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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:1393-1401 (2007)
© 2007 The Gerontological Society of America

Fat Distribution and Glucose Metabolism in Older, Obese Men and Women

Sophie E. Yeo, Nicholas P. Hays, Richard A. Dennis, Patrick M. Kortebein, Dennis H. Sullivan, William J. Evans and Robert H. Coker

1 Nutrition, Metabolism, and Exercise Laboratory, University of Arkansas for Medical Sciences, Little Rock. 2 Geriatric Research, Education, and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock.

Address correspondence to Robert H. Coker, PhD, Nutrition, Metabolism, and Exercise Laboratory, DWR Institute on Aging, 4301 W. Markham, Slot 806, University of Arkansas for Medical Sciences, Little Rock, AR 72205. E-mail: cokerrobert{at}uams.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Previous studies have identified relationships between subcutaneous abdominal fat (SAF), visceral fat (VF), and insulin resistance. In addition, lower muscle attenuation and decreased adiponectin have also been associated with insulin resistance.

Methods. In order to define these relationships within a group of older, obese adults, we studied 48 individuals (20 men; 71 ± 1 years and 28 women; 65 ± 1 years) who underwent a single, hyperinsulinemic, euglycemic clamp procedure, computed tomography scan at the L4-L5 level, and whole-body plethysmography or dual energy x-ray absorptiometry. Endogenous glucose production (basal glucose Ra) was also measured at baseline and during the clamp procedure using an infusion of [6,62H2] glucose.

Results. Mean body mass index (BMI; 31 ± 1 kg/m2) and glycosylated hemoglobin A1c (HbA1c; 5.7 ± 0.1%) levels were not significantly different between men and women. In men, there was an inverse relationship between SAF and insulin-stimulated glucose disposal (ISGD) (r = –.60, p =.01). In addition, there was a trend between thigh muscle attenuation and ISGD in men (r =.41, p =.07). Adiponectin was associated with ISGD in men (r =.46, p =.04) and women (r =.48, p =.01). There were no significant relationships between body fat distribution and basal glucose Ra in men or women, and no relationships between triglycerides and glucose metabolism.

Conclusions. Our results indicate that (i) SAF was negatively associated with ISGD in men, (ii) thigh muscle attenuation demonstrated a trend toward ISGD in men, and (iii) adiponectin was associated with ISGD in men and women.

The combination of obesity and the aging process represents an increased risk for defects in insulin action at multiple levels. The pathogenesis of insulin resistance in type 2 diabetes is normally initiated by a chronic elevation in caloric balance that facilitates increased storage of adipose tissue. In turn, excess adiposity has been linked to insulin resistance, hypertension, dyslipidemia, type 2 diabetes, and cardiovascular disease (1,2). Despite considerable evidence linking obesity to insulin resistance, the mechanisms responsible for the associations between excess adipose tissue and defects in insulin action in the liver and the muscle remain unresolved, especially in older adults.

Epidemiological studies that compared waist-to-hip circumference ratio and body mass index (BMI) were among the first to suggest the greater pathogenic influence of abdominal adiposity compared to overall obesity (3). However, more specific analysis of abdominal fat has resulted in some investigators proposing visceral fat (VF) as the primary culprit of insulin resistance (4,5) while others suggest a plausible role for subcutaneous abdominal fat (SAF) (6,7). More specifically, regional variations in the metabolic activity of fat cells have been recognized (8). As such, VF may be particularly toxic in terms of facilitating excess endogenous glucose production (glucose Ra) and reducing hepatic extraction of insulin (9). Although subcutaneous thigh fat may be associated with a protective, insulin-sensitizing role (10), the diminishing association between thigh fat and insulin resistance after adjustment for VF or SAF also suggests that abdominal adiposity has an overwhelming influence on the risk of type 2 diabetes (11).

It is well established that regional fat distribution varies by gender (12), and this may have an additional influence on the risk of type 2 diabetes in older people. In a large prospective study, central adiposity was more strongly associated with the incidence of diabetes in women than in men (13). Moreover, age-related changes in adipose tissue lipolytic activity may influence the role of regional fat distribution in insulin resistance (14). Whether gender affects the relationship between regional fat distribution and glucose metabolism (exaggerated endogenous glucose production and impaired peripheral insulin action) in older adults is not well characterized.

While excess adipose tissue contributes to insulin resistance, adiponectin, a cytokine secreted from adipose tissue, may have a protective role (15). As such, adiponectin seems to have a negative influence on the accumulation of lipids in skeletal muscle (16), and these lipids are strongly implicated in the pathogenesis of insulin resistance (17). In studies using skeletal muscle attenuation characteristics (Hounsfield units [HU]) derived from computed tomography (CT) scans, lower attenuation values represent the infiltration of lipid into skeletal muscle (18–20), and increased risk of insulin resistance in obese, middle-aged men and women (6). Therefore, the objective of our study was to examine the relationship between VF, SAF, skeletal muscle attenuation, plasma adiponectin, lipids, and glucose metabolism in older, obese men and women.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Participants
Forty-eight obese individuals, 20 men (71 ± 1 years) and 28 women (65 ± 1 years), with a mean BMI of 31 ± 1 kg/m2 were studied. [Pre- and postintervention data on the influence of dietary and/or exercise interventions on insulin-stimulated glucose disposal (ISGD) and an evaluation of insulin sensitivity indices compared to ISGD have been published previously (21–23).] Exclusion criteria included an elevated creatinine level and a serum glutamate pyruvate transaminase >2 times normal.

It is important to realize that obese volunteers often have other medical conditions. Thus, it would be impractical to exclude all persons taking medications, and we cannot ethically discontinue the use of all medications for the duration of the intervention (see Table 1 for a complete list of medications). As a result, we permitted the concomitant use of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors, thiazide diuretics, and/or antidepressant selective serotonin reuptake inhibitors. Participants taking gemfibrozil (or other fibrates), niacin, statins, or other pharmaceuticals that might have potential effects on carbohydrate or lipid metabolism were excluded. We also excluded any individual with a chronic inflammatory condition and/or malignancy or any person taking corticosteroids. Furthermore, patients with a history of coronary artery or cerebrovascular disease were excluded from the study.


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  		Table 1. Clinical Characteristics of Older, Obese Men and Women.

 
All research volunteers were recruited from the greater Little Rock area using local newspaper advertisements and flyers posted around the community and within The University of Arkansas for Medical Sciences (UAMS). Potential volunteers were screened over the telephone according to the above mentioned exclusion criteria. Upon arrival for testing according to eligibility criteria, all volunteers signed a screening consent and completed a medical examination. Those persons deemed eligible for the study were fully informed of the experimental procedures and possible risks associated with our research project, and were required to sign an informed consent form prior to participation. All study procedures and materials were approved by the Human Research Advisory Committee at UAMS and the Central Arkansas Veterans Healthcare System.

Oral Glucose Tolerance Test
A standard 2-hour oral glucose tolerance test (OGTT) was completed during the medical screening to determine participant eligibility, with a 2-hour plasma glucose of 100–199 mg/dL being required to qualify for the study. Glucose tolerance was assessed over a 2-hour period following the ingestion of 75 g of dextrose. According to the American Diabetes Association (24), a 2-hour plasma glucose concentration > 200 mg/dL is a classic indicator of type 2 diabetes; therefore, any volunteers with this symptom were excluded.

Body Weight and Composition
Total body mass was measured to the nearest 0.1 kg using an electronic scale (Ohaus, Pine Brook, NJ). Because these cross-sectional data were derived from two different intervention-based studies, we used either whole-body plethysmography (Bod-Pod; Life Measurement, Inc., Concord, CA) (men: n = 15, women: n = 24), or dual energy x-ray absorptiometry (DXA, Hologic QDR 4500W; Bedford, MA) (men: n = 5, women: n = 4) to determine fat mass and lean tissue mass, based on the study in which the volunteer was enrolled. It is important to mention that the data derived from Bod-Pod and DXA methodologies are highly correlated (r = 0.94) with a mean difference of 2.2% (25). ISGD data were calculated relative to lean tissue mass.

CT
VF, SAF, and skeletal muscle attenuation were determined from CT scans. The images from these scans allowed fat, lean tissue, and bone to be clearly identified and quantified. The scans were completed using a GE High-Speed Advantage scanner (General Electric Medical Systems, Milwaukee, WI). A lateral scout was used to identify the L4-L5 vertebral disc space, and a cross-sectional 10-mm scan was obtained using 280 mA. Total VF was determined using public domain imaging software (NIH Image available by FTP at zippy.nimh.nih.com). VF was highlighted and computed using an attenuation range of –190 to –30 HU. Total SAF cross-sectional area was determined by identifying the area between the skin and the external-most aspect of the abdominal muscle wall. The CT images obtained were digitized by HU density to separate fat, muscle, and bone compartments using the NIH Image program on a Macintosh Centris 660AV computer. A 10 mm axial scan of the skeletal muscle was obtained, and the location of the scan was derived as the distance between the anterior superior iliac crest and the inferior margin of the patella divided by 2. The calculation of skeletal muscle attenuation of the thigh was based on the mean HU of the pixels using a muscle density range of between 0 and 100 HU. In our laboratory, the coefficient of variation for the measurement of muscle and fat area is 1.0%–1.5%.

Blood samples for determination of plasma adiponectin were drawn after an overnight fast and immediately prior to the euglycemic, hyperinsulinemic clamp procedure. Blood plasma was immediately frozen and stored at –80°C, then later analyzed for plasma adiponectin by radioimmunoassay (RIA) (Linco Research, Inc., St. Charles, MO). This assay has a sensitivity of 0.01 mg/dL and intra- and interassay coefficients of variation of < 8%.

Glucose Metabolism
ISGD was derived using the hyperinsulinemic, euglycemic procedure (26). The hyperinsulinemic, euglycemic clamp technique raises insulin to postprandial concentrations, and represents the condition in which the majority of glucose disposal occurs (26). Total ISGD was corrected for glucose Ra by using a constant rate infusion of labeled glucose ([6,6-2H2] glucose) (27).

An 18-gauge intravenous catheter was inserted into the arm for insulin, dextrose, and [6,6-2H2] glucose infusions. A 20-gauge intravenous catheter was inserted retrograde into the contralateral hand for the sampling of arterialized blood, using a heated hand box at ~38°C. A priming dose of [6,6-2H2] glucose was given, followed by a constant rate infusion for 240 minutes. An infusion of Humulin R (Eli Lilly, Indianapolis, IN) began with a priming dose for 2 minutes followed by a lower dose prime, with a constant rate infusion of 40 mU/m2/min for the remaining 110 minutes of the hyperinsulinemic, euglycemic clamp procedure. A variable rate 20% dextrose infusion was used to maintain euglycemia based on plasma glucose samples taken at 5-minute intervals during the clamp procedure. A mixture of 8 mg of [6,6-2H2] glucose per g of 20% dextrose was used to prevent a marked decrease in glucose enrichment and a subsequent underestimation of glucose appearance (27). All glucose enrichments were determined using gas chromatography mass spectrometry.

Glucose Ra was estimated for the basal period and modified for nonsteady-state estimations (27) using the original equations of Steele (28). The M-value (adjusted for lean tissue mass) or ISGD was determined during the last 30 minutes of the 120-minute clamp procedure by subtracting glucose Ra from the exogenous glucose infusion rate. Indirect calorimetry was used to calculate oxidative and nonoxidative disposal (29).

Statistical Analysis
Reported values are mean ± standard error of the mean (SEM). Differences in mean values between men and women were compared by unpaired Student t test. We used Pearson correlation coefficients to assess the association between fat distribution, skeletal muscle attenuation, plasma adiponectin, and the indices of glucose metabolism (glucose Ra and ISGD).


   RESULTS
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 Abstract
 Methods
 Results
Discussion
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Participant Characteristics
A total of 48 obese, older men (20 men; 71 ± 1 years) and women (28 women; 65 ± 1 years) were recruited for this study (Table 2). As expected, female participants had a greater percentage of total body fat than did the male participants. There was no significant difference in age, BMI, or HbA1c levels between men and women (Table 2).


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  		Table 2. Number of Individuals on Pharmaceutical Therapy.

 
Adipose Tissue and Glucose Metabolism
Although VF was higher in men than in women, SAF was higher in women than in men (Table 2). No relationship existed between VF and ISGD in men (r = –0.25, p =.27) (Figure 1A). However, SAF was inversely related to ISGD in men (r = –0.60, p =.01) (Figure 1A). There was no relationship between VF or SAF and ISGD in women (Figure 1B). Neither SAF nor VF correlated with basal glucose Ra in men (Figure 2A). Although there was no relationship between VF and basal glucose Ra, there was a surprising and counterintuitive inverse relationship between SAF and basal glucose Ra in women (r = –0.41, p =.03) (Figure 2B).


Figure 01
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  		Figure 1. Relationships between visceral fat and subcutaneous abdominal fat, and insulin-stimulated glucose disposal in older, obese men (A) and women (B). Trend line indicates a significant inverse correlation coefficient between subcutaneous abdominal fat and insulin-stimulated glucose disposal in men (r = –0.60, p =.01). There was no significant relationship between visceral fat and insulin-stimulated glucose disposal in men (r = –0.25, p =.27). FFM = fat-free mass

 

Figure 02
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  		Figure 2. Relationships between visceral fat and subcutaneous abdominal fat, and basal glucose Ra in older, obese men (A) and women (B). Trend line indicates a significant inverse correlation coefficient between subcutaneous abdominal fat and basal glucose Ra in women (r = –0.41, p =.03)

 
Muscle Attenuation and Glucose Metabolism
There was a trend between thigh skeletal muscle attenuation and ISGD in men (r = 0.41, p =.07) (Figure 3). A significant relationship between thigh skeletal muscle attenuation and ISGD could not be identified in women (Figure 3).


Figure 03
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  		Figure 3. Relationships between thigh skeletal muscle attenuation and insulin-stimulated glucose disposal in older, obese men and women. Trend line indicates trend between thigh skeletal muscle attenuation and insulin-stimulated glucose disposal in men (r = 0.41, p =.07). FFM = fat-free mass; HU = Hounsfield units

 
Adiponectin and Glucose Metabolism
There was a significant positive relationship between adiponectin and ISGD in men (r = 0.46, p =.04) and women (r = 0.38, p <.05) (Figure 4). Adiponectin was not associated with basal glucose Ra in either men or women (Figure 5).


Figure 04
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  		Figure 4. Relationships between plasma adiponectin and insulin-stimulated glucose disposal in older, obese men and women. Trend line indicates significant correlation coefficient between plasma adiponectin and insulin-stimulated glucose disposal in men (r =.46, p =.04) and women (r = 0.48, p =.01). FFM = fat-free mass

 

Figure 05
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  		Figure 5. Relationships between plasma adiponectin and basal glucose Ra in older, obese men and women. No significant correlation coefficients were determined

 
Triglycerides and Glucose Metabolism
There were no significant associations between triglycerides and glucose metabolism ISGD (Figure 6) or glucose Ra (Figure 7) in men or women.


Figure 06
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  		Figure 6. Relationships between plasma triglycerides and insulin-stimulated glucose disposal in older, obese men and women. No significant correlation coefficients were determined. FFM = fat-free mass

 

Figure 07
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  		Figure 7. Relationships between plasma triglycerides and basal glucose Ra in older, obese men and women. No significant correlation coefficients were determined

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study was completed to address potential relationships among abdominal fat distribution, thigh skeletal muscle attenuation, adiponectin, and glucose metabolism in older, obese men and women. The results of our study suggest that excessive SAF and reduced skeletal muscle attenuation are inversely related to ISGD in men. Although we found a positive correlation between plasma adiponectin and ISGD in men and women, it was somewhat surprising that we found no associations between VF and ISGD in either men or women.

We did not observe a relationship between VF and ISGD in older, obese men or women. Our findings were initially somewhat unexpected, especially in light of the previous studies reporting powerful associations between VF and insulin resistance (5,30,31). On the contrary, others have found more limited correlations between VF and insulin action (6,7,27). To some extent, the disparity between these associations may be due to the marked differences in VF between the cohorts [i.e., 190 cm2 in one study (31) and 62 cm2 in the other (27)]. In a large cohort of older men and women, the threshold for VF associated with increased metabolic risk was ~195 cm2 and ~162 cm2, respectively (32). As the level of VF in our study exceeded those in previous studies (256 ± 25 cm2 in men and 232 ± 10 cm2 in women), it is difficult to explain our findings regarding VF and ISGD. One potential explanation is that the relatively homogenous VF stores in our obese participant population may limit the influence of VF on insulin action. Nevertheless, it is important to appreciate that VF is merely a marker of metabolic dysregulation, and the interplay between hormonal and metabolic activity of these fat cells in terms of FFA delivery and cytokine secretion may be far more important in the prediction of insulin resistance (8).

Previous studies suggest that SAF may be a useful indicator of insulin action (6,7). Associations between SAF and insulin sensitivity are, however, less robust in older obese populations with increased risk of insulin resistance (32). In the present study, we identified an inverse correlation between SAF and ISGD in older men, but no relationships were apparent in older women. Our findings are supported by those of Brochu and colleagues (31), who failed to identify an association between SAF and glucose disposal in older, obese, postmenopausal women. However, it was not questioned whether such a relationship exists in men. In a cohort of obese, middle-aged participants, superficial SAF comprised a greater proportion of the overall amount of SAF in women, compared to men, and deep, but not superficial SAF had a strong relationship with insulin resistance (33). While we were not able to distinguish between these two fat depots in our elderly obese volunteers, it is possible that, due to its primarily superficial SAF composition, the adverse effects of deep SAF are diluted, so that excess SAF in women is simply not characterized by the insulin-resistant properties of SAF in men.

Reduced skeletal muscle attenuation is a marker of increased muscle lipid content (19) and a strong predictor of insulin resistance in younger populations (6). We identified a trend between thigh muscle attenuation and ISGD in older male participants, but not in their female counterparts. Weak associations between muscle attenuation and glucose disposal have previously been reported in both obese premenopausal women (34). Muscle attenuation values derived from CT scans do not distinguish between intramuscular triglycerides (IMTG) and extramuscular triglycerides (EMTG). IMTG, as assessed by magnetic resonance spectroscopy, increases with aging, and is inversely related to ISGD (35). One should also recognize that IMTG-derived metabolites (i.e., long-chain fatty acyl coenzyme As, diacylglycerols, protein kinase C theta, and ceramides) may be more important in the attenuation of ISGD than the increase in IMTG (36).

Adiponectin is thought to have insulin-sensitizing properties (37), and multiple cytokines and hormones act synergistically to regulate adiponectin synthesis and secretion (8,38). Given the previously reported positive relationship between adiponectin and ISGD in obese populations (39), our data are quite supportive of continued similar relationships in obese, older individuals. It is also important to note that participants in the previous investigation were younger than those in our study, and female participants were underrepresented. It should be mentioned, though, that in a comprehensive analysis of individuals 18–81 years old there was a positive association between adiponectin and ISGD, and that adiponectin did not seem to change as a function of age (37). Our data support the contention that adiponectin remains a consistent predictor of ISGD, even among a group of older individuals within a very close age and BMI range.

Our study highlights gender as an important factor to contemplate when considering SAF, muscle attenuation, and/or adiponectin as predictors of insulin action in older, obese men and women. Previous studies have suggested that waist-to-hip ratio is closely associated with insulin resistance (40) and the risk for type 2 diabetes in obese women (41). In addition, our findings indicate that practitioners should also consider regional fat distribution specific to gender when assessing the potential risk of insulin resistance in their older patients. The mechanisms responsible for the apparent gender differences are not clear, especially when considering the lack of any association between VF and ISGD in either men or women. One interpretation is that the negative impacts of regional fat and/or muscle attenuation on insulin action are minimized by the positive insulin-sensitizing influence of adiponectin in women (16). In addition to adiponectin, it is possible that sex hormones may explain the different factors influencing ISGD in men and women (42). Unfortunately, we did not measure these hormones in the present study, and are therefore unable to clarify their potential role in our results.

With the exception of the inverse relationship between basal glucose Ra and SAF in women, we did not identify any associations between adipose tissue distribution, or adiponectin and basal glucose Ra in older, obese men or women. Our measurement of basal glucose Ra provides only an indirect assessment of hepatic insulin action. Using a more definitive approach in a population with type 2 diabetes and marked hepatic insulin resistance, a recent study used multistage insulin infusion and found a positive association between abdominal fat distribution and insulin sensitivity at the liver (43). Even though this study used a more direct approach to examine insulin action at the liver, interpretation of the results is still challenging due to two primary factors. First, their study population with type 2 diabetes exhibited excessive hepatic insulin resistance compared to our obese population. Second, there is no control regarding glucagon secretion and its influence on glucose Ra. In order to clearly identify associations between abdominal adipose tissue and glucose Ra, a more sophisticated method to selectively examine hepatic insulin action in humans is warranted.

The present study is limited by the cross-sectional design that precludes direct mechanistic conclusions regarding the importance of adipose tissue distribution, muscle attenuation, lipids, and/or the role of adiponectin in the pathogenesis of insulin resistance. Well-controlled, longitudinal studies in older, obese men and women are required. In addition, a more specific method to selectively examine hepatic and peripheral insulin action in humans is needed.

Our findings suggest that gender may be an important factor toward the complex interplay between abdominal adipose tissue and ISGD. Finally, the consistent significant relationship between adiponectin and ISGD in men and women may demonstrate the protective role of this adipokine in an older, obese population.


   Acknowledgments
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 Abstract
 Methods
 Results
 Discussion
 References
 
This work was supported by National Institutes of Health grants KO1 DK 64716-01 (RHC), RO1 AG 19346-01 (WJE), and F32 AG 21374 (NPH), and by American Heart Association grant SDA 0335172N (RHC). We also acknowledge the support of the University of Arkansas for Medical Sciences General Clinical Research Center funded through grant M01 RR14288.


   Footnotes
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 Results
 Discussion
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Decision Editor: Luigi Ferrucci, MD, PhD

Received October 3, 2006

Accepted March 25, 2007


   References
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 Discussion
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