Correspondence: Ayfer Colak, MD, Tepecik Training and Research Hospital, Department of Clinical Biochemistry, Gaziler Cad., Yenisehir, 35120, Izmir, Turkey. Tel: � 90 232 4696969. Fax: � 90 232 4330756. E-mail: ayfercolak@gmail.com

(Received 26 December 2012 ; accepted 21 April 2013 )

ORIGINAL ARTICLE

Postload hyperglycemia is associated with increased subclinical infl ammation in patients with prediabetes

AYFER COLAK 1 , BARIS AKINCI 2 , GULDEN DINIZ 3 , HAKAN TURKON 4 , FARUK ERGONEN 2 , HULYA YALCIN 1 & ISIL COKER 1

Departments of 1 Clinical Biochemistry and 2 Endocrinology, Tepecik Training and Research Hospital, Izmir, 3 Department of Pathology, Dr. Behcet Uz Children ’ s Hospital, Izmir, and 4 Department of Medical Biochemistry , Canakkale Onsekiz Mart University , Faculty of Medicine , Canakkale , Turkey

Abstract Background/aims . In this present study, we aimed: (i) To clarify if prediabetes is associated with subclinical infl ammation independent of underlying obesity, and (ii) to evaluate the effect of postload glucose concentration on subclinical infl am-mation markers in a group of patients with elevated fasting glucose. Material and methods . In a cohort of 165 patients with newly detected fasting hyperglycemia, according to 75 g oral glucose tolerance test (OGTT), subjects were classifi ed either as newly diagnosed type 2 diabetes (diabetes group, n � 40), impaired fasting glucose (IFG) plus impaired glucose tolerance (IGT) (IFG/IGT group, n � 42) or IFG only (IFG group, n � 83). A control group ( n � 47) consisted of age- and body mass index (BMI)-matched healthy subjects with a normal OGTT. Circulating concentrations of lipids, insulin, interleukin-6 (IL-6), interleukin-8 (IL-8) and high sensitive C-reactive protein (hsCRP) were measured. HOMA index was calculated. Results . Subclinical infl ammation markers were elevated in patients with diabetes and IFG/IGT compared to healthy controls and also IFG patients (diabetes vs. control: p � 0.05 for hsCRP, IL-8, and IL-6; IFG/IGT vs. control: p � 0.05 for hsCRP, and IL-6; diabetes vs. IFG: p � 0.05 for hsCRP, and IL-6; IFG/IGT vs. IFG: p � 0.05 for hsCRP, and IL-6). In multiple regression analysis, postload glucose concentration was independently associated with circulating hsCRP and IL-6 concentrations when the data was controlled for age, gender, BMI and lipid concentrations ( p � 0.05 for hsCRP, and IL-6). Conclusion . Our results suggest that patients with prediabetes, independent of underlying obesity, have increased concentrations of subclinical infl ammation which is mostly driven by postload glucose concentrations.

Key Words: Diabetes mellitus , oral glucose tolerance test , prediabetic state , interleukin-6 , interleukin-8 , C-reactive protein

Introduction

The prevalence of type 2 diabetes is increasing world-wide, in parallel with the current obesity epidemic [1]. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are mild glucose metabo-lism disorders that are thought to be intermediate stages in the progression towards type 2 diabetes [1,2]. IFG is characterized by an elevated fasting glucose concentration which is consistently above the normal range but it is also not high enough to be defi ned as diabetes ( � 5.6 and � 7.0 mmol/L). IGT is defi ned by an elevated 2-h plasma glucose concentration ( � 7.8 and � 11.1 mmol/L) after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of a fasting glucose

concentration � 7.0 mmol/L. Some patients with IFG can also be diagnosed with IGT, while many have normal responses to OGTT. It is also possible for some patients with IFG to get diagnosed with type 2 diabetes after having an OGTT.

There is evidence that type 2 diabetes is related to a chronic low-grade infl ammatory state [1 – 5]. Many complex signaling pathways regulate chronic low-grade infl ammation associated with diabetes and obesity [3]. Pro-infl ammatory cytokines are media-tors of these pathways, and recent data indicate that the adipose tissue is one of the major sources of these cytokines [1 – 3]. Cytokines play a crucial role in many physiological and pathological processes such as hematopoiesis, angiogenesis, infl ammation,

Scandinavian Journal of Clinical & Laboratory Investigation, 2013; 73: 422–427

ISSN 0036-5513 print/ISSN 1502-7686 online © 2013 Informa HealthcareDOI: 10.3109/00365513.2013.798870

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Subclinical infl ammation in IGT 423

atherosclerosis, allergy, and autoimmunity [6,7]. It has been suggested that cytokines and acute phase reactants may alter insulin sensitivity by triggering different key steps in the insulin signaling pathway and overproduction of these mediators are involved in the pathogenesis of diabetes and prediabetes [8 – 10]. Interleukin-6 (IL-6) is one of the fi rst identi-fi ed cytokines, and acts primarily on the liver to stimulate the production of a number of acute-phase proteins [11]. It is implicated as a marker of insulin resistance and cardiovascular disease [12]. Circulat-ing IL-6 concentrations have been reported to be elevated in subjects with type 2 diabetes and corre-lated with the measures of insulin resistance [11 – 13]. Interleukin-8 (IL-8) is a pro-infl ammatory cytokine that is produced by various cell types involved in atherosclerosis. Circulating concentrations of IL-8 have been found to be elevated in patients with type 2 diabetes. It has been also reported that IL-8 con-centrations correlate with measures of adiposity and insulin resistance [14]. C-reactive protein (CRP) is an acute-phase reactant, the concentrations of which rise in response to acute or chronic infl ammation. Among several cytokines and acute-phase reactants which have been associated with atherosclerotic dis-ease, high sensitivity CRP (hsCRP) is the best stud-ied marker. Increased hsCRP concentrations have been demonstrated in patients with type 2 diabetes [8]. It has also been shown that hsCRP predicts car-diovascular mortality both in the general population and in patients with type 2 diabetes.

In this present study, we focused on early stages of type 2 diabetes. In a cohort of subjects with newly detected fasting hyperglycemia, we generated study groups for IFG only, IFG plus IGT (IFG/IGT) and newly diagnosed type 2 diabetes. To clarify whether prediabetes is associated with subclinical infl amma-tion that is independent of underlying obesity, we assessed circulating concentrations of IL-6, IL-8 and hsCRP in patients in the study groups and age- and body mass index (BMI)-matched healthy controls with a normal OGTT. The effect of postload glucose concentration on subclinical infl ammation markers was evaluated.

Materials and methods

This study was performed in Izmir Tepecik Training and Research Hospital, Izmir, one of the biggest and busiest state hospitals in Turkey, in terms of outpatient clinics and patient beds. All patients included in this study were referred to our labo-ratory by the endocrinology clinic for OGTT. According to clinical follow-up protocol at the Endocrinology Department, all patients with BMI higher than 25 should be tested for OGTT. The total number of referred patients was 1100 in a study period between February 2010 and January

2011. A prepared questionnaire for this study for the purpose of detection of inclusion and exclusion criteria was given to all patients. Fasting glucose greater than 100 mg/dl (5.6 mmol/L) was the inclusion criteria for our study. Subjects were excluded if they had previously been diagnosed with diabetes. Patients with known cardiovascular disease, familial hyperlipidemia, hypertension, acute infec-tion, chronic infl ammatory disease and any other systemic diseases, or patients being administered with any kind of medication were not enrolled. Smokers and alcohol consumers were excluded. Only 165 patients were included in our study according to detected criteria. Control group was composed of 47 age- and BMI-matched healthy subjects.

The study was approved by the Institutional Review Board, and informed consent was obtained for each participant. In order to evaluate carbo-hydrate intolerance, 75-g OGTT was performed. Type 2 diabetes, impaired glucose tolerance (IGT) and im paired fasting glucose (IFG) were defi ned according to American Diabetes Association (ADA) recommendations.

Patients were classifi ed either as newly diagnosed type diabetes (diabetes group, n � 40), IFG plus IGT (IFG/IGT group, n � 42) or IFG only (IFG group, n � 83). In the control group ( n � 47), glucose intol-erance was excluded by a 75 g OGTT.

Height (m) and weight (kg) were measured under fasting conditions with subjects in light clothing and without shoes. BMI was calculated as body weight divided by square height. Blood was taken from the cannulated antecubital vein between 08:00 and 09:00 h after 12-h overnight fasting. Blood samples were transferred into tubes containing fl uoride for plasma glucose assay and gel separator tubes (Improve, Hamburg, Germany) for other parameters. Blood samples for serum preparation were allowed to clot. Samples were centrifuged at 3000 g for 10 min. Serum samples were stored at � 70 ° C for up to two months.

According to the manufacturer ’ s report, all sam-ples may be stored at � 20 ° C for up to two months without causing any instability. Glucose concentra-tions were measured by a hexokinase method with the Olympus AU-2700 analyzer. Triglycerides, total cholesterol and high density lipoprotein (HDL) cho-lesterol were measured by an enzymatic method with Olympus AU-2700 analyzer using reagents from Olympus Diagnostics (Gmbh, Hamburg, Germany). Low density lipoprotein (LDL) cholesterol was cal-culated by the Friedewald ’ s equation method. Insu-lin, IL-6, IL-8 and hsCRP concentrations were measured by a chemical immunoassay method with an Immulite Analyzer (Siemens, Llanberis, UK). The detection limits were 2 pg/mL for IL-6 and IL-8, 0.1 mg/L for hsCRP, respectively. The intra-assay and inter-assay coeffi cients of variations were 6.2% and 7.5% for IL-6, 3.8% and 7.4% for IL-8, 4.2%

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424 A. Colak et al.

and 8.3% for hs-CRP, respectively. Homeostasis model assessment (HOMA-IR) score, an estimate of insulin resistance, was calculated as fasting serum insulin (mU/L) � fasting glucose (mg/dL) / 405.

Statistical analysis was performed using Statisti-cal Package of Social Science (SPSS Inc, Chicago, IL, USA), version 15.0 for Windows. Variable distri-butions were assessed by the Kolmogorov-Smirnov normality test. According to variable distribution, one-way ANOVA followed by Bonferroni ’ s post-hoc comparisons tests or Mann-Whitney U test were used to compare variables of patients. Categorical variables were compared by the Chi-square test. Cor-relation analyses were performed using Pearson ’ s or Spearman ’ s coeffi cients, according to variable distri-bution. Regression analysis was employed to assess correlations between studied parameters. Data were expressed as mean � standard deviation (SD). A p -value of less than 0.05 was accepted as statisti-cally signifi cant.

Results

Table I shows the comparison of patient groups and healthy controls. There was no signifi cant difference in terms of age, gender and BMI between the groups ( p 0.05). Patients with newly diagnosed type 2 diabetes had slightly elevated total cholesterol ( p � 0.034) and triglyceride ( p � 0.026) concentra-tions compared to healthy controls. Triglyceride concentrations were also signifi cantly different between the diabetes and IFG groups ( p � 0.018). Diabetic patients had increased LDL cholesterol compared with IFT/IGT group (diabetes vs. IFG/IGT p � 0.037). IFG/IGT and diabetic patients had higher HOMA index compared with healthy con-trols (diabetes vs. control p � 0.008, IFG/IGT vs.

control p � 0.003). The concentrations of subclini-cal infl ammation markers were elevated in patients with diabetes compared to healthy controls ( p � 0.045 for hsCRP, p � 0.025 for IL-8, and p � 0.004 for IL-6). In the same way, patients with IFG/IGT had increased concentrations of subclini-cal infl ammation markers ( p � 0.015 for hsCRP and p � 0.002 for IL-6), although the difference in IL-8 concentrations was not statistically different ( p 0.05). On the other hand, patients with IFG had similar hsCRP, IL-6 and IL-8 concentrations compared to controls ( p 0.05). Patients in the dia-betes and IFG/IGT groups had elevated hsCRP and IL-6 concentrations compared to those in the IFG group (diabetes vs. IFG p � 0.013 for hsCRP, diabetes vs. IFG p � 0.012 for IL-6; IFG/IGT vs. IFG p � 0.002 for hsCRP, IFG/IGT vs. IFG p � 0.002 for IL-6). The concentrations of subclin-ical infl ammation markers were similar between the diabetes and IFG/IGT groups ( p 0.05).

Table II summarizes the correlation of serum infl ammation markers with the other parameters. Serum hsCRP was positively correlated with BMI, fasting glucose, post-load 2 h glucose, fasting insulin, HOMA index. Serum IL-6 concentrations were pos-itively correlated with BMI, fasting and post-load glucose concentrations. IL-8 concentrations were positively associated with age, fasting glucose, post-load glucose, total cholesterol and triglyceride con-centrations, and HOMA index.

In multiple regression analysis, fasting and post-load glucose concentrations were independently associated with circulating hsCRP and IL-6 concen-trations when the data was controlled for age, gender, BMI and lipid concentrations (fasting glucose: model r 2 : 0.257, beta: 0.143, p � 0.021 for hsCRP; model r 2 : 0.054, beta: 0.144, p � 0.039 for IL-6; postload

Table I. Comparison of characteristics and laboratory fi ndings of the subjects.

Control (mean � SEM)

IFG (mean � SEM)

IFG/IGT (mean � SEM)

Diabetes (mean � SEM)

n (M/F) 47 (12/35) 83 (24/59) 42 (6/36) 40 (15/25)Age (years) 45.1 � 1.0 45.7 � 0.9 46.9 � 1.3 46.5 � 1.3BMI (kg/m 2 ) 32.0 � 0.8 30.2 � 0.6 32.1 � 0.9 31.5 � 0.9Fasting glucose (mmol/L) 5.1 � 0.3 6.1 � 0.4 * 6.3 � 0.3 * † 7.6 � 1.3 * † ‡ Glucose 2-h (mmol/L) 5.5 � 1.2 5.6 � 1.2 9.1 � 1.0 * † 10.9 � 1.1 * † ‡ Fasting insulin (mU/L) 9.6 � 0.9 10.0 � 0.7 11.2 � 0.9 10.3 � 1.1HOMA-IR 2.2 � 0.2 2.7 � 0.2 3.1 � 0.3 * 3.4 � 0.3 * Triglycerides (mmol/L) 1.6 � 0.7 1.6 � 0.7 1.8 � 1.0 2.1 � 1.1 * † Cholesterol (mmol/L) 5.2 � 0.9 5.3 � 1.0 5.2 � 0.9 5.5 � 1.0 * HDL cholesterol (mmol/L) 1.3 � 0.3 1.3 � 0.3 1.3 � 0.3 1.1 � 0.2LDL cholesterol (mmol/L) 3.3 � 0.7 3.3 � 0.7 3.1 � 0.7 3.5 � 0.8 ‡ hsCRP (mg/L) 3.8 � 0.5 3.7 � 0.4 6.3 � 0.9 * † 6.3 � 1.0 * † IL-8 (pg/mL) 10.3 � 0.6 10.8 � 0.5 18.7 � 3.7 14.9 � 1.6 * † IL-6 (pg/mL) 2.4 � 0.2 2.6 � 0.2 7.3 � 2.2 * † 4.6 � 0.9 * †

IFG, impaired fasting glucose; IGT, impaired glucose tolerance; BMI, body mass index; HOMA-IR, homeostasis model assessment; HDL, high density lipoprotein; LDL, low density lipoprotein; IL-6, interleukin-6; IL-8, interleukin-8; hsCRP, high sensitive C-reactive protein. * p � 0.05 for the difference between IFG or IFG/IGT or diabetes and control; † p � 0.05 for the difference between IFG/IGT or diabetes and IFG; ‡ p � 0.05 for the difference between diabetes and IFG/IGT.

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glucose: model r 2 : 0.257, beta: 0.143, p � 0.021 for hsCRP; model r 2 : 0.054, beta: 0.144, p � 0.039 for IL-6). On the other hand, postload glucose, but not fasting glucose, was independently associated with a CRP concentration greater than 3 mg/L that is con-sidered high risk for cardiovascular disease (1 mg/dl increase in postload glucose; model r 2 : 0.281, OR: 1.006, 95% CI: 1.001 – 1.012, p � 0.029).

Discussion

Our results showed that IFG/ IGT, but not IFG alone, was associated with increased concentrations of circulating markers of infl ammation which would put those subject into a high risk group for develop-ing cardiovascular disorders like patients with type 2 diabetes. On the other hand, IFG was not associated with increased concentrations of infl ammation if there was no accompanying IGT. The relationship between IGT and subclinical infl ammation was inde-pendent of underlying obesity and other confound-ing factors like age and gender.

Prediabetes is a dysmetabolic state of glucose concentration between diabetes and normal glucose tolerance (NGT) [15]. Although both IFG and IGT are commonly known as prediabetes, in fact, these two conditions are somehow different in terms of the underlying pathophysiology and the severity of risk for type 2 diabetes and cardiovascular disorders. The results of recent studies demonstrate that, although both IFG and IGT are characterized by ß -cell dys-function, the defects in insulin secretion in IFG and IGT are very distinct [16]. Subjects with IGT have impaired late-phase insulin secretion and increased insulin resistance (IR) in skeletal muscle. In contrast, subjects with IFG have impaired early-phase insulin secretion and increased IR in liver [16]. Studies have also shown that physiological bases of fasting and postload glucose concentrations on OGTT are affected by different factors. Fasting glucose depends on the ability to maintain adequate basal insulin

secretion, and on appropriate concentrations of insu-lin sensitivity in the liver to control hepatic glucose output, whereas postload concentrations are associ-ated with peripheral insulin resistance, most impor-tantly at the concentration of skeletal muscle [15]. In the same way, there are some discrepancies between the clinical features of IFG and IGT. Sub-jects with IGT exhibit a more severe defi cit in insu-lin secretion [17,18]. While IFG is also associated with insulin resistance and increased risk of cardio-vascular pathology, the risk is lesser than IGT. Combination of these components have also been associated with progression to type 2 diabetes, car-diovascular disease and increased mortality [15 – 18]. In this study although infl ammation markers were not signifi cantly different between control group and IFG group, signifi cant differences was found in DM and IFG/IGT groups compared with control group. Only IL8 was not statistically different between IFG/IGT and control group. The levels of subclinical infl ammation markers were similar between diabetes and the IFG/IGT groups.

The study also demonstrated that DM and IFG/IGT groups have higher hsCRP and IL6 levels com-pared to IFG group. In multiple regression analysis, fasting and postload glucose levels were indepen-dently associated with circulating hsCRP and IL-6 levels when the data was controlled for age, gender, BMI and lipid levels. Several studies reported the association between IFG, IGT and hsCRP and they also reported that elevated hsCRP levels are more strongly associated with IGT than IFG [19,20]. It was previously reported that 2-h glucose concentra-tion measured during an OGTT is an independent cardiovascular disease risk factor whereas fasting glucose is not [21]. This present study indicates that postload glucose, but not fasting glucose, is indepen-dently associated with a CRP concentration greater than 3 mg/L that is considered high risk for cardio-vascular disease. While both IGT and IFG are known to be associated with increased risk of cardiovascular

Table II. Correlation analyses in all subjects.

IL-6 IL-8 hsCRP

r p r p r p

Age (years) 0.087 NS 0.188 0.006 0.000 NSBMI 0.237 � 0.001 0.114 NS 0.519 � 0.001Fasting glucose 0.200 0.003 0.190 0.006 0.163 0.018Glucose 2-h 0.274 � 0.001 0.200 0.003 0.227 0.001Fasting insulin 0.084 NS 0.124 NS 0.309 � 0.001HOMA-IR 0.104 NS 0.163 0.017 0.315 � 0.001Triglycerides 0.099 NS 0.265 � 0.001 0.220 NSCholesterol 0.066 NS 0.145 0.034 � 0.020 NSHDL cholesterol � 0.012 NS � 0.026 NS � 0.002 NSLDL cholesterol 0.011 NS 0.037 NS � 0.043 NS

IL-6, interleukin-6; IL-8, interleukin-8; hsCRP, high sensitive C-reactive protein; BMI, body mass index; HOMA-IR, homeostasis model assessment; HDL, high density lipoprotein; LDL, low density lipoprotein; NS, not signifi cant.

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disorders, studies have shown that the risk is much greater in case of IFG/IGT which might be partly due to increased infl ammation that was observed in our study. Different mechanisms may contribute to the relationship between elevated glucose and infl am-mation. Glucose induces proinfl ammatory changes, including activator protein-1, matrix metalloprotei-nase and tissue factor, which regulate processes that are potentially relevant to atherosclerotic plaque rup-ture and thrombosis. It has been reported that glu-cose challenge stimulates reactive oxygen species generation [7,22]. Acute increases in blood glucose concentrations may increase the production of free radicals by non-enzymatic glycation and by an imbal-ance in the ratio of NADH to NAD � induced by glucose in cells [23,24].

It has become clear that the increased adipose tissue is not a simple reservoir for excess nutrients, but rather an active and dynamic organ capable of expressing several cytokines [3,4,9,11]. Recent data have suggested that increased adiposity causes low-grade infl ammation which produce pro-infl ammatory cytokines or deregulate the cytokine response follow-ing stimulation [25,26]. A signifi cant correlation between obesity and subclinical infl ammation was also observed in our study. It is very well known that obesity is associated with insulin resistance and may lead to prediabetes and type 2 diabetes. However, in our study, IFG/IGT patients had increased concen-trations of infl ammation markers when compared to BMI matched controls. Furthermore, regression analysis showed that the relationship between IFG and subclinical infl ammation was independent of underlying obesity.

There were several limitations of our study. First, we measured circulating concentrations of infl amma-tion markers cross sectionally. Our study could not provide the readers with any prospective data on car-diovascular outcome. Second, we have just focused on biochemical markers of atherosclerosis, not on any of radiological measures like carotid intima thick-ness or fl ow mediated dilation. However, we were able to evaluate subclinical infl ammation in a very homogeneous group of subjects with IFG and IFG/IGT with no confounding factor, and compare those concentrations to both healthy subjects and patients with type 2 diabetes.

In conclusion, our results suggest that IFG/ IGT, but not IFG alone, leads to increased concentrations of subclinical infl ammation markers which is associ-ated with increased risk for cardiovascular disorders. This observation highlights the clinical importance of postload glucose concentration on OGTT.

Acknowledgements

We would like to thank Siemens Diagnostic Com-pany Turkey A.S, who supplied IL-6, IL-8 and

hsCRP kits which we used free of charge to support our study. All other fi nancial requirements were met by the authors ’ institutes.

Declaration of interest: The authors report no confl ict of interest. The authors alone are responsible for the content and writing of the article.

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oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Con

nect

icut

on

08/2

4/13

For

pers

onal

use

onl

y.