C-reactive protein and features of metabolic syndrome in Brazilian women with previous gestational diabetes

Diabetes Research and Clinical Practice 78 (2007) 23–29 www.elsevier.com/locate/diabres

C-reactive protein and features of metabolic syndrome in Brazilian women with previous gestational diabetes Taˆnia B. Ferraz a,b,*, Rosa S. Motta a,b, Camila Lousada Ferraz a,b, Diego Moreira Capibaribe a,b, Adriana C. Forti a,b, Antoˆnio R. Chacra b a b

Diabetes and Hypertension Center of Fortaleza, Ceara´, Brazil Diabetes Center of the Federal University of Sa˜o Paulo, Brazil Received 3 August 2006; accepted 8 January 2007 Available online 20 April 2007

Abstract Objective: C-reactive protein (CRP), an inflammatory biomarker, has been associated with the development of diabetes. Gestational diabetes (GDM) predicts type 2 diabetes (T2DM) and may be part of the metabolic syndrome (MS). Few studies have examined the association of CRP, MS and diabetes in women with previous GDM. Research design and methods: Women with previous GDM (n = 70) and randomly sampled women without previous GDM (n = 108) from the one center of the Brazilian Study of Gestational Diabetes participated in the study after 6 years of index pregnancy. Oral glucose tolerance test and anthropometry were performed. CRP levels were measured by the nephelometry. The MS was defined by the ATPIII criteria. Results: There was significant positive linear correlation between CRP levels, fasting insulin (R = 0.053) and HOMA IR (0.048) in previous GDM. Mean CRP levels were significantly higher in previous GDM group with abdominal obesity (1.227 95% CI 0.871– 1.584 versus 0.597, 95% CI 0.378–0.817; p = 0.001) and abnormal glucose tolerance (1.168 95% CI 0.784–1.552 versus 0.657 95% CI 0.455–0.859, p = 0.012). There were differences when considering the presence of different MS features, once the previous GDM group reported a significantly higher number of women with low HDL (74.3% versus 55.6%, p = 0.016) and abnormal glucose tolerance (45.7% versus 25%, p = 0.005) than the group without GDM. On average, the CRP levels were significantly higher in women with previous GDM and MS (0.918 95% CI 0.569; 1.268 versus 0.524 95% CI 0.373; 0.675, p = 0.044) than the control group. Conclusions: The data suggests that the presence of MS in women with previous GDM is associated with high levels of CRP. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: BMI; HDL; NGT

1. Introduction Abbreviations: GDM, gestational diabetes mellitus; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; CRP, C-reactive protein; T2DM, type 2 diabetes; MS, metabolic syndrome * Corresponding author at: Rua Vicente Linhares No. 614 apto 300, CEP 60 135-270, Fortaleza, Ceara´, Brazil. Tel.: +55 85 99889821; fax: +55 85 34866079. E-mail address: [email protected] (T.B. Ferraz).

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance with onset or first recognition during pregnancy [1]. Approximately 7% of all pregnancies are complicated by GDM [2] and the prevalence in Brazilian pregnant women was 7.6% [3]. GDM identifies a population of women at high risk of subsequent type 2 diabetes (T2DM) [4,5], representing

0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.01.025

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an early stage in the natural history of the disease [6,7]. Like T2DM, GDM results from a combination of increased insulin resistance and decreased pancreatic insulin secretion [8,9]. Elevated CRP levels, a marker of systemic inflammation, has been linked to the development of diabetes, supporting a possible role in inflammation and diabetogenesis [10,11]. Clark et al. have suggested that GDM could be added to the classical components of the MS (hyperinsulinemia, insulin resistance, obesity, dislipidemia, hypertension and T2DM or glucose intolerance) [12]. Indeed, there is an association between CRP and the MS features [13] and an association with atherosclerosis [14]. GDM is present at an early phase of the MS and can be present in a group of young women of the general population, indicating a greater risk for developing T2DM in the future [12] as well as the risk of cardiovascular diseases. CRP is emerging as an independent risk feature for cardiovascular diseases in healthy populations [15–17]. High CRP levels have been linked to an increased risk of thrombotic events including myocardial infarction [17–19]. There are few studies highlighting the evaluation of CRP levels in women with previous GDM. To examine the association of an inflammatory marker with previous GDM, this study investigated the CRP levels and the presence of defining features of MS in women with and without previous GDM. Further, it evaluated the association of CRP with the components of the MS in these women. 2. Materials and methods This study evaluated 70 women who had GDM during the Brazilian Study of Gestational Diabetes, Fortaleza center, and a group formed by 108 randomly chosen women, without GDM, after a mean of 6.2  0.8 years after their index pregnancy. All the women contacted who underwent the study, signed a term of consent approved by the local ethical committee. At the study site, the subjects underwent biochemical dosages, anthropometric evaluations and physical exams, as well as the application of standardized questionnaires. During the index pregnancy, it was performed an oral test with 75 g of glucose between the 24th and 26th weeks of gestation. The classification as to the incidence of GDM was according to the World Health Organization (WHO) criteria: (2-h glucose  140 mg/dl is considered GDM). Glucose dosage was measured using the enzymatic colorimetric method [20]. During the follow-up assessment, this study evaluated all 70 women with previous GDM and the 108 women without previous GDM, as to the real state of glucose tolerance

through and oral test with 75 g of glucose (OGTT-75 g), and a new classification was established according to the World Health Organization (WHO) 1999 criteria: [21], considering as real state of glucose tolerance: diabetes or impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). CRP was measured by kinetic nephelometry (Beckman Coulter, Galway, and Ireland). The method used in the Beckman Coulter CRP Test measures the rate of increase of light dispersion from particles suspended in solution originated from the formation of complexes during an antigen-antibody reaction. The test detects CRP concentrations in the serum within a range of 0.4–9 mg/dl using the normal 1:6 sample dilution. The intraassay coefficients of variation of 5% were obtained with the CRP Test for within-run precision evaluated by replicate testing of control serum samples at three levels. The evaluation of precision between interassays was evaluated through 20 determinations of control serum samples over a period of 10 days and the coefficient of variation was 8%. Values inferior to 0.21 mg/dl reveal low coronary risk and values inferior to 0.80 mg/dl reveal the absence of acute inflammatory diseases. Glucose measurements were recorded using the enzymatic colorimetric method and insulin was measured by radioimmunoassay (I125 DPC’s Coat-A-Count Insulin Kit; Los Angeles, CA). Total cholesterol, HDL and triglycerides were measured by the RAXT system-enzymatic method. The transformation into mmol/l was carried out according to SI. The MS was defined by the presence of at least three of the following features according to ATPIII criteria: waist circumference  88 cm, triglycerides  150 mg/dl (1.7 mmol/l), SBP  130 mmHg and/or DBP  85 mmHg, HDL cholesterol < 50 mg/dl (1.3 mmol/l), fasting glucose  110 mg/dl (6.1 mmol/l) [22]. Body mass index (BMI), as the ratio of the weight (kg) to the square of height (m2), waist-to-hip ratio (WHR), waist circumference (WC) and the measures of the systolic (SBP) and diastolic blood pressure (DBP) were all calculated. The evaluation of insulin sensitivity was performed through the HOMA IR using the Mathew’s simplified formula [23]: HOMA IR = [fasting insulin mUI/ml]  [fasting glucose mmol/l]/22.5.

3. Statistical analysis The quantitative analysis of the data was previously coded into a data bank by the EPI-INFO using the SPSS for Windows 10.0. The following statistical tests were performed: Pearson’s chi-square test and the Verisimilitude Ratio test to test associations and homogeneity among politomic variables displayed in contingency charts, exact Fischer test for analyzing association and homogeneity of dichotomic variables displayed in contingency charts; to evaluate the equality of averages of two independent groups it was used the Mann– Whitney U-test, in case of non-normality in the

T.B. Ferraz et al. / Diabetes Research and Clinical Practice 78 (2007) 23–29

distribution of the data of the variable and the t-Student test in case of normality in the distribution of the variable’s data. The maximum level of statistical significance for the tests was 5% ( p < 0.05). The variance used was a standard error of the average in all variables. We analyzed the magnitude of the association of the CRP with elements of the MS through the Spearman’s correlation. To estimate the effect of the CRP average adjusted by the MS features, age and family history of diabetes, this study used an analysis model of multiple linear regression. 4. Results The laboratorial and clinical characteristics of all 178 subjects studied as a group and according to the previous GDM diagnosis are shown in Table 1. The group with and without previous GDM did not show significant differences in most of the variables studied. However, in comparison with the group of women without previous GDM, those with previous GDM, on average, have a significantly higher age ( p = 0.019). There is a significantly higher proportion of women who have developed glucose intolerance or diabetes ( p = 0.013) with a tendency to present a lower average in the HDL cholesterol levels ( p = 0.055). CRP did not differ in the groups with and without previous GDM (0.594  0.07 versus 0.517  0.04, p = 0.8279) as in Table 1. When we evaluated the ratio in the groups with and without previous GDM according to the features

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defining MS, it was noted that: 14.3% of the subjects with previous GDM and 3.7% of those without previous GDM showed a fasting glucose of 0.110 mg/dl ( p = 0.019) and 74.3% with previous GDM showed HDLc < 1.3 mmol/l (74.3 versus 55.6, p = 0.016). This study showed a positive linear correlation of CRP levels with 2-h post-load insulin levels (r = 0.260, p = 0.034) and with HOMA IR (r = 0.243, p = 0.048). Fasting insulin also showed a tendency in both groups for positive linear correlation with CRP levels (r = 0.237, p = 0.053 and r = 0.175, p = 0.072, respectively). The adjusted averages of CRP levels (adjusted for age, family history of diabetes and others) by linear regression model to categorized features of MS and other non-defining features of MS are shown in Table 2. It also shows high prevalence of obese women (55.2%), with abdominal obesity (18%), hypertension (34.3%) and diabetes or glucose intolerance (45.7%) among women with previous GDM. Considering the five features of MS, the average of CRP levels was statistically higher on subjects with previous GDM and abdominal obesity (CC  88 cm), (1.227 95% CI 0.871–1.584 versus 0.597, 95% CI 0.378–0.817; p = 0.001) and with fasting glucose  110 mg/dl (1.168 95% CI 0.784–1.552 versus 0.657 95% CI 0.455–0.859, p = 0.012). This is concordant with the association of MS, inflammatory markers (high sensitive CRP) and previous GDM. Obese women with previous GDM (BMI  25) presented CRP levels (0.907 IC: 95% 0.663–1.151) similar to those of nonobese women (0.935 IC: 95% 0.594–1.276, p = 0.856)

Table 1 Characteristics at follow-up assessment of all women according previous GDM Characteristic

Whole group

GDM

Non GDM

p

n BMI (kg/m2) Waist-to-hip ratio Age (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mmol/l) 2 h plasm glucose (mmol/l) HDL cholesterol (mmol/l) Total cholesterol (mmol/l) Triglycerides (mmol/l) Fasting insulin (pmol/l) 2 h plasm insulin (pmol/l) HOMA IR CRP Metabolic syndrome

178 25.73  0.35 0.82  0.01 32.04  0.39 119.86  1.06 84.97  3.57 5.30  0.09 7.33  0.21 1.24  0.02 4.75  0.07 1.34  0.07 50.76  3.11 359.14  22.58 2.07  0.15 0.54  0.04 1.58  0.08

70 26.34  0.59 0.80  0.01 33.13  0.68 122.43  1.83 89.64  8.93 5.55  0.21 7.91  0.43 1.19  0.03 4.73  0.13 1.48  0.14 51.95  4.02 324.46  33.08 2.27  0.25 0.59  0.07 1.71  0.12

108 25.33  0.44 0.83  0.01 31.33  0.46 118.19  1.28 81.94  1.07 5.14  0.06 6.96  0.19 1.28  0.03 4.75  0.09 1.25  0.07 49.98  4.43 381.83  30.36 1.94  0.18 0.52  0.04 1.50  0.11

0.1666* 0.0001 0.019 0.1357 0.5465 0.2307 0.1594 0.0550* 0.9036* 0.8360 0.2771 0.1690 0.1671 0.8279 0.1747

Dates are means  S.D. or n(%). p: teste de Mann–Whitney. * Teste t-Student (to compare GDM and non GDM).

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Table 2 Adjusted means of CRP by linear regression model for categorized features of the MS and others features Variables

GDM

Non GDM a

Mean of CRPa

p

55 52

0.485  (0.22; 0.74) 0.43  (0.192; 0.67)

0.606

0.000

79 28

0.439  (0.19; 0.68) 0.465  (0.21; 0.72)

0.801

0.974  (0.69; 1.25) 0.850  (0.57; 1.12)

0.392

57 50

0.459  (0.21; 0.69) 0.445  (0.19; 0.69)

0.873

Fasting glucose (mg/dl) <110 58 110 9

0.657  (0.45; 0.85) 1.15  (0.78; 1.55)

0.012

103 4

0.529  (0.41; 0.64) 0.375  (0.00; 0.81)

0.492

Triglycerides (mmol/l) <1.7 49 1.7 18

0.957  (0.69; 1.21) 0.868  (0.57; 1.16)

0.552

87 20

0.445  (0.21; 0.67) 0.459  (0.17; 0.73)

0.906

HDL cholesterol (mmol/l) 1.3 16 <1.3 51

0.864  (0.55; 1.17) 0.961  (0.70; 1.21)

0.542

47 60

0.436  (0.18; 0.68) 0.469  (0.23; 0.70)

0.702

n

Mean of CRP

p

30 37

0.935  (0.59; 1.27) 0.907  (0.66; 1.51)

0.856

Waist circumference (cm) <88 55 88 12

0.597  (0.37; 0.817) 1.227  (0.871; 1.58)

Hypertension No Yes

44 23

BMI <25 25

a

n

Adjusted for age, familial history and others features.

when adjusted for age, family history of diabetes and other features. According to Fig. 1 there was a linear increase in CRP levels with an increase in the number of MS features within the previous GDM group. Women with four MS features, have on average, CRP levels three times higher than those without any MS features. The average of CRP levels and confidence intervals (CI 95%) were respectively 0.421 (0.000; 1.031); 0.516 (0.327; 0.705); 0.564 (0.348; 0.781); 0.521 (0.000; 1.123); 1.523 (0.687; 2.359) in the presence of 0, 1, 2, 3 or 4 MS features, respectively. There was a tendency for higher CRP levels in the group with previous GDM and with 4 features of MS when compared to the same group with 3 features of MS ( p = 0.062). When categorized as to presence (3 features) or absence of MS (<3 features), there was an average of CRP levels significantly higher (0.918 CI 0.569; 1.268 versus 0.524 CI 0.373; 0.675, p = 0.044, respectively) in the group with previous GDM and MS, thus showing an association between MS and previous GDM. The same event does not happen in the control group, without previous GDM. The majority of women with previous GDM presented more than two features of MS, so the percentage according to the number of MS features were: 0 feature (4.5%), 1 feature (45%), 2 features (34%), 3 features (10.5%), and 4 features (6%).

There was a statistically significant positive correlation between fasting glucose, fasting insulin, 2-h postload insulin, HOMAR IR and the number of MS features in both groups.

Fig. 1. Mean levels of CRP (SE represented by bars) adjusted for age, history family to diabetes according to number of MS in women with previous GDM (n = 70).

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5. Discussion In this study, results showed that the CRP levels were in average similar in both groups. Wolf et al., in a prospective study, identified an association among high levels of CRP in the first trimester of pregnancy and the subsequent risk of DMG, independently from other risk factors such as age, multiparity and smoke [24]. Retnakaran et al., in a recent publication, have shown that CRP serum levels are not related to DMG but they correlate significantly with pre-pregnancy obesity [25]. However, in this investigation, women with previous DMG and MS, i.e., with presence of three or more features, present significantly higher CRP average than women with previous GDM and without MS, corroborating Froehlich’s et al. study, who found positive correlation among CRP and several features of MS: total cholesterol, HDL cholesterol, triglycerides, BMI, glucose and uric acid in the general population [13]. Several epidemiological studies have shown a significant correlation between BMI and CRP. In this paper, no correlation was found between the CRP levels and BMI  25 in both groups with and without previous GDM. However, when we analyzed the association of CRP levels with abdominal obesity (WC  88 cm), we found statistical significance in the group with previous GDM. Circulating levels of CRP correlate highly with several measures of body fat including BMI, waist circumference, waist-to-hip ratio and fat-free mass, and adipose body mass as assessed by bioelectrical impedance [25–29]. C-reactive protein was independently associated with fasting insulinemia, a marker of insulin resistance, in a study with non-diabetic women [30]. In other studies with non-diabetic women, CRP levels were correlated with cardiovascular events and insulin resistance [15,18,31,32]. In diabetic women, CRP levels, as a marker of inflammatory diseases, have shown association with glucose control [33], glucosyled hemoglobin [34] and with fasting insulinemia [35]. This study showed that women with previous GDM and MS have higher levels of CRP, when compared to the control group. The association of inflammatory disease markers and GDM has been poorly studied. This paper showed a linear increase in the CRP levels associated with an increase in the levels of fasting insulin and at 2-h postload insulin levels in women with previous GDM. A positive linear correlation between CRP levels and HOMA IR, in the group of women without previous GDM was also found, and it corroborates with the conclusions of Yudkin’s et al. study, which shows strong

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association among inflammation markers with insulin resistance in 107 non-diabetic individuals, showing a possible inflammatory etiopathogenesis for the insulin resistance syndrome (IRS) [29]. Clark et al. has shown that components of the MS are predictors of GDM, suggesting that GDM is a phase of the insulin resistance syndrome [12]. There is evidence that a chronic inflammatory process could represent a triggering factor in the origin of IRS and eventually T2DM [36–38]. Possible inflammatory answers present during the diagnosis of DMG, with an increase in CRP levels in the first trimester of pregnancy [24] and persistent insulin resistance in the follow-up, could explain this correlation with CRP, found in this study. The chronic insulin resistance present in these women with previous GDM has been described by Buchanan et al., who suggests that the treatment of this insulin resistance with glitazone could prevent the appearance of T2DM in women with previous GDM [39]. It has also been shown a positive linear correlation between the number of features that characterize MS and the insulin resistance, evaluated by HOMA IR and fasting insulinemia and at 2-h post-load insulin for both groups. Several inflammatory markers have increased levels in the MS and in T2DM. In Hoorn study, CRP was positively correlated with the severity of the state of glucose tolerance [40,30,31,41]. A recent study in women with previous GDM evaluated another inflammatory marker of acute phase, total sialic acid, and showed an increase in this marker in women with previous GDM, when compared with those without previous GDM. This study suggests that GDM is an early manifestation of the MS and that the inflammatory marker behaves as a link between previous DGM and T2DM [42]. This study does not allow investigating which reasons led to a change in the CRP levels in women with previous GDM. The abdominal adiposity present in women with previous GDM and with higher levels of CRP regarding women without previous GDM can suggest this link between obesity, insulin resistance [43–46] and previous GDM. Later studies would be necessary to confirm this hypothesis. Recently, research studies demonstrated that the prevalence of MS was three times higher in women with previous GDM when compared with the control group [47] and was associated with increased levels of CRP [48]. The limitations of this study include the sample size in this study which may have limited the ability to detect statistical significance of differences between the two groups, and the fact that these women, during the research, could present some type of inflammatory

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process or smoke. However, this was insistently researched. A positive fact is that no woman took metformin or glitazone or any anti-inflammatory medication. Another limitation is the small number of patients and a great variability in the levels of CRP, once there was no correlation between CRP and any of the MS features. In conclusion, our study suggests that the presence of MS in women with previous GDM show possible link between GDM and inflammation states. The presence of abdominal obesity and/or altered fasting glucose in these women, are associated with greater risk of cardiovascular diseases and T2DM in the future. Reduction of these risk factors is made necessary in these women, because it is an important prevention study group in T2DM. Longer-term studies are indicated to confirm that women with previous GDM have increased cardiac morbidity and mortality and to define a potential role for lifestyle and/or pharmacological intervention. The emphasis of this study was imprinted in the idea to expand knowledge about possible inflammatory markers and GDM in identifying developers of diabetes and cardiovascular disease in the future.

References [1] The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 25 (Suppl. 1) (2002) S5–S20. [2] Gestational diabetes mellitus. American Diabetes Association. Diabetes Care 26 (Suppl. 1) (2003) S103–S105. [3] M.I. Schmidt, M.C. Matos, A.J. Reichelt, A. Costa e Forti, L. de Lima, B.B. Duncan, Prevalence of gestational diabetes mellitus—do the new WHO criteria make a difference? Brazilian Gestational Diabetes Study Group, Diabet. Me´d. 17 (5) (2000) 376–380. [4] S.L. Kjos, T.A. Buchanan, Gestational diabetes, N. Engl. J. Med. 341 (1999) 1749–1756. [5] B.E. Metzger, N.H. Cho, S.M. Roston, R. Radvany, Prepregnancy weight and antepartum insulin secretion predict glucose tolerance five years after gestational diabetes mellitus, Diabetes Care 16 (1993) 1598–1605. [6] R.J. Jarret, Gestational diabetes: a non-entity? BMJ 306 (1993) 37–38. [7] M.I. Harris, Gestational diabetes may represent discovery of preexisting glucose intolerance, Diabetes Care 11 (1988) 402– 411. [8] T.A. Buchanan, S.L. Kjos, Gestational diabetes: risk or myth? J. Clin. Endocrinol. Metab. 84 (1999) 1854–1857. [9] P.M. Catalano, L. Huston, S.B. Amini, S.C. Kalhan, Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus, Am. J. Obstet. Gynecol. 180 (1999) 903–916.

[10] A.D. Pradhan, J.E. Manson, N. Rifai, J.E. Buring, P.M. Ridker, C-reactive protein, interleukin 6, and risk of developing T2DM mellitus, JAMA 286 (2001) 327–334. [11] J.I. Barzilay, L. Abraham, S.R. Heckbert, M. Cushman, L.H. Kuller, H.E. Resnick, et al., The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study, Diabetes 50 (2001) 2384– 2389. [12] C.M.J. Clark, C. Qiu, B. Amerman, B. Porter, N. Fineberg, S. Aldasouqi, et al., Gestational diabetes: should it be added to the syndrome of insulin resistance? Diabetes Care 20 (1997) 867–871. [13] M. Frohlich, A. Imhof, G. Berg, W.L. Hutchinson, M.B. Pepys, H. Boeing, et al., Association between C-reactive protein and features of the metabolic syndrome: a population-based study, Diabetes Care 23 (2000) 1835–1839. [14] T.J. Wang, B.H. Nam, P.W.F. Wilson, P.A. Wolf, D. Levy, J.F. Polak, et al., Association of C-reactive protein with carotid atherosclerosis in men and women: The Framingham Heart Study, Arterioscler. Thromb. Vasc. Biol. 22 (2002) 1662–1667. [15] P.M. Ridker, J.E. Buring, J. Shih, M. Matias, C.H. Hennekens, Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women, Circulation 98 (1998) 731–733. [16] P.M. Ridker, C.H. Hennekens, J.E. Buring, N. Rifai, C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women, N. Engl. J. Med. 342 (2000) 836–843. [17] P.M. Ridker, M. Cushman, M.J. Stampfer, R.P. Tracy, C.H. Hennekens, Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men, N. Engl. J. Med. 336 (1997) 973–979. [18] P.M. Ridker, N. Rifai, M.J. Stampfer, C.H. Hennekens, Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men, Circulation 101 (2000) 1767–1772. [19] W. Koenig, M. Sund, M. Frohlich, H.G. Fischer, H. Lowel, A. Doring, et al., C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992, Circulation 99 (1999) 237–242. [20] P. Trinder, Determination of glucose in blood using oxidase with an alternative glucose acceptor, Ann. Clin. Biochem. 6 (1969) 24–27. [21] World Heath Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation, World Health Organization, Geneva, 1999. [22] National Institute of Health, Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), JAMA 285 (2001) 2486–2497. [23] M.S. Haffner, C. Gonzalez, H. Miettiner, E. Kennedy, P.M. Stern, A prospective analysis of the HOMA model, Diabetes Care 19 (1996) 1138–1141. [24] M. Wolf, L. Sandler, K. Hsu, K. Vossen-Smirnakis, J.L. Ecker, R. Thadhani, First-trimester C-reactive protein and subsequent gestational diabetes, Diabetes Care 26 (3) (2003) 819–824. [25] R. Retnakaran, A.G. Hanley, N. Raif, P.W. Connelly, M. Sermer, C-reactive protein and gestational diabetes: the central role of

T.B. Ferraz et al. / Diabetes Research and Clinical Practice 78 (2007) 23–29

[26] [27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36] [37]

maternal obesity, J. Clin. Endocrinol. Metab. 88 (8) (2003) 3507–3512. E.S. Ford, Body mass index, diabetes, and C-reactive protein among U.S. adults, Diabetes Care 22 (1999) 1971–1977. A. Festa, B. D’Agostinho Jr., K. Williams, A.J. Karter, E.J. Mayer-Davis, R.P. Tracy, et al., The relation of body fat mass and distribution to markers of chronic inflammation, Int. J. Obes. 25 (2001) 1407–1415. T.S. Han, N. Sattar, K. Williams, C. Gonzalez-Villalpando, M.E. Lean, S.M. Haffner, Prospective study of C-reactive protein in relation to the development diabetes and metabolic syndrome in the Mexico City Diabetes Study, Diabetes Care 25 (11) (2002) 2016–2021. J.S. Yudkin, C.D.A. Stehouwer, J.J. Emeis, S.W. Coppack, Creactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 19 (1999) 972–978. A.D. Pradhan, N.R. Cook, J.E. Buring, J.E. Manson, P.M. Ridker, C-reactive protein is independently associated with fasting insulin in non diabetic women, Arterioscler. Thromb. Vasc. Biol. 23 (4) (2003) 650–655. A. Festa, R. D’Agostino Jr., G. Howard, L. Mykka¨nen, R.P. Tracy, S.M. Haffner, Chronic subclinical inflammation as part of the insulin resistance syndrome the Insulin Resistance Atherosclerosis Study (IRAS), Circulation 102 (2000) 42–47. P.M. Ridker, N. Rifai, L. Rose, J.E. Buring, N.R. Cook, Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events, N. Engl. J. Med. 342 (20) (2002) 1557–1565. D.E. King, A.G. Mainous III, T.A. Buchanan, W.S. Pearson, Creactive protein and glycemic control in adults with diabetes, Diabetes Care 26 (5) (2003) 1535–1539. T. Wu, J.P. Dorn, R.P. Donahue, C.T. Sempos, M. Trevisan, Associations os serum C-reactive protein with fasting insulin, glucose, and glycosylated hemoglobin, Am. J. Epidemiol. 155 (2002) 65–71. I. Juhan-Vague, M.C. Alessi, PAI-1, obesity, insulin resistance and risk of cardiovascular events, Thromb. Haemost. 78 (1997) 656–660. J.C. Pickup, M.A. Crook, Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41 (1998) 1241–1248. J.C. Pickup, M.B. Mattock, G.D. Chusney, D. Burt, NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X, Diabetologia 40 (1997) 1286–1292.

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[38] M.I. Schmidt, B.B. Duncan, A.R. Sharret, G. Lindeberg, P.J. Savage, S. Offenbacher, et al., Markers of inflammation and prediction of diabetes mellitus in adults (atherosclerosis risk in communities study): a cohort study, Lancet 353 (1999) 1649– 1652. [39] T.A. Buchanan, Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of T2DM, J. Clin. Endocrinol. Metab. 86 (3) (2001) 989–993. [40] A. Jager, V.W. Van Hinsbergh, P.J. Kostense, J.J. Emeis, J.S. Yudkin, G. Nijpels, et al., Von Willebrand feature, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects the Hoorn Study, Arterioscler. Thromb. Vasc. Biol. 19 (1999) 3071–3078. [41] A. Festa, R. D’Agostinho Jr., R.P. Tracy, S.M. Haffner, Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of T2DM: the Insulin Resistance Atherosclerosis Study, Diabetes 51 (2002) 1131–1137. [42] M. Sriharan, A.J. Reichelt, M.L. Opperman, B.B. Duncan, S.S. Mengue, M.A. Crook, et al., Total sialic acid and associated elements of the metabolic syndrome in women with and without previous gestational diabetes, Diabetes Care 25 (8) (2002) 1331– 1335. [43] B. Thorand, H. Lowel, A. Schneider, H. Kolb, C. Meisinger, M. Frohlich, et al., C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984–1998, Arch. Intern. Med. 163 (1) (2003) 93–99. [44] J.-P. Bastard, C. Jardel, J. Delattre, B. Hainque, E. Bruckert, F. Oberlin, Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects, Circulation 99 (1998) 2221–2222. [45] A. Verma, C.M. Boney, R. Tucker, B.R. Vohr, Insulin resistance syndrome in women with prior history of gestational diabetes mellitus, J. Clin. Endocrinol. Metab. 87 (2002) 3227–3235. [46] J.C. Pickup, Inflammation activated innate immunity in the pathogenesis of T2DM, Diabetes Care 27 (2004) 813–823. [47] J. Lauenborg, E. Mathiesen, T. Hansen, C. Glu¨mer, T. Jørgensen, K. Borch-Johnsen, et al., The prevalence of the Metabolic Syndrome in a Danish Population of women with previous gestational diabetes mellitus is three fold higher than in the general population, J. Clin. Endocrinol. Metab. 90 (7) (2005) 4004–4010. [48] G. Di Cianni, C. Lencioni, L. Volpe, A. Ghio, I. Cuccuru, G. Pellegrini, et al., C-reactive protein and metabolic syndrome in women with previous gestational diabetes, Diabetes Metab. Res. Rev. 23 (2) (2007) 135–140.