Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) have been used to diagnose new-onset diabetes mellitus (DM) in order to simplify the diagnostic tests compared with the 2-hour oral glucose tolerance test (OGTT; 2-hPG). We aimed to identify optimal cut-off points of high sensitive C-reactive protein (hs-CRP) in new-onset DM people based on FPG, 2-hPG, or HbA1c methods. Data derived from recent population-based survey in Turkey (TURDEP-II). The study included 26,499 adult people (63% women, response rate 85%). The mean serum concentration of hs-CRP in women was higher than in men (
The relation between chronic subclinical low-grade inflammation and insulin resistance (IR) has long been known [
Compared with the conventional OGTT (2-hPG) as recommended by WHO as gold standard, fasting plasma glucose (FPG) and HbA1c are more convenient, simpler, and cost-effective diagnostic methods that are currently in use for the diagnosis of T2DM [
To the best of our knowledge, there is no previous report specifically comparing the role of hs-CRP in people with newly diagnosed DM with the criteria based on the 2-hPG, FPG, and HbA1c. Therefore, the aim of this study was to identify the optimal cut-off points of hs-CRP in new-onset (previously undiagnosed) people with DM diagnosed based on the current 2-hPG, FPG, and HbA1c diagnostic criteria. In this study, hs-CRP results obtained from a nationally representative population-based survey are being reported.
Data derived from “The Turkish Epidemiology Survey of Diabetes, Hypertension, Obesity and Endocrine Diseases (TURDEP-II),” a population-based study, which was included randomly assigned 26,499 adult people from 270 urban and 270 rural centers. The field survey was performed between January and June 2010, with a participation rate of 85%. The study protocol was described elsewhere [
People with known DM or other systemic diseases who had hs-CRP levels of 10 mg/L (95.2 nmol/L) or above were excluded from this study due to a possible infection. Final assessments included 21,485 (63.6% women) participants. All biochemical tests including glucose, insulin, and lipid profile were measured in fasting blood samples using Roche Diagnostics Modular Autoanalyzer System (Roche Diagnostics, Germany) in the Central Biochemistry Laboratory of Istanbul Medical Faculty. Concentration of hs-CRP was analyzed by immunoturbidimetric assay (Roche/Hitachi 912, Modular P analyzers: ACN 210; CRPL3 Tina-quant C-reactive protein Gen. 3) and HbA1c by turbidimetric inhibition immunoassay; both the system and the laboratory have been regularly certified (Roche Diagnostics TQ HbA1c Gen. 3; NGSP Certificate of Traceability; September 2010-2011).
A detailed medical history of each participant was obtained, and measurements of anthropometry (height, weight, waist, and hip circumference) and systolic and diastolic blood pressure (SBP, DBP) were done. Body mass index (BMI), HOMA-IR (= fasting glucose × fasting insulin/405), and non-HDL-cholesterol (= total cholesterol − HDL-cholesterol) were calculated accordingly. Glomerular filtration rate (eGFR) was estimated using “Chronic Kidney Disease Epidemiology Collaboration” CKD-EPI equation [
The mean values of continuous variables were compared using
Data were analyzed using SPSS for Windows (version 21.0; SPSS/IBM, Chicago, IL). A
Demographic characteristics and laboratory findings of women and men in TURDEP-II study are presented in Table
Clinical characteristics and laboratory findings of TURDEP-II study population
Parameter | Women ( |
Men ( |
|
---|---|---|---|
Age (year) | 43 (15) | 44.7 (15.6) | <0.000001 |
BMI (kg/m2) | 28.6 (5.7) | 27.2 (4.3) | <0.000001 |
Waist (cm) | 91.3 (14.5) | 96.4 (12.8) | <0.000001 |
Hip (cm) | 108.6 (13.2) | 105.1 (10.3) | <0.000001 |
SBP (mmHg) | 118 (27) | 120 (22) | 0.000008 |
DBP (mmHg) | 74 (13) | 75 (12) | <0.000001 |
HR (beat/min) | 79.5 (8.7) | 78.3 (9.2) | <0.000001 |
hs-CRP (mg/L) |
1.85 (3.09) |
1.47 (2.33) |
<0.000001 |
FPG (mmol/L) | 5.5 (1.03) | 5.48 (1.18) | 0.000449 |
HbA1c (mmol/mol) |
38 (7) |
37 (8) |
0.003493 |
1-hPG (mmol/L) | 8.9 (2.5) | 8.76 (2.52) | 0.000013 |
2-hPG (mmol/L) | 7.2 (2.1) | 6.34 (2.04) | <0.000001 |
Creatinine ( |
64.0 (11.0) | 82.0 (14.4) | <0.000001 |
Triglycerides (mmol/L) | 1.4 (0.8) | 1.67 (1.15) | <0.000001 |
HDL-cholesterol (mmol/L) | 1.3 (0.3) | 1.09 (0.27) | <0.000001 |
Non-HDL-cholesterol (mmol/L) | 3.5 (1.0) | 3.69 (1.01) | <0.000001 |
Fasting insulin (pmol/L) | 56.4 (49.6) | 56.9 (60.5) | 0.570725 |
HOMA-IR | 1.9 (2.9) | 2.0 (3.1) | 0.258439 |
eGFR |
101.0 (17.4) |
98.8 (16.9) |
<0.000001 |
1-hPG, oral glucose tolerance test 1st hour plasma glucose; 2-hPG, oral glucose tolerance test 2nd hour plasma glucose; BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL-cholesterol, high density lipoprotein cholesterol; HOMA-IR, homeostasis model of assessment; HR, heart rate; hs-CRP, high sensitive C-reactive protein; IQR, interquartile range; SBP systolic blood pressure.
There was a positive correlation between hs-CRP levels and age, BMI, waist, hip, SBP, DBP, pulse, FPG, HbA1c, 1-hPG, 2-hPG, TG, non-HDL-cholesterol, and HOMA-IR; and there was a negative correlation with HDL-cholesterol and eGFR. When we repeated the analysis after controlling for HT, age, sex, smoking and alcohol use, BMI, and waist circumference, the positive correlations between hs-CRP levels and HbA1c, 1-hPG, 2-hPG, TG, non-HDL-cholesterol, eGFR, and HOMA-IR and the negative correlation with HDL-cholesterol and creatinine remained significant (Table
Pearson correlation analysis (unadjusted and adjusted) of hs-CRP and other parameters.
Unadjusted Pearson correlation: hs-CRP versus |
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|
Controlled for age, sex, smoking, alcohol, BMI, waist, HT, and medications: hs-CRP versus |
|
|
---|---|---|---|---|---|
Age | 0.18 | <0.001 | HbA1c | 0.08 | <0.001 |
BMI | 0.37 | <0.001 | 1-hPG | 0.07 | 0.001 |
Waist | 0.30 | <0.001 | 2-hPG | 0.07 | <0.011 |
Hip | 0.29 | <0.001 | Creatinine | −0.05 | 0.001 |
SBP | 0.12 | <0.001 | Triglycerides | 0.09 | <0.001 |
DBP | 0.13 | <0.001 | Total cholesterol | 0.05 | 0.018 |
HR | 0.07 | <0.001 | HDL-cholesterol | −0.06 | 0.002 |
FPG | 0.12 | <0.001 | Non-HDL-cholesterol | 0.07 | 0.001 |
HbA1c | 0.19 | <0.001 | Fasting insulin | 0.07 | <0.001 |
1-hPG | 0.19 | <0.001 | HOMA-IR | 0.06 | 0.002 |
2-hPG | 0.15 | <0.001 | eGFR | 0.05 | 0.014 |
Creatinine | −0.12 | 0.001 | |||
HDL-cholesterol | −0.10 | <0.001 | |||
Non-HDL-cholesterol | 0.20 | <0.001 | |||
Fasting insulin | 0.13 | <0.001 | |||
HOMA-IR | 0.11 | <0.001 | |||
eGFR | −0.13 | <0.001 |
1-hPG, oral glucose tolerance test 1st hour plasma glucose; 2-hPG, oral glucose tolerance test 2nd hour plasma glucose; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL-cholesterol, high density lipoprotein cholesterol; HOMA-IR, homeostasis model of assessment; HR, heart rate; hs-CRP, high sensitive C-reactive protein; HT, hypertension; SBP, blood pressure.
Among people with new DM, the highest hs-CRP level was in the group detected by HbA1c criterion (hs-CRP median [IQR]; HbA1c: 3.45 [3.82] mg/dL, 32.9 [36.4] nmol/L; 2-hPG: 2.7 [3.14] mg/dL, 25.4 [29.9] nmol/L; and FPG: 2.4 [3.0] mg/dL, 22.4 [28.5] nmol/L, data not shown).
High sensitive CRP level was significantly higher in women than men with newly diagnosed DM groups based on 2-hPG, FPG, and HbA1c criteria. Among the newly diagnosed DM groups, the median [IQR] level of hs-CRP was highest in those detected with HbA1c in both genders (HbA1c-group: women: 4.0 [4.1] mg/dL, 38.4 [39.1] nmol/L; men: 2.7 [3.1] mg/dL, 25.9 [29.1] nmol/L; FPG group: women: 3.3 [4.1] mg/dL, 31.1 [39.3] nmol/L; men: 2.4 [3.0] mg/dL, 22.4 [28.5] nmol/L; and 2-hPG group: women: 2.8 [3.3] mg/dL, 26.5 [31.3] nmol/L; men: 2.4 [2.8] mg/dL, 23.3 [26.9] nmol/L).
Sex differences in hs-CRP did not change after the data adjusted with respect to age, BMI, waist circumference, and HT; the mean hs-CRP was highest in newly diagnosed patients based on HbA1c criterion in both sexes. Again, the average hs-CRP levels of women were higher than men (Table
hs-CRP levels in women and men with newly detected DM using the FPG, 2-hPG, or HbA1c criteria
Diagnostic methods | hs-CRP; mg/L [nmol/L] | |||
---|---|---|---|---|
Women | Men | |||
Mean (SEM), ( |
95% CI | Mean (SEM), ( |
95% CI | |
FPG-DM |
3.3 (0.1), ( |
3.0–3.5 |
2.5 (0.2) ( |
2.13–2.80 |
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2-hPG-DM |
3.2 (0.1) ( |
3.0–3.40 |
3.0 (0.2) ( |
2.7–3.4 |
|
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HbA1c-DM |
4.0 (0.1) ( |
3.8–4.3 |
3.1 (0.1) ( |
2.9–3.40 |
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Post hoc comparisons | FPG-DM versus 2-hPG-DM, |
FPG-DM versus 2-hPG-DM, |
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FPG-DM versus HbA1c-DM, |
FPG-DM versus HbA1c-DM, |
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2-hPG-DM versus HbA1c-DM, |
2-hPG-DM versus HbA1c-DM, |
The specificity and sensitivity of the optimal cut-off points for hs-CRP to detect DM in women were for the FPG group, 60% and 57% for 2.5 mg/L (23.6 nmol/L), 2-hPG group, 60% and 54% for 2.1 mg/L (19.7 nmol/L), and 65% and 64% for HbA1c group, 2.9 mg/L (27.5 nmol/L). In men the corresponding specificity and sensitivity values were as follows: FPG group: 60% and 57% for 1.8 mg/L (16.9 nmol/L); 2-hPG group: 60% and 57% for 1.8 mg/L (16.9 nmol/L); and HbA1c group: 65% and 60% for 2.0 mg/L (19.0 nmol/L) (ROC curves Figure
(a) The area under the curve (AUC) and (b) the best cut-off points for hs-CRP to identify newly detected DM based on the FPG, 2-hPG, or HbA1c criteria in women and men.
Method | Gender | AUC | SEM |
|
95% CI |
---|---|---|---|---|---|
FPG | Women | 0.622 | 0.012 | <0.001 | 0.598–0.646 |
Men | 0.617 | 0.015 | <0.001 | 0.588–0.646 | |
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2-hPG | Women | 0.599 | 0.011 | <0.001 | 0.577–0.621 |
Men | 0.640 | 0.017 | <0.001 | 0.606–0.673 | |
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HbA1c | Women | 0.700 | 0.012 | <0.001 | 0.676–0.723 |
Men | 0.656 | 0.016 | <0.001 | 0.625–0.686 |
Method | Best cut-off points | |||||
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Women | Men | |||||
hs-CRP mg/L [nmol/L] | Sensitivity | Specificity | hs-CRP mg/L [nmol/L] | Sensitivity | Specificity | |
FPG | 2.5 [23.6] | 0.60 | 0.57 | 1.8 [16.9] | 0.60 | 0.57 |
2-hPG | 2.1 [19.7] | 0.60 | 0.54 | 1.8 [16.9] | 0.60 | 0.57 |
HbA1c | 2.9 [27.5] | 0.65 | 0.64 | 2.0 [19.0] | 0.60 | 0.62 |
ROC curves in women and men new-onset DM groups diagnosed with (a) FPG, (b) 2-hPG, and (c) HbA1c criteria (ROC: receiver operating characteristic curve; FPG: fasting plasma glucose; 2-hPG: 2-hour plasma glucose during OGTT; HbA1c: hemoglobin A1c).
The positive and negative predictive values (PPV and NPV) corresponding to the above-mentioned cut-points of hs-CRP in women were calculated as 58% and 59% for FPG, 57% and 58% for 2-hPG, and 64% and 65% for HbA1c and in men were 58% and 59% for FPG, 58% and 59% for 2-hPG, and 61% and 61% for HbA1c. The best results for PPV and NPV were obtained by the HbA1c method.
Our current population-based study identified 1,727 people with newly diagnosed DM based on at least one of the three methods. However, the people identified to have DM were substantially different for each of the three methods. In other words, the concordance rate for DM among the different methods of glycaemia testing was low. There are probably several reasons for this discrepancy. Characteristics of the people with DM and their risk factors may vary by the method used for the detection of DM.
Several studies have suggested that inflammation is associated with IR that takes part in the pathogenesis of T2DM and atherosclerotic disease [
Festa et al. demonstrated that people who developed DM (detected by an OGTT) had higher baseline serum CRP levels than those who did not develop DM [
A recent meta-analysis including 18 prospective studies demonstrated that high baseline CRP levels associated with future T2DM diagnosed based on FPG and/or 2-hPG criteria [
In our study, we found a positive correlation between hs-CRP levels and all glycaemia and IR parameters. However, after adjustment for age, sex, smoking, BMI, waist, and HT, positive correlations were maintained with HbA1c, 1-hPG and 2-hPG, fasting insulin, and HOMA-IR but not with FPG. In their later report Festa et al. stated that postchallenge glucose but not FPG was strongly correlated with baseline CRP [
Our results showed that among people with new DM the highest hs-CRP levels were obtained in those identified with the HbA1c criterion. HbA1c elevation at diagnosis is an indication of overt DM, but in a more advanced stage compared with new-onset DM detected with the FPG or 2-hPG criteria. As we did show a positive correlation between hs-CRP and HbA1c, it has been reported that people with DM with poorer glycaemic control had higher CRP levels [
Aronson et al. reported that CRP levels among middle-aged people were higher in those with DM and IFG when compared with the healthy subjects [
Wu and coworkers reported that high levels of hs-CRP were correlated with high levels of HbA1c and FPG in men and with only FPG in women [
We estimated the optimal cut-off hs-CRP and AUC-CRP with 95% CIs for DM for each of the three diagnostic methods separately. To the best of our knowledge, this is the first study aiming at determining hs-CRP cut-off points indicating new DM compared with each of the three methods assessing hyperglycaemia. The highest cut-off point for hs-CRP was obtained with HbA1c based new DM detection compared to FPG and 2-hPG methods. In fact we previously showed that new DM group detected with HbA1c has a more advanced metabolic disorder (higher BMI, waist, blood pressure, non-HDL-cholesterol, triglycerides, and insulin but lower HDL-cholesterol) than other new DM groups detected with FPG or 2-hPG [
den Engelsen et al. attempted to find a cut-off point for hs-CRP that would indicate the presence of the MS [
One of the greatest strengths of the present study is its national representative sampling with a large sample size and wide age range. In addition, this is the first study where all three currently proposed methods (2-hPG, FPG, and HbA1c) were used to define DM and each of them was compared with the inflammation marker, hs-CRP. The major limitations are the cross-sectional design and somewhat higher participation rate in women, controlled in the data analyses.
In brief, an hs-CRP level ≥1.8 mg/L (16.9 nmol/L) generally detects more than half of the people with new DM. External validation of our findings needs to be carried out in additional studies in other populations with reasonably large sample size before these findings can be generalized.
Our results revealed that hs-CRP may not further strengthen the diagnosis of new-onset DM. However, the highest hs-CRP among people with new DM was found in those identified with the HbA1c criterion. This suggests that high HbA1c may recognize new DM cases at a more advanced stage than FPG or 2-hPG in an OGTT. Clinical implications of this finding deserve further evaluation. It would be important to find out if people with newly detected DM with high hs-CRP require a more intensive therapy than those with low hs-CRP.
The funding agencies had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the paper.
The authors declare that they have no conflict of interests.
Ilhan Satman designed the study. Yildiz Tutuncu and Ilhan Satman completed the main data analysis and the preparation of the paper. Selda Celik, Nevin Dinccag, Kubilay Karsidag, Aysegul Telci, Sema Genc, Jaakko Tuomilehto, and Beyhan Omer contributed to interpretation of the data and preparation of the paper. Halim Issever contributed to statistical analysis and interpretation of the results. All authors read and approved the final paper.
This study was funded by the Turkish Scientific and Technical Research Council, TUBITAK (Project no. 109S166), The Society of Endocrinology and Metabolism of Turkey (SEMT), the Association of Diabetes Obesity and Metabolism (DOM), and Istanbul University Scientific Research Fund (Project nos. 6417 and 6418). The authors wish to thank the members of the TURDEP–II Study Group and other employees of the Ministry of Health for their valuable contribution. The authors also acknowledge Roche Diagnostics, BMS, Sanofi, Novo Nordisk, Eli Lilly, Novartis, Pfizer, Bayer Diagnostics, Medtronic, Boehringer-Ingelheim, Merck Sharp & Dohme, Sanofi-Pasteur, Astra Zeneca, Bilim Ilac, Becton-Dickinson, Merck Serono, Takeda, Abbott Medical, Tamek, Tetra-Pak, NUD, and NFGUD for providing unrestricted and unconditioned grants for the study. Special thanks are due to Monitor CRO for logistic assistance during the field survey and data entry. The authors are grateful to Sibel Kalaca for comments on the paper.