFA concentrations and insulin sensitivity (i.e. the so-called glucose-fatty acid cycle). However, the previous studies evaluating the Randle cycle (35) were, in general, carried out in subjects with noninsulin-dependent diabetes (36, 37) and in more obese individuals than included in the present study (mean BMI, 30–33 kg/m-2 compared with 28 kg/m-2 in our study; Refs. 36 and 38). Furthermore, only a few studies have considered body fat distribution (40, 41).

Abdominal obesity either measured as waist circumference (42), with CT (43), magnetic resonance imaging (44), or dual-energy x-ray absorptiometry scanning (45), has been demonstrated to be strongly correlated with insulin-stimulated glucose metabolism, although in the latter study the relationship was significant only in the subgroup of lean subjects. Although most of these studies have pointed at the fundamental role of the intra-abdominal fat, at least two studies have emphasized the role of sc fat (44, 46). Our data demonstrate that intra-abdominal fat can explain 24% of the variance in insulin sensitivity, whereas FFA did not have any significant influence.

How is this compatible with a role for FFA in mediating an inhibitory effect on insulin-stimulated glucose uptake in muscle? Most of the Randle cycle is due to competition between oxidation of FFA and glucose. At the insulin concentrations in the present study, only about 30–50% of glucose, depending on the degree of insulin resistance, is metabolized by the oxidative pathway, whereas the rest is stored as glycogen (47). The inhibitory effect of FFA on glycogen synthesis is only seen at supraphysiological concentrations of FFA and during prolonged infusions of fat (48). In addition, the FFA concentrations in peripheral blood may not accurately reflect intracellular FFA concentration in muscle (or liver). An enhanced lipolysis of intra-abdominal fat could provide an abundance of FFA for triglyceride syntheses in the liver, especially if insulin concentrations are elevated.

On the other hand, FFA released from lipolysis in extra-abdominal (sc) tissues may, to some extent, escape the liver. This hypothesis could explain the better correlation between intra-abdominal fat, triglycerides, and impaired insulin-stimulated glucose metabolism. Triglycerides could be deposited in peripheral muscles, and, in fact, several studies have shown a correlation between elevated intramuscular triglyceride levels and impaired glucose metabolism in muscle (49, 50).

Nicklas et al. (51) found that visceral obesity was associated with increased rates of lipolysis in both abdominal and gluteal sc adipocytes in postmenopausal women. This suggests that the relationship between visceral adiposity and impaired glucose metabolism may not be solely due to increased release of FFA into the portal circulation, but may also be attributed to an increased lipolytic responsiveness in sc adipose tissue of viscerally obese individuals. Increasing fat cell size is associated with increased basal lipolysis (52). According to Jensen et al. (53), abdominally but not nonabdominally obese women had increased adipose tissue FFA release. The increase in fat cell size in abdominally obese women occurs primarily in the sc abdominal fat compartment (54). Martin and Jensen (55) showed that abdominal FFA release increases proportionally with increase in fat mass in the sc abdominal but not in the sc nonabdominal fat compartment, which could explain the relationship between plasma FFA and sc abdominal fat compartment found in our study.

In a study on premenopausal obese women (56), HDL-cholesterol but not LDL-cholesterol was found to be related to intra-abdominal fat (r = -0.35, P < 0.01). This could not be confirmed in the present study, where the correlation between HDL-cholesterol and intra-abdominal fat did not reach our predefined level of significance (r = -0.3, P = 0.025).

It has previously been demonstrated that leptin expression is higher in sc (extra-abdominal) than in visceral (intra-abdominal) adipose tissue (57, 58). Accordingly, the sc fat depot is the main source of leptin in women because it is the major depot and also has a higher secretion rate of leptin (59). This is in accordance with the finding of a closer relationship between serum-leptin and the abdominal sc compared with the intra-abdominal fat compartment in our study.

CT is a good technique for the measurement of intra-abdominal vs. sc fat. The levels of the CT slices used in this study were chosen to correspond roughly to conventional measurements of waist and hip circumferences. Bony landmarks (i.e. the iliac crest and the major trochanter) for the levels on a scoutview were used to allow comparable follow-up. Abdominal and gluteal sc fat seem to have different metabolic characteristics (34), but CT does not allow for discrimination between the gluteal and the abdominal fat within the sc fat compartment in our pelvic slice.

Within the intra-abdominal fat compartment, it is difficult to separate ip from extraperitoneal fat because the parietal peritoneum is very rarely visible on CT. Concerning the two levels for measurement of intra-abdominal/intrapelvic fat chosen in our study, the intra-abdominal represents both extra and ip fat, and the intrapelvic represents mainly extraperitoneal fat. The presence of ip fat in the intra-abdominal area could be the explanation for the stronger correlation coefficients obtained between the intra-abdominal fat and glucose uptake and insulin release compared with the intrapelvic fat.

In summary, this study demonstrates that in early postmenopausal women the amount of intra-abdominal fat strongly influences insulin sensitivity and plasma triglyceride levels, whereas plasma FFAs are closely related to the amount of sc abdominal fat. Accordingly, from a metabolic standpoint, it seems most essential to reduce the amount of intra-abdominal fat in postmenopausal women.


   Acknowledgments
 
We thank Barbro Palmqvist and Philippe Burri for skilful technical assistance and Jan Åke Nilsson for statistical advice.


   Footnotes
 
1 Supported by grants from the Swedish Heart and Lung Foundation, Crafoords Foundation, the Ernhold Lundströms Research Foundation, Research Funds of Malmö University Hospital, and the Albert Påhlsson Research Foundation. Back

Received December 7, 1999.

Revised June 1, 2000.

Revised October 4, 2000.

Accepted October 30, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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