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Original Studies |
Unitat de Diabetologia, Endocrinologia i Nutricio, University Hospital of Girona Dr. Josep Trueta, 17007 Girona; Unitat d’Endocrinologia, Hospital of Tarragona Joan XXIII, Facultat Medicina, Institut d’Estudis Avançats, Universitat Rovira i Virgili, 43007 Tarragona, Spain
Address all correspondence and requests for reprints to: J. M. Fernandez-Real, M.D., Ph.D., Unitat de Diabetologia, Endocrinologia i Nutricio, University Hospital of Girona Dr. Josep Trueta, Carretera de França s/n, 17007 Girona, Spain. E-mail: endocrino{at}htrueta.scs.es
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Abstract |
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The plasma IL-6 concentration was significantly and similarly associated with systolic (SBP) and diastolic (DBP) blood pressure, fasting insulin, and the fasting insulin resistance index (FIRI) in all subjects. When smokers were excluded from the analysis, plasma IL-6 levels correlated with percent fat mass (r = 0.19; P = 0.02), absolute fat mass (r = 0.17; P = 0.03), SBP, DBP, fasting insulin levels, and FIRI. The latter associations persisted after controlling for body mass index (r = 0.15 and r = 0.19; P = 0.02 and P = 0.0004 for SBP and DBP, respectively; r = 0.24 and r = 0.19, P = 0.004 and P = 0.03, for fasting insulin and FIRI, respectively).
Gender and smoking status significantly influenced the results. Although IL-6 levels were significantly associated with fasting insulin and FIRI in men, these significant correlations were not observed in women. Conversely, although IL-6 levels were significantly associated with SBP and DBP in women, these coefficients were not statistically significant in men. All of these associations were lost among smokers and remained significant in nonsmokers.
As IL-6 is the major mediator of the acute phase response by hepatocytes and induces the synthesis of C-reactive protein (CRP), we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all the subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS), in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers. For insulin and FIRI they were stronger in women and in nonsmokers. CPR significantly correlated with the WHR only in men (r = 0.22; P = 0.01).
Using multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of its variance in men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, only SBP (P = 0.04) contributed to 5% of its variance. When CRP was introduced into the model, again only SBP (P = 0.01) contributed to 10% of the variance in IL-6 levels.
In 25 of these subjects, insulin sensitivity was determined using the frequently sampled iv glucose tolerance test with minimal model analysis, and circulating IL-6 levels were strongly associated with the insulin sensitivity index (r = -0.65; P < 0.0001). Again, this relationship was even stronger in men (r = -0.75; P < 0.001) and was not significant in women (r = -0.26; P = NS). In all of these subjects, only insulin sensitivity (P = 0.0037), not fat mass, contributed to 21% of the variance of IL-6 levels in a multiple linear regression analysis.
In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitute a significant proatherogenic cytokine. The mechanisms of these associations should be further investigated.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Elevated IL-6 levels are associated with mortality in the elderly (8), and Yudkin et al. speculated that IL-6 is the link among obesity, inflammation, stress, and coronary heart disease (9). This link may be mediated through insulin resistance. Administration of recombinant human IL-6 to normal subjects induces the metabolic changes found in catabolic states, increasing plasma glucose levels in a dose-dependent fashion without changing plasma insulin or C peptide concentrations (10). In another study in cancer patients, administration of recombinant human IL-6 led to an increase in the metabolic clearance of glucose (11). In vitro, IL-6 induced a dose-dependent inhibition of the glucose-stimulated insulin release of rat pancreatic islets (12, 13). All of these findings are in contrast with the increased IL-6 levels that have been described in patients with cancer along with insulin resistance (14) or the higher plasma IL-6 concentrations in patients with the insulin resistance syndrome and type 2 diabetes (15, 16, 17). Furthermore, we have described differences in insulin sensitivity among apparently healthy subjects that have been attributed to constitutive variations in the transcription rates of this cytokine (18). To clarify the physiological role of IL-6 in insulin resistance we aimed to study its circulating levels in 228 otherwise healthy men and premenopausal women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Two-hundred and twenty-eight subjects (96 women) were evaluated between July 1 and September 15, 1997, as a part of an ongoing epidemiological study. None of the subjects was taking any medication or had any evidence of metabolic disease other than obesity. All subjects were of Caucasian origin and reported that their body weight had been stable for at least 3 months before the study; all were normotensive and normolipemic. Inclusion criteria were 1) body mass index (BMI; weight in kilograms divided by the square of height in meters) less than 40 kg/m2, 2) absence of any systemic disease, and 3) absence of any infections in the previous month. Smokers were defined as any person consuming at least 1 cigarette a day in the previous 6 months. Resting blood pressure was measured after subjects had been in a sitting position for a minimum of 15 min using a mercury sphygmomanometer and was read three times on the right arm by the same investigator. The mean of three measurements was used for this study. Liver disease and thyroid dysfunction were specifically excluded by biochemical work-up. All women had regular menstrual cycles. The protocol was approved by the hospital ethics committee, and informed consent was obtained from each subject.
Anthropometric measurements
All subjects were evaluated by BMI and waist to hip ratio (WHR). Each subject’s waist was measured with a soft tape midway between the lowest rib and the iliac crest. The hip circumference was measured at the widest part of the gluteal region.
Fat mass and percent fat mass were calculated using bioelectric impedance (Holtain BC Analyzer, Cambridge, UK).
Determination of insulin sensitivity through the minimal model analysis
In a subset of 25 subjects, randomly selected by sex (13 men and 12 premenopausal women; all nonsmokers; mean age, 37.1 ± 7.9; mean BMI, 29.8 ± 5 kg/m2; fasting glucose, 5.4 ± 0.9 mmol/L; fasting insulin, 12.6 ± 7 mU/L; IL-6, 9.2 ± 6 pg/mL), insulin sensitivity was measured using the frequently sampled iv glucose tolerance test. In brief, the experimental protocol started between 0800 and 0830 h after an overnight fast. A butterfly needle was inserted into an antecubital vein, and patency was maintained with a slow saline drip. Basal blood samples were drawn at -30, -10, and -5 min, after which glucose (300 mg/kg BW) was injected over 1 min starting at time zero, and insulin (Actrapid, Novo, Copenhagen, Denmark; 0.03 U/kg) was administered at 20 min. Additional samples were obtained from a contralateral antecubital vein until 180 min as previously described (18).
Analytical methods
The serum glucose concentration was measured in duplicate by the glucose oxidase method. The serum insulin level was measured in duplicate by monoclonal immunoradiometric assay (Medgenix Diagnostics, Fleunes, Belgium). The lowest limit of detection was 4.0 mU/L. The intraassay coefficient of variation was 5.2% at a concentration of 10 mU/L and 3.4% at 130 mU/L. The interassay coefficients of variation were 6.9% and 4.5% at 14 mU/L.
Insulin resistance was then calculated through the fasting insulin resistance index (FIRI): fasting glucose (mmol/L) x fasting insulin (mU/L)/25. In our experience, FIRI correlates with the insulin sensitivity index calculated from a frequently sampled iv glucose tolerance test with minimal model analysis (r = 0.79; P < 0.0001; n = 40).
Total serum cholesterol was measured through the reaction of cholesterol esterase/cholesterol oxidase/peroxidase. Total serum triglycerides were measured through the reaction of glycerol phosphate oxidase and peroxidase. Serum C-reactive protein (Beckman Coulter, Inc., Fullerton, CA) was determined by routine laboratory tests. Serum IL-6 was measured using a commercial immunoassay (MEDGENIX IL-6 EASIA, Biosource Technologies, Inc., Europe S.A., Fleunes, Belgium), with coefficients of variation less than 6%.
Statistical analysis
Descriptive results of continuous variables are expressed as the
mean ± SD. Before statistical analysis, normal
distribution and homogeneity of the variances were tested. Parameters
that did not fulfill these tests (IL-6, CRP, and insulin sensitivity)
were log-transformed. We used the 
2 test for
comparisons of proportions. Comparison of variables between groups of
subjects was performed using Student’s t test.
Relationships between variables were also sought by stepwise
multivariate linear regression analysis with forward selection. Smoking
status was introduced as a categorical variable (0 = nonsmoker;
1 = smoker). The level of statistical significance was set at
P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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. In all subjects, circulating IL-6
levels were significantly and similarly associated with systolic (SBP)
and diastolic (DBP) blood pressure, fasting insulin, and FIRI (Table 2), but not with fat mass or percent fat
mass. IL-6 was not significantly associated with BMI, WHR, or glucose,
cholesterol, or triglyceride levels. However, WHR and triglyceride
levels tended to be positively associated with IL-6 levels among men
(P = 0.08 and P = 0.084,
respectively).
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). The latter associations
persisted after controlling for BMI (r = 0.15 and r = 0.19;
P = 0.02 and P = 0.0004 for SBP and
DBP, respectively; r = 0.24 and r = 0.19; P =
0.004 and P = 0.03, for fasting insulin and FIRI,
respectively). Although IL-6 levels were significantly associated with
fasting insulin or FIRI in men, these significant correlations were not
observed in women (Table 2). Conversely, although IL-6 levels were
significantly associated with SBP and DBP in women, these coefficients
were not statistically significant in men. All of these associations
were lost among smokers and remained significant in nonsmokers (Table 2
and Fig. 1).
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As IL-6 is the major initiator of the acute phase response by hepatocytes and induces the synthesis of CRP, we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS) in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers, and for insulin and FIRI were stronger in women and nonsmokers. CRP significantly correlated with WHR only in men (r = 0.22; P = 0.01).
In a multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of the variance in IL-6 men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, in the first model SBP (P = 0.04), but not smoking status, FIRI, or fat mass, contributed to 5% of the variance in IL-6. When CRP was introduced into the model, again SBP (P = 0.01), but not FIRI, fat mass, or CRP, contributed to 10% of the variance in IL-6 levels.
In the 25 subjects in whom insulin sensitivity was determined using the
frequently sampled iv glucose tolerance test with minimal model
analysis, BMI was statistically different from the mean BMI of the
total population studied, because we selected 50% lean (BMI, <25
kg/m2) and 50% obese (BMI, >30
kg/m2) subjects. In these subjects, circulating
IL-6 levels were strongly associated with the insulin sensitivity index
(r = -0.65; P < 0.0001; Fig. 2). Again, this relationship was even
stronger in men (r = -0.75; P < 0.001) and was
not significant in women (r = -0.26; P = NS). In
all of these subjects, in a multiple linear regression in a stepwise
manner to predict circulating IL-6, only insulin sensitivity
(P = 0.0037), not fat mass, contributed to 21% of the
variance in IL-6.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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In contrast, blood pressure was the only significant and independent predictor of IL-6 levels in women. A similar sexual dimorphism has been confirmed in a recent study. Straub et al. found that blood pressure independently predicted serum IL-6 levels in women, but not in men (7). IL-6 stimulates the central nervous system and the sympathetic nervous system, which may result in hypertension (20, 21). In recent studies the administration of IL-6 led to increased heart rate in healthy women and increased norepinephrine levels and heart rate in women with fibromyalgia (22). However, other mechanisms cannot be excluded. IL-6 might increase in concert with the modification of the redox state of the vascular wall in chronic hypertension, as occurs in some hypertensive animal models (23).
According to our findings, the activity of the sympathetic nervous system, grossly measured by blood pressure, even within the normal range was a significant contributor to peripheral IL-6 levels in women, but not in men. In the latter, smoking and insulin resistance were significant and independent predictors of peripheral IL-6 levels. Tappia et al. had already demonstrated that smoking influences cytokine production (24). We found that men who were smokers showed significantly higher IL-6 levels (9.6 ± 7.6 vs. 6.2 ± 6.6; P = 0.013) and similar BMI (24.9 ± 4.2 vs. 25.3 ± 3.5; P = 0.6) compared with nonsmokers. In fact, smoking was the main confounding factor in the relationship between measures of body fat and circulating IL-6 levels. In previous studies, abdominal arterial IL-6 was associated with BMI (3). Vgontzas et al. reported that plasma IL-6 levels were higher in obese patients with sleep apnea, but not in obese controls compared with normal weight controls (6). Straub et al. found that the relationship between BMI and serum IL-6 was only observed in postmenopausal women, and this relationship was lost among those women with hormone replacement (7). Estrogens are well known inhibitors of IL-6 secretion (25). As proposed by Straub et al. (7), adipose tissue-derived estrogens in postmenopausal women would not be sufficient to reduce IL-6 in a similar way as endogenous estrogens in premenopausal women, i.e. those subjects who have been evaluated in this study.
In this study we report that serum IL-6 and insulin action, evaluated using the frequently sampled iv glucose tolerance test with minimal model analysis, are associated in healthy volunteers. We are only aware of 1 preliminary study in Pima Indians (26). Hanson and Pratley evaluated insulin sensitivity in 45 healthy Pima Indians and found that IL-6 reflects insulin resistance independently of obesity (26). We extend this observation to a greater number of subjects in our population. In this study IL-6 levels were found to be associated with fasting insulin and the fasting insulin resistance index after controlling for BMI, absolute fat mass, and percent fat mass in men. IL-6 levels independently contributed to the variance in insulin sensitivity determined using minimal model analysis in a sample of subjects. The mechanism involved in these associations remains to be elucidated. Glucose-dependent IL-6 production by human peripheral blood monocytes has been demonstrated in 1 study, but 33 mmol/L glucose induced only a 1.56-fold increase in IL-6 compared with treatment with 11 mmol/L glucose (27). Thus, this mechanism is not operative in our study subjects with normal fasting glucose levels. As stated above, adipose tissue contributes to approximately one third of circulating IL-6 levels (3), and probably in this context the coefficients of correlation between IL-6 levels and the degree of insulin resistance are not very high. In fact, immune, endothelial, and several other cells contribute to circulating IL-6. Acute infections determine insulin resistance, and even after clinical recovery some impairment in carbohydrate metabolism persists (28). Both IL-6 action (13) and acute infections (28) are characterized by a defect in insulin-stimulated glucose utilization despite normal carbohydrate oxidation. We cannot exclude that chronic or subclinical infections contribute simultaneously to increased IL-6 levels and insulin resistance in men.
Several lines of evidence suggest, however, that obesity per se constitutes a low grade inflammatory state. Elevated CRP levels have consistently been demonstrated in overweight and obese adults, even among young adults aged 17–39 yr (29). The relationship between CRP and insulin might be due to insulin resistance itself. Insulin attenuates IL-6-type cytokine stimulation of most acute phase protein genes in human hepatoma cells (30). Thus, the relative lack of insulin action, as found in insulin resistance, would not be able to block IL-6 actions, leading to a prolonged acute phase reaction.
We reported that CRP was associated with several metabolic parameters in men and women, but in a multiple linear regression analysis CRP was associated independently with IL-6 only in men. Interestingly, both constitutive and IL-6-dependent acute phase expression of the human CRP transgene require testosterone in transgenic mice, implying a potential mechanism for this gender dimorphism (31).
The link between insulin resistance and inflammation has been viewed as a disease of the innate immune system (32). We have speculated that insulin resistance is inherent to a prolonged acute phase response that replaces the normal physiological mechanisms with new set-points that presumably contribute to defensive or adaptive capabilities (33).
In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitutes a significant proatherogenic cytokine, as further suggested by recent studies in which the serum IL-6 concentration was an independent predictor of cardiovascular mortality. The mechanisms of these associations should be further investigated. In evolutionary terms, these findings are in agreement with the hypothesis that IL-6 belongs to a network of signals that provide thriftiness, preserving substrates (glucose) for brain metabolism. A genetic and phenotypic predisposition to inflammation could have been beneficial for our ancestors in the response to starvation and injury (33).
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Note Added in Proof |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Received September 15, 2000.
Revised October 31, 2000.
Accepted November 10, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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, in vivo. J Clin Endocrinol Metab. 82:4196–4200.This article has been cited by other articles:
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