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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4206-4210
Copyright © 2004 by The Endocrine Society

Obesity: Special Feature

Regional Adiposity and Insulin Resistance

Abhimanyu Garg

Division of Nutrition and Metabolic Diseases, Endowed Chair in Human Nutrition Research, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9052

Address all correspondence and requests for reprints to: Dr. Abhimanyu Garg, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.


   Introduction
Top
 Introduction
Relationship of regional...
 Conclusion
 References
 
It is well recognized that persons with generalized obesity suffer from a high risk of insulin resistance and its metabolic complications, such as type 2 diabetes mellitus, hypertriglyceridemia, low levels of high density lipoprotein cholesterol, hypertension, hepatic steatosis, hyperuricemia, and atherosclerotic vascular disease (1, 2, 3). However, whether accumulation of adipose tissue in a particular anatomical compartment (regional adiposity) confers an excess risk of insulin resistance and its complications remains controversial. This controversy at the clinical and molecular level has been discussed in several recent review articles (4, 5, 6, 7, 8, 9). This article focuses on the clinical evidence related to impact of regional adiposity on insulin resistance.

From an anatomical standpoint, the most peculiar regional adipose tissue is present inside the abdominal cavity (intraabdominal fat). Based on magnetic resonance imaging (MRI), it has been estimated that the men and women may contain about 15–18% and 7–8% of their total body fat, respectively within the abdominal cavity (10). In contrast, only minor amounts of body fat are contained within the thoracic cavity. The intraabdominal adipose tissue can be further subdivided into ip and retroperitoneal adipose tissue compartments. The venous drainage of the ip adipose tissue is unique; it drains directly into the liver through the portal vein compared with the retroperitoneal adipose tissue, which drains into the systemic circulation. Thus, it is likely that free fatty acids (FFA), glycerol and other adipocytokines released from the ip adipose tissue may have peculiar effects on hepatic metabolism of glucose, triglycerides, insulin, and other substrates and hormones.

Another clear anatomical distinction exists between the sc adipose tissue located centrally in the truncal region and that in the peripheral region in the upper and lower extremities and in the hips. Although both the central and peripheral sc adipose tissue depots drain into the systemic circulation, accumulation of fat in these depots may confer different susceptibilities to developing insulin resistance. The total amount of fat present in the truncal region, called truncal fat, constitutes both the intraabdominal and intrathoracic fat depots as well as sc fat present in the thoracic and abdominal regions.

Originally, Vague (11) in 1947 initiated the concept of unique contribution of regional adiposity to metabolic complications. He described two patterns of body fat distribution based on somatotypes, i.e. android, or male pattern, and gynoid, or female pattern. Subsequently, he attributed different risk of metabolic complications to different patterns of body fat distribution in obese patients (12). In comparison with the gynoid obesity, android obesity was more frequently associated with diabetes mellitus, coronary artery disease, gout, and uric acid renal stones. Subsequently, the android pattern has also been referred to as the upper body, truncal, central, abdominal, or visceral obesity, and the gynoid pattern has been termed lower body, gluteo-femoral, or peripheral obesity.

To obtain an objective assessment of the regional adiposity (truncal or abdominal), various anthropometric methods have been suggested, such as the waist to hip circumference ratio, iliac to thigh circumference ratio, subscapular to triceps skinfold thickness ratio, and femoral to subscapular skinfold thickness ratio. Several epidemiological studies, including cross-sectional and longitudinal, have reported association of increasing waist to hip circumference ratio with hyperinsulinemia, impaired glucose tolerance, type 2 diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hyperuricemia (13, 14, 15, 16), and atherosclerotic vascular diseases (17, 18, 19, 20, 21, 22). Some investigators have attributed this association of increased waist circumference with metabolic complications to increased intraabdominal or visceral obesity. Bjorntorp (23) further proposed that the fat in the ip region (portal fat) may be more detrimental and may have a unique influence on insulin sensitivity. However, direct measurement of the volume or mass of visceral adipose tissue requires computed tomography (CT) or MRI techniques, and such measurements have not been conducted in population-based epidemiological studies.

The portal fat hypothesis was based on both a unique venous drainage of ip adipose tissue and its increased metabolic activity, particularly lipolytic activity, compared with other depots, such as sc and retroperitoneal adipose tissue. Thus, it was proposed that high FFA and glycerol flux from ip fat may reduce hepatic insulin sensitivity, increase hepatic glucose output, and affect hepatic lipid metabolism. According to Randle’s hypothesis (24), excessive FFA release may induce peripheral insulin resistance by inhibiting skeletal muscle glucose uptake. However, for the portal fat to affect peripheral insulin sensitivity, ip adipose tissue should contribute substantially more to the systemic FFA flux than other adipose tissue depots combined. In fact, ip adipose tissue (splanchnic fat) contributes only approximately 15% of the total systemic FFA flux; the majority of FFAs (~75%) are contributed by nonsplanchnic adipose tissue from the upper body, from the head, neck, trunk, and upper extremities (25). The contribution of lower extremities to systemic FFA flux is only about 10%. Women with upper body obesity had higher basal and postprandial FFA release rate than those with lower body obesity (26). Similarly, patients with type 2 diabetes had higher total systemic FFA flux than nondiabetic subjects (27). However, even in subjects with upper body obesity and those with type 2 diabetes, nonsplanchnic upper body adipose tissue contributed almost 75% of the total FFA to the systemic circulation (26, 27). Thus, these elegant kinetic studies of regional FFA flux (25, 26, 27) cast doubt on the impact of excess of ip adipose tissue on peripheral insulin sensitivity.

Another set of clinical studies has assessed the relationship between regional adiposity and insulin resistance in nondiabetic subjects with various degrees of obesity and in patients with type 2 diabetes by directly correlating the regional fat volume or mass with insulin-mediated glucose disposal rates measured during euglycemic, hyperinsulinemic, and glucose clamp studies. In the following discussion, such studies are reviewed in depth.


   Relationship of regional adiposity and insulin resistance (clinical studies)
Top
 Introduction
 Relationship of regional...
Conclusion
 References
 
The first requirement to study the relationship of regional adiposity to insulin resistance is to have reliable techniques to measure these two variables. The gold standard technique to measure insulin sensitivity is the euglycemic, hyperinsulinemic, glucose clamp study (28, 29). The rate of glucose disposal (Rd value) during the hyperinsulinemic phase of the study provides a measure of peripheral insulin sensitivity. Although most investigators report the Rd values as milligrams of glucose used per kg body weight per min, many others normalize the data for lean body mass (milligrams per kilogram of lean body mass per minute) (29). Most of the studies are performed choosing an insulin infusion rate of 40 mU/m2 body surface area·min to achieve a physiological level of serum insulin around 600 pmol/liter (100 µU/ml). At this level of hyperinsulinemia (~600 pmol/liter), endogenous hepatic glucose output is totally suppressed in normal healthy subjects, and thus, estimation of Rd values is highly accurate. However, endogenous hepatic glucose output may not be totally suppressed in patients with generalized and regional obesity at serum insulin concentrations of approximately 600 pmol/liter, which may introduce an error in the estimation of Rd values. Under such conditions, simultaneous infusion of either radiolabeled or stable isotopes of glucose, which allows for estimation of hepatic glucose output during the fasting condition and during the hyperinsulinemic phase, is required. An alternative way is to use higher rates of insulin infusion, e.g. 100 mU/m2·min, to achieve higher serum insulin concentrations to suppress hepatic glucose output even in those subjects who are expected to be insulin resistant. The suppression of hepatic glucose output during hyperinsulinemia also provides an estimate of hepatic insulin sensitivity.

Although anthropometric measurements such as skinfold thicknesses and body circumferences provide some information about central or peripheral adiposity, direct measurement of intraabdominal fat requires either CT or MRI, and these techniques have been validated (14, 30, 31, 32). Although some investigators have attempted to use dual energy x-ray absorptiometry or ultrasound to estimate intraabdominal fat, these estimations may not be reliable. Even with CT or MRI methods, different investigators have used different protocols to estimate intraabdominal fat. Some have used a single axial slice of CT or MRI. Most investigators have used an axial slice between the fourth and fifth lumbar vertebrae (L4–L5 level) or at iliac crest level (33, 34, 35, 36, 37, 38, 39), although we showed that intervertebral disc level L2–L3 is the best predictor of sc abdominal, ip, and retroperitoneal fat in men (40). Again, all other investigators have reported total intraabdominal fat without distinguishing between the ip and retroperitoneal compartments. Besides our studies (41, 42), only a few investigators have calculated total intraabdominal fat volume or mass from multiple slices of CT or MRI of the abdominal region (43, 44, 45, 46).

In view of the preceding discussion, only those studies that have used a euglycemic, hyperinsulinemic, glucose clamp study to estimate insulin sensitivity and either a CT or MRI method to estimate intraabdominal adiposity have been reviewed in this paper.

In the studies conducted by our group, the MRI method that involves scanning the entire abdominal region using contiguous axial 10-mm slices was used (41, 42). The MRI technique has several potential advantages over the CT scan for the estimation of adipose tissue mass besides lack of radiation exposure. The MRI provides a better definition of fat than CT scan because of a short T1 and a long T2 proton relaxation time of fat, which differ markedly from those of the other tissues. On T1-weighted MR images, adipose tissue is distinctly visualized as bright areas with high signal intensity that contrast with other tissues. The high cost certainly is a disadvantage of the MRI method.

Intraabdominal adipose tissue was distinguished and separated into ip and retroperitoneal adipose tissue compartments using anatomical points, such as ascending and descending colon, aorta, and inferior vena cava, by visual mapping of anatomical area of each slice on the computer screen using a track ball (mouse) (41). The pixels were counted in each compartment, i.e. sc abdominal, ip, and retroperitoneal, and were converted into a volume by multiplying the number of pixels by 0.04 cm3. Assuming the density of adipose tissue to be 0.9196 kg/liter (47), adipose tissue mass in each compartment was calculated.

Before we applied the MRI method to living humans, we documented its accuracy and precision in human cadavers (31). The masses of the three abdominal compartments estimated by this method were compared with those obtained by direct weighing of adipose tissue after dissection. The difference between MRI estimate and direct measurement by dissection was less than 5%. The intraobserver coefficient of variation for various adipose tissue compartments was less than 14% (31).

First, we studied the relationships between regional adiposity and insulin sensitivity in a group of nondiabetic, middle-aged men with varying degrees of obesity (41). We reported that compared with variation in ip fat mass, variation in sc abdominal fat mass was a better predictor of insulin sensitivity (Rd value). The sum of truncal skinfold thickness also was a better predictor of insulin resistance than ip, retroperitoneal, or peripheral sc fat. A strong relationship was also noted between sc truncal obesity and hepatic insulin sensitivity (41). Further analysis of the data revealed that posterior sc abdominal fat mass was a better predictor of insulin sensitivity than anterior sc abdominal fat mass (48). We then conducted similar studies in men with type 2 diabetes mellitus (T2DM), which also showed a strong relationship between amounts of sc truncal fat and Rd values (42).

Thus, using state of the art techniques to assess insulin sensitivity and measure intraabdominal fat, our results suggested only a minor role of ip fat in the causation of insulin resistance in men. Although the precise mechanisms for a strong relationship between sc truncal fat and insulin sensitivity are not entirely clear, a simple explanation may arise from anatomical considerations. The sc abdominal fat mass is approximately two times more than the ip fat mass in men, and the total sc truncal mass could be as much as 4–5 times larger than the ip fat mass (41, 42, 49). In women, sc abdominal area at the L4–L5 level is estimated to be more than 5 times that in the visceral fat area (49, 50, 51). Thus, presuming equal metabolic activity of sc truncal and ip fat, sc truncal fat should release more FFA and glycerol in the systemic circulation and have more influence on peripheral insulin sensitivity. As reviewed previously, kinetic studies of regional FFA metabolism in nonobese, obese, and T2DM subjects do reveal a major contribution to the total systemic FFA flux by upper body nonsplanchnic adipose tissue (25, 26, 27). The ip fat mass accounts for only approximately 10–11% and 5% of the total body fat mass in men and women, respectively (10). Therefore, for ip fat to have a unique influence on peripheral insulin sensitivity, it should be at least 10 times more active than sc fat to contribute more FFA and glycerol to the systemic circulation. The in vivo studies of regional FFA flux do not support an important role of splanchnic adipose tissue in contributing to systemic FFA flux (25, 26, 27, 52, 53).

A review of the data from other investigators is presented in Tables 1Go and 2Go. All other investigators have calculated visceral fat, which represents total intraabdominal fat, and have not attempted to quantify ip or retroperitoneal fat masses or volumes separately. Six of the eight groups of investigators who studied normal, nondiabetic healthy subjects have supported our observations and have revealed similar degree of relationships between Rd values and visceral fat or sc abdominal fat (Table 1Go) (33, 34, 35, 37, 38, 44). These investigators used different protocols to assess regional adiposity, including single or multiple slices of CT. These relationships were reported in both men and women. Only two groups of investigators reported a significant relationship between Rd value and visceral fat, but not with sc abdominal fat (36, 45, 46). Ross et al. (45, 46) used an MRI technique, whereas Brochu et al. (36) used a CT scan to assess regional adiposity. Interestingly, both of these groups were studying obese men and women only. The range of body mass index for women in the study by Brochu et al. (36) was 27–49; similarly, the range of body mass index in studies by Ross et al. (45, 46) was more than 27 for men and 26–38 for women. In contrast, all other investigators, including our studies, included both lean and obese men and women. It is likely that inclusion of a skewed population of subjects in the studies by Ross et al. (45, 46) and Brochu et al. (36) resulted in findings at variance with those of other studies.


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  		TABLE 1. Relationships among glucose disposal rates during euglycemic, hyperinsulinemic glucose clamp study, and abdominal adipose tissue compartments in nondiabetic, healthy subjects

 

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  		TABLE 2. Relationships among glucose disposal rates during euglycemic, hyperinsulinemic glucose clamp study, and abdominal adipose tissue compartments in patients with type 2 diabetes mellitus

 
Only two other groups of investigators besides us have studied the relationship between insulin sensitivity and regional adiposity in patients with T2DM (Table 2Go). Banerji et al. (43) reported significant relationships between Rd value and both visceral and sc abdominal fat in Africa-American men, but in women the relationship between Rd value and visceral fat achieved statistical significance. Miyazaki et al. (39), however, observed a similar degree of relationships between Rd values and visceral and sc abdominal fat in men, but not in women. The reasons for the discrepant results in men and women with T2DM are not clear. It is important to note that in the study by Banerji et al. (43), only 20 women were examined compared with 32 men, and the r value of –0.34 between the Rd and sc abdominal fat in women may have approached statistical significance. In the study by Miyazaki et al. (39), the precise r value between the Rd and sc abdominal fat in women was not reported. In our study only those patients who were receiving diet therapy were included, so as to avoid confounding effects of hypoglycemic medications on insulin sensitivity, but Banerji et al. (43) and Miyazaki et al. (39) also included patients receiving sulfonylurea therapy.


   Conclusion
Top
 Introduction
 Relationship of regional...
 Conclusion
References
 
It is well recognized that overall obesity causes insulin resistance. Some investigators have proposed that regional adiposity, particularly an excess of ip fat, contributes additionally to insulin resistance. Our results, which have been supported by other investigators, however, do not indicate that variation in ip or visceral fat has any unique effect on insulin sensitivity. Instead, our data support a role for excess sc truncal fat in causing insulin resistance in nondiabetic subjects as well as in patients with T2DM. Thus, our findings change the focus of the fat distribution-insulin resistance relationship from ip or portal fat to sc truncal fat. Because various adipose tissue depots may have unique characteristics related to differential expression of enzymes involved in triglyceride synthesis, lipolysis, adipocytokines synthesis, as well as other functions, molecular studies elucidating these differences may help in understanding the unique contributions of various adipose tissue depots to disorders of glucose and lipid metabolism.


   Footnotes
 
This work was supported in part by NIH Grants R01-DK-54387 and M01-RR-00633 and grants from the Southwest Medical Foundation.

Abbreviations: CT, Computed tomography; FFA, free fatty acid; MRI, magnetic resonance imaging; Rd, rate of glucose disposal; T2DM, type 2 diabetes mellitus.

Received April 13, 2004.

Accepted June 13, 2004.


   References
Top
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 Relationship of regional...
 Conclusion
 References
 

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