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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0694
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5336-5342
Copyright © 2005 by The Endocrine Society

Hyperglycemia Alters Tumor Necrosis Factor-{alpha} Release from Mononuclear Cells in Women with Polycystic Ovary Syndrome

Frank González, Judi Minium, Neal S. Rote and John P. Kirwan

Departments of Reproductive Biology (F.G., J.M., N.S.R.) and Medicine (J.P.K.), Schwartz Center for Metabolism and Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109

Address all correspondence and requests for reprints to: Frank González, MetroHealth Medical Center, Department of Obstetrics and Gynecology, Hamann S4-44, 2500 MetroHealth Drive, Cleveland, Ohio 44109. E-mail: fgonzalez{at}metrohealth.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Women with polycystic ovary syndrome (PCOS) are often insulin resistant and have chronic low-level inflammation.

Objective: The purpose of this study was to determine the effects of hyperglycemia on lipopolysaccharide (LPS)-stimulated TNF{alpha} release from mononuclear cells (MNC) in PCOS.

Design: The study was designed as a prospective controlled study.

Setting: The study was carried out at an academic medical center.

Patients: Sixteen reproductive age women with PCOS (eight lean, eight obese) and 14 age-matched controls (eight lean, six obese) participated in the study.

Main Outcome Measures: Insulin sensitivity (IS) was derived from a 2-h 75-g oral glucose tolerance test (ISOGTT). Percentage of truncal fat was determined by dual-energy absorptiometry. TNF{alpha} release was measured from MNC cultured in the presence of LPS from blood samples drawn fasting and 2 h after glucose ingestion.

Results: ISOGTT was lower in women with PCOS compared with controls (3.9 ± 0.4 vs. 6.3 ± 1.0; P < 0.03) and was negatively correlated with percentage of truncal fat (r = 0.56; P < 0.002). Truncal fat was greater in lean women with PCOS compared with lean controls (29.8 ± 2.6 vs. 23.8 ± 2.5%; P < 0.04). The TNF{alpha} response was different between obese and lean controls (–96.9 ± 21.2 vs. 24.4 ± 21.6 pg/ml; P < 0.03) and obese and lean women with PCOS (–94.1 ± 34.5 vs. 30.4 ± 17.6 pg/ml; P < 0.002). Fasting plasma C-reactive protein was elevated (P < 0.003) in obese PCOS and obese controls compared with lean controls.

Conclusion: An increase in abdominal adiposity and increased TNF{alpha} release from MNC after hyperglycemia may contribute to insulin resistance in lean PCOS patients. In contrast, obese PCOS patients have more profound chronic inflammation, and thus may have LPS tolerance that protects them from relatively mild excursions in blood glucose.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE POLYCYSTIC OVARY syndrome (PCOS) is the most common cause of female infertility and one of the most common endocrinopathies in women, affecting between 4 and 10% of reproductive age women (1, 2). The disorder is characterized by hyperandrogenism, chronic oligo- or anovulation and polycystic ovaries, with two of these three findings required to diagnose PCOS (3, 4). Insulin resistance is a predominant feature in PCOS, affecting as many as 70% of women with the disorder (4, 5). The compensatory hyperinsulinemia is considered to be the cause of hyperandrogenism in these individuals (6, 7). In addition, women with PCOS are often obese, which is strongly associated with insulin resistance and hyperglycemia (8, 9).

PCOS is a proinflammatory state as evidenced by elevated plasma concentrations of C-reactive protein (CRP) (10, 11). It remains controversial whether the elevated CRP levels observed in women with PCOS are a function of obesity (12, 13). In contrast, we have previously reported that in PCOS, plasma concentrations of the proinflammatory cytokine, TNF{alpha}, are elevated independent of obesity (14). Our findings have subsequently been corroborated by other investigators (15, 16).

In obesity-related diabetic syndromes, TNF{alpha} is overexpressed in adipose tissue (17, 18) and induces insulin resistance through acute and chronic effects on insulin-sensitive tissues. TNF{alpha} acutely truncates insulin receptor signaling in cultured adipocytes, hepatocytes, and skeletal muscle (19, 20, 21). Chronic exposure to TNF{alpha} decreases the expression of GLUT 4, the insulin-sensitive glucose transport protein (22). Because decreased GLUT 4 expression has been identified in PCOS, it is possible that TNF{alpha} contributes to this postreceptor defect (23, 24).

The source of excess circulating TNF{alpha} in PCOS is likely to be adipose tissue in the obese, but remains unknown in lean women with the disorder. Increased visceral adiposity has been proposed as a source of excess TNF{alpha} in lean women with PCOS. Although increased abdominal adiposity has been reported in lean women with PCOS, (25, 26, 27) there is a lack of consensus whether this increase is related to greater visceral adiposity in relation to peripheral fat (28, 29). Peripheral blood mononuclear cells (MNC) are known to migrate into adipose tissue to activate adipocyte TNF{alpha} production (30, 31). More importantly, it is now clear that the major source of TNF{alpha} in adipose tissue of the obese is MNC-derived macrophages present in the stromal-vascular compartment (31, 32, 33, 34). Thus, it is possible that in PCOS, MNC are an additional source of TNF{alpha} aside from adipose tissue.

Hyperglycemia may modulate TNF{alpha} release from MNC of women with PCOS. MNC exhibit increased oxidative stress in response to hyperglycemia, which, in turn, activates nuclear factor {kappa}B, a proinflammatory transcription factor that stimulates TNF{alpha} gene transcription (35, 36, 37). We previously have reported that hyperglycemia-induced alteration in lipopolysaccharide (LPS)-stimulated TNF{alpha} release from MNC is related to increased abdominal adiposity in insulin-resistant older men and obese reproductive age women (38, 39). However, this relationship has never been explored in PCOS.

Thus, we embarked on a study to determine the status of TNF{alpha} release from MNC in response to hyperglycemia in women with PCOS. We hypothesized that LPS-stimulated TNF{alpha} release from MNC is altered in women with PCOS in response to an oral glucose challenge compared with weight-matched controls, and that there is a relationship between MNC-derived TNF{alpha} release and measures of adiposity.


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

Sixteen women with PCOS (eight lean and eight obese) between 20–33 yr and 14 weight-matched control subjects (eight lean and six obese) between 20–40 yr volunteered to participate in the study. Obesity is defined as a body mass index (BMI) between 30–40 kg/m2. Lean subjects had a BMI between 18–25 kg/m2. The women with PCOS were diagnosed on the basis of oligo-amenorrhea and hyperandrogenemia after excluding nonclassic congenital adrenal hyperplasia, Cushing’s Syndrome, hyperprolactinemia, and thyroid disease. Polycystic ovaries were present on ultrasound in all subjects with PCOS. All control subjects were ovulatory as evidenced by regular menses and a luteal phase serum progesterone level greater than 5 ng/ml. All control subjects exhibited normal circulating androgen levels and the absence of polycystic ovaries on ultrasound.

All subjects were screened for diabetes or inflammatory illnesses, and none were taking medications that would affect carbohydrate metabolism or immune function for at least 6 wk before study participation. None of the subjects were involved in any regular exercise program for at least 6 months before the time of testing. All of the subjects provided written informed consent in accordance with the Case Western Reserve University and MetroHealth Medical Center guidelines for the protection of human subjects.

Study design

All study subjects reported to the General Clinical Research Center at MetroHealth Medical Center to undergo an oral glucose tolerance test (OGTT) between days 5 and 8 after the onset of menses. All subjects were provided with a healthy diet consisting of 50% carbohydrate, 35% fat, and 15% protein for three consecutive days (d 1–3) before the test. The test was performed on the morning of d 4 after an overnight fast of approximately 12 h. All subjects also underwent body composition assessment on the same day the OGTT was performed.

OGTT

Fasting baseline blood samples (5 ml each) were drawn for glucose and insulin determination. A 75-g glucose beverage was subsequently ingested over 10 min. Blood samples (5 ml each) were again drawn for glucose and insulin determination at 30, 60, 90, and 120 min after glucose ingestion. Upon completion of the test, subjects were fed a high carbohydrate snack. Plasma glucose concentrations were assayed immediately from the blood samples collected. Additional plasma was isolated from the fasting blood samples and stored at –70 C until assayed for CRP. Glucose tolerance was assessed by the World Health Organization criteria with normal glucose tolerance defined as a 2-h glucose-stimulated value less than 140 mg/dl (40). Insulin sensitivity (IS) was derived by ISOGTT using the following formula: 10,000 divided by the square root of (fasting glucose x fasting insulin) x (mean glucose x mean insulin) (41).

Body composition assessment

Height without shoes was measured to the nearest 1.0 cm. Body weight was measured to the nearest 0.1 kg. Waist circumference was measured at the level of the umbilicus and used to estimate abdominal adiposity (42). In addition, all subjects underwent dual-energy absorptiometry to determine percentage of total body fat and percentage of truncal fat using the QDR 4500 Elite model scanner (Hologic Inc., Waltham, MA). Truncal fat content was defined as the area between the dome of the diaphragm (cephalad limit) and the top of the great trochanter (caudal limit) (43).

Analytical methods

MNC isolation and culture were performed on a 20-ml blood sample drawn at 0 (pre) and 2 (post) h during the OGTT. The cells were isolated by Histopaque-1077 density gradient centrifugation (44), washed two times in pyrogen-free saline, resuspended in RPMI (0.3 mg/ml L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin) with serum substitute TCH, and seeded in coated culture plates (2.5 x 106 cells/ml). The cells were then incubated (humidified, 5% CO2, 37 C) for 24 h with LPS endotoxin (1 ng/ml). Cell supernatants (10,000 g for 2 min) were subsequently collected and stored at –70 C until analysis.

Plasma glucose concentrations were measured by the glucose oxidase method (YSI, Yellow Springs, OH), whereas plasma insulin concentrations were measured by a double antibody RIA (Linco Research, St. Charles, MO). LH, testosterone, androstenedione, and dehydroepiandrosterone-sulfate (DHEA-S) levels were measured by RIA (Diagnostic Products Corporation, Los Angeles, CA). Plasma CRP concentrations were measured by a high sensitivity ELISA (Alpha Diagnostics International, San Antonio, TX). TNF{alpha} concentrations were also measured by ELISA (BioSource International, Inc., Camarillo, CA). All samples from each subject were measured in duplicate in the same assay at the end of the study. The interassay and intraassay coefficients of variation for all assays were 7 and 12%, respectively.

Statistics

The StatView statistical package (SAS Institute, Cary, NC) was used for data analysis. The difference between the pre and postglucose challenge values for primary dependent variables such as TNF{alpha} release from MNC, was calculated to represent the maximum incremental change ({Delta} max). Descriptive data and the {Delta} max of variables were compared between groups using the unpaired Student’s t test or ANOVA for multiple group comparisons. Detection of significance by ANOVA was followed by a post hoc analysis using unpaired Student’s t tests between groups to identify the source of significance. Differences between pre and postglucose challenge variables within groups were analyzed using the paired Student t test. Correlation analyses were performed by linear regression using the method of least squares. All values are expressed as means ± SE. An {alpha}-level of 0.05 was used to determine statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Obese women with PCOS were similar in age compared with obese controls, whereas lean women with PCOS were slightly younger (P < 0.04) than lean controls (Table 1Go). All groups were similar in height. Weight, BMI, percentage of total body fat, and waist circumference were significantly (P < 0.03) greater in obese subjects compared with those who were lean whether or not they had PCOS, but were similar when women with PCOS were compared with weight-matched controls. The obese also exhibited a significantly (P < 0.0003) greater percentage of truncal fat compared with lean individuals whether or not they had PCOS. However, percentage of truncal fat was significantly (P < 0.04) greater in lean women with PCOS compared with lean controls.


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  		TABLE 1. Subject characteristics

 
Circulating levels of LH, testosterone, and androstenedione were significantly (P < 0.009) higher in women with PCOS compared with control subjects independent of body mass (Table 2Go). Circulating DHEA-S levels were significantly (P < 0.009) elevated in lean women with PCOS, but were similar in obese women with PCOS when compared with lean or obese control subjects. Levels of glucose while fasting and 2-h postglucose ingestion were similar in women with PCOS compared with controls independent of body mass. All subjects had a normal glucose response during the OGTT with 2-h glucose levels ranging between 62–134 mg/dl. Fasting insulin levels were significantly higher (P < 0.03) in the obese whether or not they had PCOS, but were similar when women with PCOS were compared with weight-matched controls.


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  		TABLE 2. Plasma hormone, glucose, insulin, and CRP levels

 
ISOGTT was significantly lower in women with PCOS compared with controls (3.7 ± 0.4 vs. 5.7 ± 0.9, P < 0.04). When subjects were grouped by body mass (Table 1Go), ISOGTT was significantly (P < 0.02) lower in the obese whether or not they had PCOS compared with lean controls. Lean women with PCOS also exhibited an ISOGTT that was significantly (P < 0.04) lower than that of lean controls but similar to that of either obese group. As depicted in Fig. 1Go, ISOGTT was negatively correlated with percentage of truncal fat (r = 0.56, P < 0.002) for the combined groups. ISOGTT was also negatively correlated with BMI (r = 0.58, P < 0.0009), percentage of body fat (r = 0.52, P < 0.004), and waist circumference (r = 0.38, P < 0.05) for the combined groups (data not shown).



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  		FIG. 1. Correlation between ISOGTT and percentage of truncal fat. Data are shown for the 14 control subjects and the 16 women with PCOS. {circ}, Control subjects; •, women with PCOS.

 
Fasting plasma concentrations of CRP were significantly (P < 0.009) higher in the obese whether or not they had PCOS (Table 2Go). CRP concentrations were also elevated in lean women with PCOS compared with lean controls, but not significantly. LPS-stimulated TNF{alpha} release from MNC in the fasting state was also similar when women with PCOS were compared with controls regardless of body mass. However, the oral glucose load resulted in significant (P < 0.03) suppression of LPS-stimulated TNF{alpha} release from MNC of lean controls and obese women with PCOS but no change in obese controls and lean women with PCOS (Table 3Go and Fig. 2Go). The {Delta} max TNF{alpha} response between obese and lean controls was significantly different (P < 0.03). There was also a significant difference (P < 0.002) between the diametrically opposite {Delta} max TNF{alpha} response of obese and lean women with PCOS. The {Delta} max TNF{alpha} response and ISOGTT were not correlated in control subjects, but were positively correlated with ISOGTT (r = 0.65; P < 0.007; Fig. 3Go) in women with PCOS. There was a positive correlation between the {Delta} max TNF{alpha} response and CRP levels in control subjects (r = 0.42, P < 0.02), and a negative correlation between these two parameters in women with PCOS (r = 0.52; P < 0.04) (data not shown).


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  		TABLE 3. TNF{alpha} release from MNC while fasting and in response to oral glucose challenge in control subjects and in women with PCOS

 


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  		FIG. 2. Incremental change in TNF{alpha} release (picograms per milliliter) from MNC cultured with LPS for 24 h when fasting samples (pre) were compared with the samples collected 120 min after glucose ingestion (post). *, Post was significantly lower than pre in lean controls and obese women with PCOS, P < 0.03. {dagger}, TNF{alpha} response to oral glucose challenge in lean controls was significantly different from that of obese controls, P < 0.003. {ddagger}, TNF{alpha} response to oral glucose challenge in lean women with PCOS was significantly different from that of obese women with PCOS, P < 0.002.

 


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  		FIG. 3. Correlation between the incremental change in TNF{alpha} release and ISOGTT in women with PCOS. Data are shown for 16 women with PCOS with normal glucose tolerance. {cjs2123}, Lean women with PCOS; •, obese women with PCOS.

 
As depicted in Fig. 4Go, control subjects exhibited a direct relationship between the MNC-derived {Delta} max TNF{alpha} response and percentage of truncal fat (r = 0.75, P < 0.002). There was also a direct relationship between the MNC-derived {Delta} max TNF{alpha} response and BMI (r = 0.66, P < 0.01), percentage of total body fat (r = 0.74, P < 0.003), and waist circumference (r = 0.78, P < 0.002) (data not shown). In contrast, women with PCOS exhibited an inverse relationship between the MNC-derived {Delta} max TNF{alpha} response and percentage of truncal fat (r = 0.55, P < 0.03; Fig. 4Go) as well as BMI (r = 0.77, P < 0.0005) and percentage of total body fat (r = 0.57, P < 0.03) (data not shown).



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  		FIG. 4. A, Correlation between the incremental change in TNF{alpha} release and percentage of truncal fat in control subjects. {cjs2123}, Lean controls; •, obese controls. B, Correlation between the incremental change in TNF{alpha} release and percentage of truncal fat in women with PCOS. {cjs2123}, Lean women with PCOS; •, obese women with PCOS. TNF{alpha} release was measured from LPS-stimulated MNC obtained at 0 and 120 min of an oral glucose challenge test. Abdominal obesity was estimated from percentage of truncal fat measured by dual-energy absorptiometry.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data clearly show that the MNC-derived TNF{alpha} response to physiological hyperglycemia of women with PCOS is diametrically opposite to that of control subjects. Obese controls demonstrate impairment of the normal suppressive response to LPS-stimulated TNF{alpha} release from MNC evident in lean controls under postprandial-like conditions. In contrast, lean women with PCOS have impaired suppression of TNF{alpha} release that is similar to obese controls. These findings provide further support for the role of inflammation in the development of insulin resistance, and that TNF{alpha}, in particular, may contribute to the decline in insulin action in obese controls and lean women with PCOS. The paradoxical suppression of LPS-stimulated TNF{alpha} release observed in obese women with PCOS may represent a preactivation of MNC known to occur in chronic inflammatory states. Furthermore, the independent associations of TNF{alpha} with BMI, percentage of total body fat, percentage of truncal fat, and waist circumference suggest that increased adiposity, especially increased abdominal adiposity, may be a key determinant of the observed differences in the MNC-derived TNF{alpha} response and its potential role in modulating insulin action.

The normal in vivo response of MNC to physiological hyperglycemia may be to suppress the release of TNF{alpha}. Lean controls showed a 70% decrease in LPS-stimulated TNF{alpha} release from MNC in response to hyperglycemia. We have previously reported similar results in young healthy lean men and women (38, 39). Decreased TNF{alpha} release from MNC may be a physiological benefit in the presence of hyperglycemia when there is a need to increase glucose disposal. TNF{alpha} is known to cause a decrease in insulin receptor tyrosine phosphorylation and an increase in serine phosphorylation of insulin receptor substrate-1 leading to inhibition of downstream insulin signaling and impairment of glucose uptake (18, 21). Thus, lean controls may be capable of facilitating glucose disposal by controlling TNF{alpha} release to optimize insulin signaling in the postprandial state.

The MNC of lean women with PCOS may have an impaired ability to down-regulate TNF{alpha} release in response to physiological hyperglycemia that is similar to obese controls. Both of these groups have a similar degree of insulin resistance based on ISOGTT. The elevated plasma CRP concentrations observed in lean women with PCOS and obese controls is consistent with previous reports and are indicative of being in a proinflammatory state (10, 45, 46, 47). In contrast, suppression of LPS-stimulated TNF{alpha} release in obese women with PCOS in response to physiological hyperglycemia may represent LPS tolerance of preactivated MNC. TNF{alpha} release from MNC increases during an acute response to inflammatory stimuli, but decreases during LPS tolerance due to persistent stimulation of MNC (48). LPS tolerance has been described in chronic inflammatory states such as in the late stages of sepsis, surgical recovery, and normal pregnancy (49, 50, 51). In these circumstances, the inflammation pathway is down-regulated through mechanisms that interfere with nuclear factor {kappa}B activation and subsequent transcription of TNF{alpha} (52, 53). The TNF{alpha} responses observed in the present study were derived from MNC studied in vitro raising a concern that they may not reflect physiology in vivo. In the case of LPS tolerance, however, reproduction of the in vivo phenomenon in vitro is well documented (48). The association between the change in TNF{alpha} release from MNC and CRP levels suggests that obese women with PCOS are chronically inflamed. Thus, the suppressed TNF{alpha} response observed in this group may be due to a more profound degree of chronic inflammation compared with obese controls and lean women with PCOS.

In PCOS, there may be a link between adiposity and MNC-derived TNF{alpha} release. There was a direct relationship between the change in TNF{alpha} release from MNC after physiological hyperglycemia and measures of adiposity, particularly abdominal adiposity in control subjects. Abdominal adiposity was also increased in lean women with PCOS. Activated MNC-derived macrophages are the major source of TNF{alpha} in excess adipose tissue, and are capable of inducing further TNF{alpha} production in adipocytes (32, 33, 34, 35). Inflamed adipose tissue, especially in the abdominal region, may perpetuate the inability to suppress MNC-derived TNF{alpha} release after hyperglycemia in lean women with PCOS and obese controls. These findings are consistent with previous observations in young adults demonstrating that changes in IS are a function of abdominal adiposity (54, 55). Indeed, our data demonstrate an inverse relationship between IS and abdominal adiposity. Thus, the uncontrolled TNF{alpha} release may, in turn, promote the insulin resistance observed in lean women with PCOS and obese controls.

In contrast, obese women with PCOS demonstrate a paradoxical relationship between MNC-derived TNF{alpha} release and both adiposity and IS. The change in TNF{alpha} release from MNC after physiological hyperglycemia was negatively correlated with measures of adiposity in women with PCOS for the combined weight groups, and was positively correlated with IS in obese women with PCOS. These findings reflect the suppressed TNF{alpha} response in obese women with PCOS that may reflect LPS tolerance. Thus, the combination of PCOS and increased adiposity in obese women with PCOS may result in a greater degree of chronic inflammation. Given the suppressed TNF{alpha} response, however, other factors such as free fatty acids may be involved in mediating insulin resistance in obese women with PCOS (56).

In conclusion, women with PCOS exhibit an altered MNC-derived TNF{alpha} response during physiological hyperglycemia in relation to adiposity. Lean women with PCOS respond in a fashion that is similar to obese controls by failing to suppress LPS-stimulated TNF{alpha} release when compared with lean controls. This unique observation may contribute to the metabolic abnormalities related to insulin resistance known to afflict many of these individuals. Suppression of LPS-stimulated TNF{alpha} release evident in obese women with PCOS may be due to LPS tolerance reflecting a greater degree of inflammation compared with lean women with PCOS and obese controls.


   Acknowledgments
 
We thank the nursing staff of the General Clinical Research Center for supporting the implementation of the study and assisting with data collection. We also thank Christine Marchetti for assistance with the graphics preparation.


   Footnotes
 
This research was supported by National Institutes of Health Grants HD-01273 (Women’s Reproductive Health Research Program) to the Department of Obstetrics and Gynecology at MetroHealth Medical Center and MO1 RR-080 to the General Clinical Research Center.

First Published Online June 28, 2005

Abbreviations: CRP, C-reactive protein; DHEA-S, dehydroepiandrosterone sulfate; IS, insulin sensitivity; LPS, lipopolysaccharide; MNC, mononuclear cells; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome.

Received March 30, 2005.

Accepted June 16, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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