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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1875
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1285-1291
Copyright © 2008 by The Endocrine Society

Abdominal Obesity in Older Women: Potential Role for Disrupted Fatty Acid Reesterification in Insulin Resistance

Catherine W. Yeckel, James Dziura and Loretta DiPietro

The John B. Pierce Laboratory (C.W.Y., L.D.) and the Departments of Epidemiology & Public Health (C.W.Y., L.D.) and Internal Medicine (J.D.), Yale University School of Medicine, New Haven, Connecticut 06519

Address all correspondence and requests for reprints to: Loretta DiPietro, Ph.D., M.P.H., The John B. Pierce Laboratory, 290 Congress Avenue, New Haven, Connecticut 06519. E-mail: ldipietro{at}jbpierce.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Excess abdominal adiposity is a primary factor for insulin resistance in older age.

Objectives: Our objectives were to examine the role of abdominal obesity on adipose tissue, hepatic, and peripheral insulin resistance in aging, and to examine impaired free fatty acid metabolism as a mechanism in these relations.

Design: This was a cross-sectional study.

Setting: The study was performed at a General Clinical Research Center.

Participants: Healthy, inactive older (>60 yr) women (n = 25) who were not on hormone replacement therapy or glucose-lowering medication were included in the study. Women with abdominal circumference values above the median (>97.5 cm) were considered abdominally obese.

Main Outcome Measures: Whole-body peripheral glucose utilization, adipose tissue lipolysis, and hepatic glucose production were measured using in vivo techniques according to a priori hypotheses.

Results: In the simple analysis, glucose utilization at the 40 mU insulin dose (6.3 ± 2.8 vs. 9.1 ± 3.4; P < 0.05), the index of the insulin resistance of basal hepatic glucose production (23.6 ± 13.0 vs. 15.1 ± 6.0; P < 0.05), and insulin-stimulated suppression of lipolysis (35 vs. 54%; P < 0.05) were significantly different between women with and without abdominal obesity, respectively. Using the glycerol appearance rate to free fatty acid ratio as an index of fatty acid reesterification revealed markedly blunted reesterification in the women with abdominal adiposity under all conditions: basal (0.95 ± 0.29 vs. 1.35 ± 0.47; P < 0.02); low- (2.58 ± 2.76 vs. 6.95 ± 5.56; P < 0.02); and high-dose (4.46 ± 3.70 vs. 12.22 ± 7.13; P < 0.01) hyperinsulinemia. Importantly, fatty acid reesterification was significantly (P < 0.01) associated with abdominal circumference and hepatic and peripheral insulin resistance, regardless of total body fat.

Conclusion: These findings support the premise of dysregulated fatty acid reesterification with abdominal obesity as a pathophysiological link to perturbed glucose metabolism across multiple tissues in aging.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
The putative relationship between excess abdominal adiposity and insulin resistance is amplified in women after menopause (1, 2) because older age is associated with increased fat deposition around the abdomen and the redistribution of fat from sc to visceral abdominal depots due to attenuating secretions of lipid-mobilizing sex steroid hormones. Upper body sc adipose tissue lipolysis is very active, accounting for the majority of peripherally circulating fatty acids (3, 4, 5). Therefore, persons with abdominal obesity often are characterized by higher levels of plasma free fatty acids (FFAs) than are individuals with adipose tissue distributed mainly in the lower body (5). Normally, insulin suppresses intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), while stimulating intravascular adipose tissue lipoprotein lipase (LPL) to enhance hydrolysis of circulating triglycerides and capture their fatty acids for storage after a meal (6, 7, 8, 9). Thus, a blunted ability for reesterification of fatty acids may be an important mechanism of the excess availability of FFAs with abdominal obesity. A consequence of elevated circulating FFAs is peripheral insulin resistance (8, 10, 11, 12). Likewise, deep abdominal (visceral) adipose tissue (particularly that drained by the portal vein) is especially responsive to lipolytic stimuli, thus creating the potential for an elevated delivery of FFAs to the liver with resulting minimized suppression of hepatic glucose production (HGP) and inhibition of hepatic insulin clearance (1, 10, 13). Resistance to insulin can develop simultaneously in adipose tissue, liver, and skeletal muscle; however, its severity may vary among these organs (12). This may be especially true in older age, during which time a greater degree of heterogeneity in functional decline often is observed relative to that in younger people.

Although the pathways linking excess abdominal adiposity and dyslipidemia to insulin resistance have been well documented, few studies have examined these relations in older people. We studied 25 healthy, inactive older women to: 1) determine the association between abdominal obesity and simultaneous measurements of adipose tissue, hepatic, and peripheral insulin resistance; and 2) examine the role of the impaired fat metabolism in response to insulin as a possible mechanism in these relations. A second aim of this study was to determine the influence of abdominal obesity on multiple tissue insulin resistance independent of overall body fat in older age.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Older (≥60 yr) women were recruited by advertisement from private older adult residential communities in Connecticut and from local community senior centers. Eligible study subjects included those who reported no regular (less than two times per week) physical activity for the previous 6 months, were nonsmokers, and not on hormone replacement therapy or glucose-lowering medication. Older volunteers were screened by their personal physician for cardiovascular disease, neuroendocrine disorders, and other uncontrolled chronic disease. A 75-g oral glucose tolerance test was performed according to the guidelines of the American Diabetes Association (14) to exclude frank type 2 diabetes. In addition, peak aerobic capacity was determined on a treadmill using a modified Balke protocol according to methods previously described by our laboratory (15). All protocols were approved by the Human Investigations Committee of Yale University School of Medicine, and all eligible study subjects gave written informed consent before their participation.

Body composition

Height and weight were measured on a stadiometer and balance beam scale, respectively, and the abdominal circumference (cm) was measured in triplicate at the umbilicus by the same examiner. This measure of abdominal adiposity is distinct from the commonly used waist circumference, which may misclassify older women as abdominally obese (i.e. false positives) by as much as 45% (16). In contrast, we have observed a strong correlation (r = 0.80–0.83; P < 0.001) between the abdominal circumference and the visceral fat area measured by computed tomography in our older female study populations (17), suggesting that this simple circumference measure is a good somatic indicator of visceral fat accumulation in older women as well as an adequate measure of total abdominal adiposity. An abdominal circumference more than or equal to 95 cm is roughly equivalent to a visceral fat area more than or equal to 100 cm2 (18), which is a standard risk cutpoint for cardiovascular health risk. Overall body composition [whole body muscle (kg) and fat mass (kg; %)] scans were obtained using dual-energy x-ray absorptiometry.

Euglycemic-hyperinsulinemic clamp

Whole-body insulin-stimulated glucose utilization was determined using a two-step euglycemic-hyperinsulinemic clamp according to methods described by DeFronzo et al. (19). For 3 d before the study, subjects were asked to avoid sustained moderate or vigorous activity and were provided a weight-standardized diet (~30 kcal/kg·d–1)) comprising 60% carbohydrate and 20% fat. Body weight was assessed during this 3-d period to ensure that subjects remained weight stable. To measure HGP, a [6,6–2H]glucose (99% enriched Cambridge Isotope Laboratories, Inc., Andover, MA) prime (18 µmol·kg–1) was given for 5 min at the beginning of a 2-h basal (equilibrium) period, followed by a constant infusion (0.22 µmol/kg·min–1), which was maintained throughout the baseline and remainder of the clamp procedure. To determine changes in peripheral lipolysis, a continuous infusion of [2H5]glycerol (0.2 µmol/kg·min–1) (99% enriched Cambridge Isotope Laboratories, Inc.) was given during the basal period and during the clamp to measure glycerol turnover. The infusion rate was chosen to ensure approximately 5% plasma enrichment. After the baseline period, regular human insulin (Squibb-Novo, Princeton, NJ) was infused as a primed-continuous low-dose infusion (10 mU·m–2·min–1) for 120 min, followed by a higher dose infusion (40 mU·m–2·min–1) for 120 min. Simultaneously, a primed-variable infusion of glucose (20% dextrose) was started and the rate adjusted to maintain plasma glucose at approximately 100 mg/dl–1during hyperinsulinemia. Blood samples for determining HGP and glycerol turnover were collected before the tracer infusions and at 10-min intervals during the last 30 min of the basal period and last 30 min of each step of hyperinsulinemia. Plasma insulin, glycerol, and FFA concentrations were determined at baseline and every 30 min throughout the study. Plasma glucose concentrations were determined every 5 min. All clamps were performed in the General Clinical Research Center of Yale University-New Haven Hospital under medical supervision.

Blood analyses

Samples were centrifuged at 4 C, and the plasma was stored at –70 C until analyzed in the Core Laboratory of the General Clinical Research Center. Plasma glucose concentrations were analyzed using the glucose oxidase method (YSI 2300; Yellow Springs Instruments Co., Yellow Springs, OH). Plasma immunoreactive insulin concentrations were determined with a double antibody RIA (Diagnostic, Webster, TX). Plasma concentrations of FFAs were determined by standard microflourimetric procedures (Sigma-Aldrich, St. Louis, MO). Blood samples for the determination of glucose kinetics (20) and glycerol turnover (21) were analyzed by standard procedures at the Diabetes Endocrinology Research Center of Yale University School of Medicine.

Calculations

The rate of whole-body insulin-stimulated glucose utilization (M value) (mg/kg lean mass·min–1) under low and higher dose insulin infusion was calculated from the average glucose infusion rate during the final 60 min of each step and was corrected for changes in the glucose pool sizes according to methods described by DeFronzo et al. (19). The glucose appearance rate (Ra) was calculated from plasma [6,62H]glucose enrichments and the rate of tracer infusion by the equation: Ra = [(atoms percent excess (APE) infusate/APE plasma glucose) – 1]·F, where F represents the isotope infusion rate (µg·kg–1·min–1). HGP was then calculated as the difference between Ra and the glucose infusion rate. The index of the insulin resistance of glucose production (IRGP) was calculated as the product of basal HGP (Ra over the final 30 min of the basal period) and basal insulin to characterized hepatic insulin resistance under fasting conditions (22). Glycerol turnover was calculated from plasma [2H5]glycerol and the rate of tracer infusion by the equation: Ra = [(APE infusate/APE plasma glycerol) – 1]·F. The ratio of the glycerol appearance rate (Raglyc) (normalized for total mass or for fat mass) to circulating FFA concentrations over the duration of the clamp was calculated to determine whether there was proportional lipolysis to FFA availability under insulin stimulation, and was used as a novel index of fatty acid reesterification.

Fat and carbohydrate oxidation

Continuous (i.e. 30 min) indirect calorimetry by the ventilated hood technique (Sensormedics, Anaheim, CA) was performed before and during the last 30 min of each step of the clamp (e.g. 90–120 and 210–240 min). Resting metabolic rate (RMR) was determined from expired air and expressed as kilocalories per kg of lean mass over 24 h. Fat and carbohydrate oxidation was estimated from the respiratory quotient (RQ): CO2/O2.

Analysis

Univariate statistics (mean ± SD) first were generated on all study variables. Simple correlations among the study variables were tested using simple linear regression and the Spearman rank order correlation coefficient. For descriptive purposes, the abdominal circumference was then dichotomized according to the median value (≤/> 97.5 cm), and cross-sectional differences in the levels of all study variables were compared between the two groups using a t test for independent samples. We next used multivariable ANOVA modeling to determine the role of abdominal obesity in insulin resistance independent of total fat mass (kg). Statistical significance was set at an {alpha}-level of 0.05. Data were analyzed using SAS Windows, 9.1 (SAS Institute, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
On average, older women with and without abdominal obesity were similar with regard to age (72 ± 4 vs. 74 ± 4 yr, respectively) and level of aerobic capacity (21.3 ± 3.9 vs. 19.1 ± 3.3 ml/kg·min–1, respectively). Given that the level of lean mass was similar between groups, the significant group difference in body weight likely was attributable to the greater relative and absolute amounts of overall body fat in women having an abdominal circumference more than 97.5 cm (Table 1Go).


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  		TABLE 1. Anthropometric values by level of abdominal adiposity

 
The abdominal circumference and total fat mass were highly intercorrelated (r = 0.83; P < 0.001). Overall, the abdominal circumference was significantly correlated with the Ra under basal (r = –0.54; P < 0.01) and low insulin stimulation (r = –0.60; P < 0.001), and with the Raglyc/FFA index under both low (r = –0.61; P < 0.001) and higher (r = –0.77; P < 0.0001) dose insulin stimulation. Abdominal adiposity was only modestly correlated with the peripheral rate of glucose utilization (M value) during these same conditions (–0.44 > r > –0.35). Interestingly, however, when the data were stratified by median level of abdominal circumference, the M value at the 40-mU insulin dose was significantly different between women with and without abdominal obesity (6.3 ± 2.8 vs. 9.1 ± 3.4 mg/kg lean·min–1; P < 0.05).

The RMR was similar between older women with and without abdominal obesity (33 ± 19 vs. 31 ± 17 kcal/kg lean·24 h–1, respectively), as was the basal RQ (0.83 ± 0.06 vs. 0.81 ± 0.06), and the RQ at both low- (0.85 ± 0.06 vs. 0.83 ± 0.04) and high-dose (0.91 ± 0.08 vs. 0.91 ± 0.09) insulin infusion, indicating a reasonable level of muscle metabolic flexibility in both groups under insulin stimulation. Together, these data suggest that these abdominally obese women had compromised glucose uptake, combined with disrupted nonoxidative glucose storage.

The low-dose insulin clamp was used to determine adipose tissue and hepatic insulin sensitivity more precisely. Rates of HGP were similar between groups under basal conditions; however, the index of the IRGP was significantly greater in the abdominally obese women compared with the leaner women (P < 0.05; Table 2Go). Insulin suppression of HGP during the low-dose infusion was blunted in women with abdominal obesity compared with those without, although this difference was of marginal statistical significance (58 vs. 81%; P < 0.06).


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  		TABLE 2. Hepatic glucose production at low-dose insulin by level of abdominal circumference in older women

 
With regard to adipose tissue lipolysis, the Raglyc was identical between the two groups under basal conditions; however, during the low-dose insulin phase (0–120 min) of the clamp, we observed a significantly greater rate of appearance in older women with excess abdominal adiposity (0.19 ± 0.09 vs. 0.13 ± 0.07 mg/kg·min–1; P < 0.05), indicating that low-dose insulin was not as effective in suppressing adipose tissue lipolysis in these women compared with the women without abdominal obesity. Indeed, during low-dose insulin infusion, women with abdominal obesity achieved only 35% glycerol suppression, in contrast to the 54% suppression observed in the women without abdominal obesity (P < 0.05). With higher dose insulin infusion, both groups achieved more than or equal to 50% glycerol suppression. When the Ra glycerol data were normalized for total fat mass, group differences in adipose tissue lipolysis essentially disappeared (0.44 ± 0.12 vs. 0.44 ± 0.13 mg/kg·min–1). Similar to the glycerol data, suppression of plasma FFA concentrations during low-dose insulin infusion was significantly blunted in women with excess abdominal adiposity compared with those without (P < 0.01; Fig. 1Go), even though basal FFA concentrations were similar between groups.


Figure 1
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  		FIG. 1. Insulin-stimulated suppression of FFAs by the level of abdominal circumference during the euglycemic-hyperinsulinemic clamp. *, Between-group differences P < 0.05; and **, P < 0.01 based on the t test for independent samples.

 
Because fat oxidation was similar between groups, we examined the glycerol Ra normalized for prevailing FFA concentrations (Raglyc to FFA ratio). The intent of this novel index was to determine whether adipose tissue response to insulin stimulation was proportional between the two groups (albeit, lower in the abdominally obese group). During the basal period of the clamp, the Raglyc to FFA ratio was similar between groups when Raglyc was expressed per kg of body weight, but was significantly lower in the women with abdominal obesity when expressed per kg of fat mass (0.98 ± 0.29 vs. 1.35 ± 0.47; P < 0.02). These group differences in the Raglyc to FFA ratio remained present under low- (2.58 ± 2.75 vs. 6.76 ± 5.69; P < 0.02) and high-dose (4.46 ± 3.70 vs. 12.22 ± 7.13; P < 0.01) insulin infusion, suggesting that abdominally obese women had a blunted ability for reesterification of fatty acids under basal and insulin-stimulated conditions compared with their nonobese counterparts. Individual changes in the Raglyc to FFA ratio with insulin stimulation are presented in Fig. 2Go and present a more striking picture. Although we observed no statistical correlation between the glycerol Ra per se and either hepatic or peripheral insulin sensitivity, this Raglyc/FFA index was significantly correlated with both hepatic (–0.51 ≤ r ≤ –0.60; P < 0.01) and peripheral insulin sensitivity during both low (r = 0.45; P < 0.03) and higher (r = 0.65; P < 0.01) insulin stimulation.


Figure 2
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  		FIG. 2. Individual changes in the Raglyc/FFA index under basal and insulin-stimulated conditions by level of abdominal adiposity. The ratio of Ra glycerol (mg·min–1) adjusted for total fat mass (kg) over FFA (µmol·liter–1) concentration. To convert to Systeme International units (µmol), multiply glycerol values by 10.86.

 
The association between excess abdominal adiposity and the insulin-stimulated Raglyc/FFA index, as well as plasma FFA suppression, remained statistically significant after adjustment for total fat mass in the multivariable modeling (Table 3Go). In contrast, group differences in several other estimates of insulin resistance were attenuated, suggesting the continued importance of overall body fat to multitissue insulin resistance in aging. However, these main effects were distorted by the fact that the distinct influence of total fat mass on insulin resistance appeared to vary by level of abdominal girth (Fig. 3Go). For instance, total fat was strongly correlated with the M value in women with low abdominal fat, but not in women with abdominal obesity. Together, these findings indicate the distinct and independent connection between abdominal obesity and insulin resistance via enhanced fatty acid availability.


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  		TABLE 3. Hyperinsulinemic responses in older women by abdominal circumference, adjusted for total body fat mass

 

Figure 3
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  		FIG. 3. The association between total fat mass and hepatic insulin resistance under basal (A) and low insulin (B) stimulation, between fat mass and peripheral insulin sensitivity (C), and between fat mass and adipose tissue reesterification (D), all by level of abdominal adiposity. Solid circles and lines indicate an abdominal circumference less than or equal to 97.5 cm. Open circles and dashed lines represent an abdominal circumference more than 97.5 cm. IRGP is under basal conditions. HGP is at the low insulin dose. The ratio of Ra glycerol (mg·min–1) adjusted for total fat mass (kg) over FFA (µmol·liter–1) concentration. To convert to Systeme International units, multiply glucose values by 5.5 or glycerol values by 10.86. M40mU, Glucose utilization rate under higher insulin stimulation; ns, not significant.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We know of few studies in older people that have measured insulin resistance simultaneously at the level of adipose tissue, liver, and skeletal muscle using highly precise in vivo techniques. We examined insulin responses in older women specifically as a function of excess abdominal adiposity. HGP, as well as peripheral glucose uptake, was less responsive to insulin stimulation in the women with abdominal obesity, indicating central fat deposition compounds the impact of aging on glucose metabolism. Furthermore, both hepatic and peripheral responses were linked not to impaired suppression of lipolysis per se but, presumably, to the inability for adipose tissue to retain and/or capture fatty acids, thereby increasing their availability in the circulation. Importantly, we measured directly the RMR, fat oxidation rate, lean mass, and level of cardiorespiratory fitness (peak aerobic capacity) and observed no differences in these factors between women with and without abdominal obesity. Therefore, we are confident that one or more of these factors did not influence the abdominal obesity/insulin resistance phenotype in older age; rather, these data suggest that reesterification of fatty acids under insulin-stimulated conditions is likely a distinct dysfunction in these older women. Indeed, the consequent increase in fatty acid availability (i.e. low Raglyc/FFA index) observed in the abdominally obese older women under both low and higher dose insulin stimulation was highly correlated with impaired action of insulin in the liver and at the periphery, regardless of total body fat.

Adipose tissue is heterogeneous with regard to lipolysis in vivo, with upper-body adiposity being more metabolically active than lower-body fat (5, 23). Even so, the "hyperlipolysis" of visceral fat over sc abdominal fat may be a myth related to the strong statistical correlation between visceral fat and several metabolic complications (5). In fact, several studies have implicated upper-body sc fat (compared with leg or splanchnic fat) as the primary contributor to systemic FFAs in both lean and obese humans under postabsorptive conditions (23, 24, 25). Furthermore, this distinct adipose tissue distribution can exist in older age in the absence of frank overall obesity, as was the case with most of our older women.

As stated previously, older women with abdominal obesity showed a markedly attenuated insulin-stimulated glucose uptake; however, women in both groups maintained a similar level of muscle metabolic flexibility to insulin, as demonstrated by a comparable shift from basal fat oxidation to the predominance of carbohydrate utilization with insulin stimulation. This profile of compromised glucose uptake with adequate metabolic flexibility is in contrast to the typical middle-aged obese phenotype (26), and, therefore, our results suggest an additional mechanism to that of an excess burden on muscle mitochondrial function with abdominal obesity in aging (27). In fact, the net result of lower glucose uptake but similar levels of carbohydrate oxidation in our older female subjects suggests a defect in insulin-stimulated nonoxidative storage with excess abdominal adiposity. Together, increased fatty acid availability in the abdominally obese older women appears to impede both glucose uptake and glucose partitioning toward storage. Interestingly, the poor glucose uptake but similar magnitude of disposal by oxidation is in accord with the pathophysiology of insulin resistance observed in obese adolescents (28).

The role of abdominal adiposity (visceral and/or sc) to insulin sensitivity independent of overall obesity is complex and controversial (3, 4, 29, 30, 31, 32, 33), especially because these two variables are so highly intercorrelated and often obscure the contributions of each other to insulin resistance when present in the same statistical model. More importantly, we observed that total body fat was indeed associated with hepatic and peripheral insulin resistance, but only in women having low abdominal adiposity. Among older women with abdominal obesity, the additional contribution of total fat mass was marginal.

In general, the proportion of FFAs delivered specifically to hepatic tissue is positively correlated with visceral fat area, especially among older women. In obese subjects, visceral fat can contribute about 20–30% of FFAs delivered to the liver, whereas only about 15% of systemic FFAs are derived from the visceral depot (25). Therefore, the contribution of visceral lipolysis to peripheral FFA is limited even in obesity, and, thus, although visceral obesity per se could contribute specifically to hepatic insulin resistance, it is unlikely to be related directly to insulin resistance at the periphery (5).

Several links between abdominal obesity and insulin resistance have been described (12, 34, 35). Presumably, excess FFA release relative to low metabolic demand with obesity creates defects in metabolic regulation initiated, at least in part, by ectopic fat deposition. A recent study by Boden et al. (13) has demonstrated that high levels of peripherally circulating fatty acids can also greatly diminish the ability of insulin to shut off the flux of glycogenolysis-derived HGP. Moreover, excess fatty acid availability early in the postprandial period (when it is normally suppressed by insulin) is estimated to influence glucose uptake by as much as 50% (7). Typically, insulin exerts an inhibitory effect on adipose tissue lipolysis via HSL, while in a coordinated fashion stimulates adipose tissue LPL to enhance intravascular hydrolysis of circulating triglycerides and capture their fatty acids for storage. Our finding of less-efficient insulin-stimulated fatty acid reesterification in the presence of abdominal obesity suggests that the inability to suppress lipolysis via HSL is likely not the primary defect with regard to adipose tissue (and consequent multitissue) insulin resistance observed in these older women. This interpretation is in accord with tracer and arteriovenous balance investigations under insulin conditions (9, 36, 37). Thus, our findings are consistent with the notion that increased efficiency of reesterification may decrease fatty acid availability and thereby improve insulin sensitivity.

A dual tracer approach was not incorporated into the design of this study, so we do not know the specific rates of appearance of the fatty acids from which to estimate adipose tissue intracellular triglyceride-fatty acid cycling; although during an insulin clamp, fatty acid concentrations have been highly correlated with the rate of appearance of fatty acids (38). Likewise, it is possible that fatty acids are taken up and reesterified at a higher rate in nonadipose tissues in the women without abdominal obesity. However, this would serve to increase ectopic triglyceride concentrations (e.g. intramuscular triglyceride), which would be inconsistent with the greater insulin sensitivity observed in this group. It should be stressed here that the Raglyc/FFA index is not appropriate under all physiological conditions but was feasible in the present study due to similarities in fat oxidation under conditions of insulin stimulation. Our findings, and those of others, support the premise that dysregulated adipose tissue metabolism in older women with abdominal obesity demonstrates a pathophysiological link to perturbed glucose metabolism across multiple tissues, although the influence of regional over total body fat is difficult to disentangle completely. Furthermore, we identified a unifying factor (i.e. poor insulin stimulation of fatty acid reesterification) that was associated with abdominal obesity, as well as both hepatic and peripheral insulin resistance in these older women, regardless of total body fat. Although we are unable to quantify the specific contribution of the visceral relative to the sc abdominal depot to these putative relationships, the Raglyc to FFA ratio does reflect peripherally circulating fatty acids and, most likely, the inability of sc abdominal adipose tissue to retain LPL-derived triglyceride fatty acids (9, 36). Data presented here demonstrate the importance of preventing the accumulation of excess abdominal fat with age because there was a clear potential for additional multitissue insulin resistance burden.


   Acknowledgments
 
We thank Jodi L. Crimmins, Anne Marie Cheatham, Jennifer Fawcett, and the nursing and technical staffs of the Hospital Research Unit of the Yale University Center for Clinical Investigations, and the Yale University Diabetes Endocrinology Research Center for their technical expertise, and the study subjects for their commitment to this research. We also thank David Chinkes, Ph.D., for his thoughtful comments on an earlier draft of this manuscript.


   Footnotes
 
This work was supported by Grants RO1 AG.17163 (to L.D.), MO1 RR.00125, P30 AR.46032, and P30 DK.45735.

Present address for J.D.: Yale University Center for Clinical Investigation, 2 Church Street South, New Haven, Connecticut 06519.

Disclosure Statement: The authors have nothing to disclose.

First Published Online January 15, 2008

Abbreviations: APE, Atoms percent excess; F, isotope infusion rate; FFA, free fatty acid; HGP, hepatic glucose production; HSL, hormone sensitive lipase; IRGP, insulin resistance of glucose production; LPL, lipoprotein lipase; M value, rate of whole-body insulin-stimulated glucose utilization; Ra, glucose appearance rate; Raglyc, glycerol appearance rate; RMR, resting metabolic rate; RQ, respiratory quotient.

Received August 21, 2007.

Accepted January 9, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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