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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 20  |  Issue : 3  |  Page : 245-258

Association between the inflammatory biomarker YKL-40 (chitinase-3-like 1) in type-2 diabetic patients and ischemic heart diseases


1 Department of Medical Biochemistry, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission18-Sep-2020
Date of Decision13-Dec-2021
Date of Acceptance08-Feb-2022
Date of Web Publication11-Oct-2022

Correspondence Address:
MSc Aisha H.T.M Abdelhafez
Department of Medical Biochemistry, Faculty of Medicine for Girls, Al-Azhar University, 11754, Nasr City, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_157_20

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  Abstract 


Background and aim 4Low-grade inflammation plays an important role in type-2 diabetes and coronary-artery disease pathogenesis. YKL-40 is expressed in cells of innate immunity and is associated with endothelial dysfunction. The research aims to see if YKL-40 levels in the blood could be used as a diagnostic biomarker in type-2 diabetic patients. Additionally, to evaluate if there is a link between YKL-40 and ischemic heart disease in diabetic patients.
Patients and methods The study was carried out on 75 Egyptian individuals (25 healthy persons as control, 25 type-2 diabetic patients without ischemic heart disease, and 25 type-2 diabetic patients with ischemic heart disease). Enzyme-linked immunosorbent assay was used to assess YKL-40 levels.
Results There was a significant elevation in the levels of YKL-40 when patients with type-2 diabetes mellitus (T2DM) uncomplicated by ischemic heart disease and patients with T2DM complicated by ischemic heart disease compared with the control group (P<0.05). The optimal YKL-40 cutoff threshold was greater than 65 ng/ml. Furthermore, the level of YKL-40 was significantly higher (P<0.05) in patients with T2DM complicated by ischemic heart disease compared with individuals with T2DM not complicated by ischemic heart disease. The best cutoff point for YKL-40 to differentiate between those two groups was greater than 110 ng/ml.
Conclusion In type-2 diabetic patients, YKL-40 could be a valuable diagnostic marker for vascular complications.

Keywords: coronary-artery disease, inflammation, type-2 diabetes mellitus, YKL-40


How to cite this article:
Abdelhafez AH, El Shawaf ZA, Abbas MA, El-Kader MA, Ibrahim EE. Association between the inflammatory biomarker YKL-40 (chitinase-3-like 1) in type-2 diabetic patients and ischemic heart diseases. Al-Azhar Assiut Med J 2022;20:245-58

How to cite this URL:
Abdelhafez AH, El Shawaf ZA, Abbas MA, El-Kader MA, Ibrahim EE. Association between the inflammatory biomarker YKL-40 (chitinase-3-like 1) in type-2 diabetic patients and ischemic heart diseases. Al-Azhar Assiut Med J [serial online] 2022 [cited 2023 Jan 27];20:245-58. Available from: http://www.azmj.eg.net/text.asp?2022/20/3/245/358037




  Introduction Top


Diabetes is a group of metabolic disorders characterized by high blood sugar levels caused by a deficiency in insulin secretion, insulin action, or both. Insulin resistance and, in most cases, relative insulin deficit characterize type-2 diabetes disease, which affects 90–95% of diabetics [1].

The CHI3L1 protein, also known as YLK-40, is a heparin, chitin, and collagen-binding glycoprotein discovered in mouse breast cancer cells. Human YKL-40 is a single 383-aminoacid polypeptide chain with an isoelectric point of 7.6 and an estimated molecular mass of 40,476 Da [2].

The crystallographic three-dimensional structure of human YKL-40 shows the typical fold of family-18 glycosyl hydrolases. The N-terminal catalytic domain of the glycohydrolase-18 family adopts the triosephosphate isomerase (TIM) fold, which is characterized by the (/)Y-barrel structure [3]. Because the catalytically required glutamic acid residue in the active site of YKL-40 has been replaced, the protein exhibits no enzymatic activity [4].

The structure of YKL-40 is organized into two globular domains, a large-core domain that contains a (β/α)8 domain structure with a TIM-barrel fold, and a small α/β domain with five antiparallel β-strands and one α-helix that is inserted into the loop between strand β7 and helix α7 of the TIM-barrel fold ([Figure 1]) [5].
Figure 1 The crystallographic three-dimensional structures of human YKL-40. The (β/α)8 barrel domain is colored blue and yellow. The α+β domain is represented in light blue. The N-glycosylation at residue Asn60 is shown as ball-and-stick. The β-strands of the (β/α)8 barrel are labeled b1–b8.

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YKL-40 is produced by monocytes/macrophages, neutrophils, osteoclasts, chondrocytes, vascular smooth-muscle cells, fibroblasts, endothelial cells, and dendritic cells, among others. YKL-40 is produced locally by inflammed tissues, such as adipose tissues in type-2 diabetes mellitus (T2DM) [4].

YKL-40 has been linked to a variety of ligands in numerous studies. The glycoprotein was discovered to be able to assist the cross-linking of integrin and syndecan-1. Syndecan-1 is a transmembrane receptor composed of heparin-sulfate proteoglycans. Syndecan-1’s interaction with other receptors, such as integrins, has been shown to promote cell adhesion and angiogenesis [6].

The focal adhesion kinase is activated as a result of this interaction [7], which results in angiogenesis through the stimulation of mitogen-activated protein/kinaseErk (P-ERK). Focal adhesion kinase can also activate the PI3K/Akt-signaling pathways, which are essential for cell survival, differentiation, and fibrogenesis [8], by phosphorylating a number of downstream targets like BAD (BCL2 antagonist of cell death), caspase 9, FKHR (forkhead transcriptional factor), mTOR (mammalian target of rapmycin), and IKK (I b kinase) (glycogen-synthase kinase-3).

Interleukin-13 subunit 2 (IL-13Ra2) has been identified as a potential YKL-40 receptor. The activation of YKL-40 was shown to be independent of its interaction with IL-13Ra2, revealing the presence of a coreceptor [6].

YKL-40 regulates apoptosis, pyroptosis, inflammasome activation, oxidative damage, antimicrobial responses, melanoma metastasis, and TGF-1 activation via IL-13R2-dependent processes via stimulating the signaling pathways for mitogen-activated protein kinase and protein kinase B (Akt) [6].

The islets from DM patients had the characteristic histology of inflammatory tissue with immune-cell infiltration. Inflammasomes, which serve as sensors for innate immunity, recognize metabolic risk signals by detecting elevated glucose levels [9]. The inflammasomes activate caspase-1, which converts pro-IL-1β to active IL-1β, which then binds to its membrane receptor and activates the transcription factor NF-B, leading to the production of a variety of cytokines and chemokines, as well as the recruitment of immune cells, including macrophages [4].

Increased glucose concentrations boost the production of inflammatory mediators in pancreatic islets produced by free fatty acids [10]. Free fatty acids cause IR by inducing inflammation in adipose tissue via the Toll-like receptor-4 (TLR4) and Toll-like receptor-2 (TLR2) pathways [11].

As a key contributor to the pathophysiology of several metabolic diseases, obesity has a significant impact on both immune system function and inflammation [12]. The innate and adaptive immune systems’ cells invade insulin-sensitive organs during obesity, inducing an inflammatory response [4]. Protein kinases involved in Toll signaling, such as inhibitor of kappa-B kinase and c-jun N-terminal kinase, as well as TNF receptors, are activated in response to this, and are capable of phosphorylating insulin receptor substrate 1 at the serine-307 residue. This reduces insulin receptor substrate 1’s interaction with the beta subunit of the insulin receptor, resulting in reduced insulin signaling [13].

Obesity generates low-grade inflammation, which is characterized by macrophage infiltration of adipose tissue [14], which is the primary source of various circulating inflammatory chemicals observed in the obese condition and is critical in the development of IR. As a result, IR is induced by a combination of macrophage accumulation and insulin target-cell dysfunction [15]. The emergence of IR and T2DM has thus been linked to obesity and low-grade inflammation [16].

YKL-40 is one of numerous inflammatory and metabolic dysfunction-promoting chemicals generated by adipose tissue [17].

Many chemokine genes show increased expression in adipose tissue as a result of obesity. One of these is MCP-1, which is mostly generated in the extracellular space and acts as a local factor. MCP-1 is a crucial link between the inflammatory response in adipose tissue and IR, since it alters adipocyte function, increases chemotaxis, and monocyte migration into the subendothelial space [18].

YKL-40 stimulates macrophages to produce MCP-1 and other inflammatory chemokines like CXCL2 and MMP-9. Consequently, adipocyte function may be affected, and monocyte infiltration into the subendothelia area may be increased. As a result, YKL-40 may influence insulin sensitivity in adipose tissue by regulating macrophage infiltration and subsequent activation [7].

When smooth-muscle cells migrate across the intima in response to external stimuli during the formation of atherosclerotic plaques, YKL-40 enhances their adhesion, spreading, and migration. This supports the theory that YKL-40 plays a role in the formation of atherosclerotic plaques [4].

The purpose of this research is to assess if YKL-40 levels in the blood could be used as a diagnostic biomarker in Egyptians with type-2 diabetic patients. Additionally, we aim to see if there is a link between YKL-40 and ischemic heart diseases in type-2 diabetic patients.


  Patients and methods Top


The current case–control study took place between September 2017 and March 2018. Samples were collected from Al zahraa University Hospital in Cairo (Department of Internal Medicine) and investigations were carried out at Faculty of Medicine, Al-Azhar University for Girls. The study was approved by the Medical Ethics Committee in the faculty and an informed written consent was obtained from all participants. The study was conducted following Helsinki standards as revised in 2013. It included 75 participants that were classified into three groups:
  1. Control group (group I) that included 25 participants (14 females and 11 males) showing no symptoms or signs of diabetes mellitus or ischemic heart diseases were selected as a control group and confirmed by normal blood glucose and normal lipid profile. Their mean age was 57.00±7.19 years.
  2. Diabetic group not complicated with ischemic heart disease (group II) included 25 patients (10 females and 15 males) suffering from diabetes mellitus type-2. Their mean age was 58.56±7.22 years.
  3. Diabetic group complicated with ischemic heart disease (group III) included 25 patients (17 females and eight males) suffering from T2DM in combination with ischemic heart disease. The average age of the group was 60.96±5.13 years.


Those with an acute infection, asthma, rheumatologic diseases, or cancer were excluded from further analysis to avoid potential confounding factors.

Complete blood count, blood glucose level (fasting and postprandial), glycated hemoglobin (HbA1c), lipid profile, and serum creatinine and urea were all performed on both the patients and the controls, in addition to a complete history taking, full clinical examination, and BMI calculation. YKL-40 levels were measured by enzyme-linked immunosorbent assay (ELISA).

Specimen collection

Each case had 10 ml of blood drawn from the antecubital vein after an overnight fast of 8–12 h. HbA1c was measured using 2 ml of fresh blood. At room temperature, eight milliliters of blood were allowed to coagulate. The samples were then centrifuged at 3000 revolutions per minute for 10 min. Fresh serum fasting glucose, urea, creatinine, and lipid profile measurements were performed on some of the separated sera. The rest sera were maintained at −80°C, until they were used in the YKL-40 assay using an ELISA.

Two further milliliters of blood were collected 2 h after a light meal and allowed to clot at room temperature. After that, the samples were centrifuged at 3000 rpm for 10 min to determine the 2-h postprandial blood glucose level.

Methods

Determination of serum glucose levels (fasting and postprandial) [19], lipid profile, total cholesterol [20], triglyceride [21], high low-density lipoproteins (HDL) [22], low-density lipoprotein (LDL) [23], HbA1c [24], serum urea [25], and serum creatinine [26].

Estimation of YKL-40 in serum using an ELISA kit developed by SinoGeneClon Biotech Co. Ltd, HangZhou, China (Catalog No: SG-10388). By covering a microtiter plate with purified human YKL-40/CHI3L1 antibody, producing solid-phase antibody, and then adding YKL-40/CHI3L1 to the wells, the kit can assess the quantitative level of YKL-40/CHI3L1 in a sample. To make an antibody–antigen–enzyme–antibody complex, combine YKL-40/CHI3L1 antibody with labeled HRP; then, after thoroughly washing, add TMB substrate solution; TMB substrate turns blue when HRP enzyme is catalyzed; the reaction is stopped by adding a stop solution, and color change is measured at 450 nm. The concentration of YKL-40/CHI3L1 in the samples is determined by comparing the OD of the samples to the standard curve.

Statistical methods

The data were collected, edited, coded, and entered into IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. version 23 (Statistical Package for Social Science). Nonparametric data were expressed as a percentage of the total and as a numeric value, while parametric data were expressed as a mean and SD.

The following formulas were used to calculate the mean and SD:





where Σ: sum.

(Xi): each value in the series.

n: number of values in the series.

Comparing the mean±SD of two groups was done using the unpaired t-test:



where t (df): value at the degrees of freedom. df: degrees of freedom.

X: mean of sample X. Y: mean of sample Y. nX: number of sample X.

nY: number of sample Y. SDp: pooled SD (SD of both samples).

Measuring the mutual correspondence between two values was done

using the Spearman correlation coefficient



Where Σ: sum.

X: mean of sample X.

Xi: each value in the series.

Y: mean of sample Y.

Yi: each value in the series.

Nonsignificant is defined as a P value greater than 0.05.

P value less than 0.05 is considered significant.


  Results Top


In terms of clinical data, the study groups were control (group I), diabetes patients without cardiovascular disorders (group II), and diabetic patients with cardiovascular complications (group III). Our research found no statistically significant differences (P>0.05) between the three groups in terms of sex or age. In comparison with group I, group III had a statistically significant increase in BMI (P2<0.05). However, no statistically significant differences in BMI were found between groups I and II (P1>0.05) or groups II and III (P3>0.05). In addition, group III had a significantly longer duration of diabetes than group II (P<0.05). When compared with group II, group III had diabetes for a significantly longer period of time (P<0.05) .

In terms of laboratory data, our research found a significant increase in fasting blood sugar (FBS), postprandial blood sugar (PPBS), HbA1C, and creatinine in group III (P2<0.05) and group II (P1<0.05) as compared with group I. The difference between groups III and II, however, was not statistically significant (P3>0.05).

In comparison with group I, there was a significant increase (P2<0.05) in urea in group III. The difference between groups I and II, however, was not statistically significant (P1>0.05). Additionally, no statistically significant difference (P3>0.05) existed between groups III and II.

Cholesterol, triglyceride, and LDL values were higher in group II (P1<0.05) and group III (P2<0.05) as compared with group I. In addition, there was a significant increase in group III (P3<0.05) when compared with group II.

Cholesterol, triglyceride, and LDL values were increased in group II (P1<0.05) and group III (P2<0.05) as compared with group I. Furthermore, there was a significant increase in group III (P3<0.05) when compared with group II. HDL values in group II (P1<0.05) and group III (P2<0.05) were significantly lower than in group I. Furthermore, these were considerably lower in group III compared with group II (P3<0.05). Furthermore, they were significantly lower in group III (P3<0.05) as compared with group II.

The mean YKL-40 values in groups I, II, and III were 42.51±25.95, 96.90±20.28, and 148.70±34.19 ng/ml, respectively, in this study. The differences between the three groups were statistically significant (P<0.05). Group II (P1<0.05) and group III (P2<0.05) showed a significant increase when compared with group I. Furthermore, there was a significant increase in group III (P3<0.05) when compared with group II [Table 1] and [Figure 2]. [Figure 3] and [Table 2] illustrate:
Table 1 Mean (standard deviation (SD) of serum YKL-40 level in the control group (group I) and patient subgroups group II and group III

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Figure 2 Mean serum YKL-40 (ng/ml) in control group (group I) versus patients and subgroups group II and group III.

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Figure 3 Receiver-operating characteristic curve for YKL-40 as predictor to differentiate between (a) control and diabetes mellitus (DM), (b) control and DM with IHD, and (c) DM and DM with IHD.

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Table 2 Sensitivity and specificity of serum YKL-40 in diabetes type-2 and ischemic heart disease prediction

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For the YKL-40 level, the best cutoff to differentiate between healthy control and diabetic patients was found to be greater than 65 ng/ml with a sensitivity of 100%, specificity of 96%, and area under the curve (AUC) of 96.9% on the receiver-operating characteristic curve (ROC) ([Figure 3]a).{Figure 3}

The optimal cutoff point for YKL-40 levels in diabetic individuals with IHD and healthy controls is revealed by the ROC. It was found to be greater than 65 ng/ml, with a sensitivity of 100%, specificity of 96%, and AUC of 97.6% ([Figure 3]b).

The ROC demonstrates the optimal cutoff point for the YKL-40 level to distinguish between diabetic patients without IHD complications and diabetic patients with IHD complications. It was found greater than 110 ng/ml with a sensitivity of 92%, a specificity of 84 percent, and an AUC of 88.2% ([Figure 3]c).


  Discussion Top


Diabetes mellitus is a metabolic disorder characterized by hyperglycemia caused by a lack of insulin synthesis, insulin action, or both. Diabetes-related chronic hyperglycemia has been associated with numerous long-term microvascular complications affecting the eyes, nerves, and kidneys, in addition to an increased risk of cardiovascular disease [27].

T2D is characterized by subclinical systemic inflammation, which plays a role in the development of atherosclerosis in all stages and is linked to the development of stroke, peripheral vascular disease, and myocardial infarction, as well as mortality from cardiovascular disease. A variety of systemic inflammatory markers, such as acute-phase reactants, proinflammatory cytokines, and cell adhesion molecules, have been associated with metabolic-syndrome parameters, including insulin resistance. Innate immunological activation is therefore likely to be one of the underlying causes of both atherosclerosis and T2D [28].

The protein YKL-40 is classified as an acute-phase protein as it is secreted by a range of cells involved in infection and inflammation. Following an inflammatory stimulus, serum concentration rises in patients with chronic inflammatory diseases and acute infections. Furthermore, vascular smooth-muscle cells and endothelial cells release YKL-40. This stimulation of vascular endothelial cells and VSMC migration, reorganization, and adhesion suggests a function in angiogenesis. As a result, YKL-40 has been presented as a viable inflammatory biomarker and biomarker for angiogenesis/atherosclerosis, making it analogous to other inflammatory biomarkers raised in disorders, including insulin resistance and diabetes type-2 [28].

This study focuses on the effects of YKL-40 on the development of diabetes and associated cardiovascular consequences. All patients and controls were biochemically evaluated through estimation of their serum glucose levels (FBS and PPBS), HbA1c, lipid profile, and kidney-function tests (BUN and creatinine). The level of YKL-40 in serum was also measured using ELISA in both the control and patient groups. The results of the patients were correlated to the control group as regards clinicopathological data.

The mean YKL-40 concentrations in the control group (group I), diabetes patients without cardiovascular complications (group II), and diabetics with cardiovascular complications (group III) were 42.51±25.95, 96.90±20.28, and 148.7±34.19 ng/ml, respectively ([Table 1]). Both diabetic-patient groups (group II and group III) had significantly higher mean values of YKL-40 than the control group (group I). In addition, the YKL-40 level in group III was significantly higher than in group II.

These findings support those of Kulkarni et al. [29] and Kumari et al. [1], who found that serum levels of YKL-40 were significantly higher in patients with T2DM than in controls (P<0.05). They believe that higher YKL-40 levels in diabetic individuals are attributed to endothelial dysfunction and low-grade inflammation.

When comparing diabetic patients to the controls, Paarivalavan et al. [30] and Han et al. [31] found that the levels of YKL-40 increased significantly (P>0.05). They suggested that YKL-40 could be involved in a range of metabolic disturbances in diabetics with chronic complications.

In a study similar to ours, Rndbjerg et al. [32] found significantly greater levels of YKL-40 in diabetic patients compared with controls. They claimed that endothelial dysfunction plays an essential role in diabetic microangiopathy and macroangiopathy development. YKL-40 enhances chemotaxis, cell adhesion, spreading, and migration of endothelial cells, implying that it aids in the development of atherosclerotic plaques by causing vascular smooth-muscle cells to emigrate beyond the intima in response to exogenous signs.

Other studies were completed by Nielsen et al. [33] and Rathcke et al. [28] who noticed increased levels of YKL-40 in diabetic patients. They claimed that YKL-40 is a marker of inflammation in general and it is probable that YKL-40 plays a vital role in atherosclerotic pathologies like cardiovascular disease and diabetic-complication progression.

These findings support those of EL-Attar et al. [34], who noticed that the levels of YKL-40 were significantly higher in both diabetes groups without and with cardiovascular complications (both P<0.05) when compared with the controls. In addition, when comparing diabetic patients with cardiovascular complications to diabetic patients without cardiovascular complications, the level of YKL-40 was significant (P=0.005).

They stated that active macrophages take up lipids during the onset and progression of atherosclerosis, and these lipid-rich macrophages subsequently produce mediators of inflammation that encourage migration and proliferation of VSMC, resulting in atherosclerosis. Activated macrophages, neutrophils, and VSMC produce YKL-40 in many tissues during inflammation. As a result, the role of YKL-40 in atherosclerosis and CAD in the initial stages may be explained.

The levels of YKL-40 were considerably higher in diabetic patients and/or IHD by Thomsen et al. [35]. According to the study, innate immune-system activation and low-grade inflammation are involved in endothelial dysfunction, insulin resistance, and the progress of diabetes and atherosclerosis.

In terms of gender, our research found no statistically significant differences between group III [17 (68.0%) females, eight (32.0%) males), group II (10 (40.0%) females, 15 (60.0%) males], and group I [14 (56.0%) females, 11 (44.0%) males] ([Table 3]).
Table 3 Mean(SD of different clinical data of the control group (group I) vs patients’ subgroups group II and group III

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This finding is consistent with Huang et al. [36], who found no significant differences between the three groups regarding sex (P>0.05).

Pu et al. [37] disagree with the results in this study as they showed significant increase in male patients in the diabetic patients complicated with IHD group when compared with diabetic patients − not complicated with IHD.

In our research, the mean age of type-2 diabetic patients with IHD (group III) (60.96±5.13 years), diabetic patients without IHD (group II) (58.56±7.22 years), and the control group (group I) (57.00±7.19 years) showed no significant differences (P>0.05) ([Table 1]). YKL-40 and age in the patient’s groups did not correlate significantly (r=0.051 and P>0.05) ([Table 7]).

Draz et al. [38] found no significant differences in age (P>0.05) between diabetic participants with IHD and diabetics without IHD groups.

These findings contradict the results of Yoo et al. [39], who found that the age (P<0.05) showed a significant increase between diabetic patients with CAD and patients with diabetes without CAD.

When comparing group III (11.44±5.90 years) to group II (8.80±1.30 years) in this study, diabetes duration had a significant increase (P<0.05) in the mean value ([Table 1]). YKL-40 and diabetes duration were significantly correlated positively (r=0.418 and P<0.05) ([Table 7]).

These findings are consistent with the results of El-Attar et al. [34], who found that the diabetes duration was high significantly (P<0.05) in diabetic patients with IHD than diabetic patients without IHD. They explained that this result goes with the longer duration of diabetes, the more the predisposition to cardiovascular complications being exposed to more risk factors, and the pathology of diabetes on the blood vessels. Additionally, they found that the YKL-40 and diabetes mellitus duration correlated positively (P>0.05).

The mean BMI in groups I, II, and III was 24.84±2.97, 26.20±2.18, and 26.80±3.00 kg/m2, respectively, in this study. In comparing group III and group I, there was an increase (P<0.05) in BMI significantly. However, there was no difference (P>0.05) between group II and group I or group II and group III ([Table 1]). In the patients’ group, YKL-40 and BMI did not show any correlation (r=−0.058 and P>0.05) ([Table 7]).

These results agree with that of Draz et al. [38] and Yoo et al. [39]. They reported that the BMI was not significantly different (P>0.05) when comparing diabetic individuals with CAD to diabetic patients without CAD.

On the other hand, Scarabin-CarrÌet al. [40] found that diabetic patients complicated with cardiovascular disease and cerebrovascular disease had higher BMI than the noncomplicated group.

In this study, the mean FBS values in group I, group II, and group III were 84.88±14.40, 133.20±12.32, and 136.84±10.10 mg/dl, respectively. In comparison with group I, there is an increase significantly in group II (P1<0.05) and group III (P2<0.05). However, there is no statistical difference (P3>0.05) between group II and group III ([Table 4]), which we may explain by the similarities in the history of medication usage, which includes oral hypoglycemic medications and insulin. In both patient subgroups, group II (r=0.554 and P<0.05) and group III (r=0.406 and P<0.05), YKL-40 and FBS was correlated positively ([Table 7]).
Table 4 Mean(SD of different laboratory parameters in the control group (group I) and patient subgroups group II and group III

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Our results agree with Han et al. [31], who found that FBS increased significantly (P<0.05) in diabetic patients compared with the control group. In addition, they found that YKL-40 and FBS had a significant positive correlation (P<0.05).

In addition, Kim et al. [41] agree with the results in the presenting study as they found nonsignificant differences between diabetic patients − complicated with IHD and diabetic patients − not associated with IHD (P>0.05). They found in both groups that the history of medication use, including oral hypoglycemic agents, insulin, antihypertensive agents, and statins was similar, this might explain these results.

Xu et al. [42] disagree with the results in this study as they reported that FBS levels were significantly increased (P<0.05) in diabetic patients complicated with IHD in comparison with diabetic patients − not associated with IHD. They explained that hyperglycemia for a long time directly damages the vascular endothelial cells, promotes leukocyte aggregation, platelet aggregation, and other factors, inducing atherosclerosis.

In our study, the mean values of PPBS were 115.56±10.73, 205.08±25.25, and 209.96±31.83 mg/dl in group I, group II, and group III, respectively. There is an increase in group II (P1<0.05) and group III (P2<0.05) in comparison with group I significantly. But, group III and group II did not show any significant difference (P3>0.05) ([Table 4]). We can explain that by similarity in medication use history, including insulin and oral hypoglycemic agents. YKL-40 and PPBS did not show significant correlation in patients’ groups (r=0.244 and P>0.05) ([Table 7]).

Kim et al. [41] agree with our results as they reported that diabetic patients with IHD and diabetic individuals without IHD did not show statistically significant differences (P>0.05). They found that both groups had similar histories of medication treatment for diabetes, HTN, and dyslipidemia, which could explain the findings.

In this study, the mean HbA1c readings in group I, group II, and group III were 5.70±0.50, 7.19±0.70, and 7.50±0.58%, respectively. Additionally, there is an increase significantly in group II (P1<0.05) and group III (P2<0.05) in comparison with group I. However, group III and group II did not display significant differences between them (P3>0.05) ([Table 4]). In the patients’ group, YKL-40 and HbA1C had a significant positive correlation (r=0.404 and P=0.05) ([Table 7]).

Rndbjerg et al. [32] found that the mean HbA1c in diabetic patients was significantly higher than the controls (P<0.05), which is similar to the findings of our study.

Draz et al. [38] found that the mean HbA1c in diabetic-complicated patients did not show any significant differences compared with noncomplicated patients (P>0.05), indicating that CAD could occur even in asymptomatic patients with few risk factors.

These findings confront the results of Dale et al. [43], who found that diabetic elderly patients complicated with CAD had elevated HbA1c and increased death risk fourfold from IHD compared with a control without diabetes and diabetic patients with good diabetes control. This difference from our findings could be since the age of the noncomplicated group was lower in the study of Dale.

In this study, the mean cholesterol levels in group I, group II, and group III were 154.92±10.19, 175.48±34.31, and 200.76±33.77 mg/dl, respectively. Group II (P1<0.05) and group III (P2<0.05) revealed a significant increase in comparison with group I. In addition, group III had a significant increase (P3<0.05) as compared with group II ([Table 5]). YKL-40 and cholesterol did not have any significant correlation (r=0.252 and P>0.05) in the patient’s group ([Table 7]).
Table 5 Mean(SD of lipid profile in the control group and patient subgroups (group II and group III)

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These are consistent with the findings of Huang et al. [36], who found a significant increase in serum cholesterol levels in diabetic patients when compared with the control group, as well as a significant increase (P<0.05) in cholesterol levels in diabetic patients with IHD when compared with diabetic patients without IHD.

However, this opposes Pu et al. [37] findings, which did not show any significant changes between diabetic patients with IHD complications and diabetic patients without IHD complications regarding blood-cholesterol levels (P>0.05). We can explain that by the fact that the individuals in the research were on lipid-lowering medications.

In this study, triglyceride (TG) levels in group I, group II, and group III were 92.52±13.02, 118.32±18.53, and 131.52±33.65 mg/dl, respectively. Group II (P1<0.05) and group III (P2<0.05) revealed a significant increase in comparison with group I. In addition, group III had a significant increase (P3<0.05) as compared with group II ([Table 5]). YKL-40 and triglyceride did not have any significant correlation (r=0.111 and P>0.05) in the patient’s group ([Table 7]).

These findings concur in some ways but differ in others from those of EL-Attar et al. [34], who found that the level of serum triglyceride was significantly greater (P=0.05) in the diabetic patients with IHD compared with the diabetic patients without IHD. They did not find any significant difference (P>0.05) between the DM − complicated with IHD and the DM − not complicated with IHD groups, contradicting our findings. They also revealed that YKL-40 and triglyceride had a strong positive correlation (P<0.05) in the patient’s group.

These contradict the findings of Yoo et al. [39], who found no significant differences in serum triglyceride levels (P>0.05) when comparing diabetic individuals with asymptomatic CAD to diabetic patients without CAD. These findings could be specific to patients with no symptoms or related to the selection process since they chose the patients from an outpatient clinical setting.

In this study, HDL values in group I, group II, and group III were 43.39±1.22, 38.48±1.94, and 32.48±0.92 mg/dl, respectively. Group II (P1<0.05) and group III (P2<0.05) revealed a significant decrease in comparison with group I. In addition, group III had a significant decrease (P3<0.05) as compared with group II ([Table 5]). YKL-40 and HDL has a significant negative correlation (r=−0.619 and P<0.05) in the patient’s group.

This finding is consistent with that of Pintó et al. [44], as they found that HDL showed a significant decrease (P<0.05) in diabetic patients with IHD complications compared with diabetic patients without IHD complications.

Xu et al. [42] did not agree with the results in this study as they reported that HDL levels were not significantly different (P>0.05) between diabetic patients with IHD complications and diabetic patients without IHD complications.In this study, the mean LDL levels in group I, group II, and group III were 96.36±13.22, 110.52±10.57, and 122.00±10.00 mg/dl, respectively. Group II (P1<0.05) and group III (P2<0.05) revealed a significant increase in comparison with group I. In addition, group III had a significant increase (P3<0.05) as compared with group II ([Table 5]). They also revealed that YKL-40 and LDL had a positive correlation (r=0.484 and P<0.05) ([Table 7]) in the patient’s group.

These are consistent with the findings of Kulkarni et al. [29] and Paarivalavan et al. [30], who found a significant elevation in LDL (P<0.05) in diabetic individuals when compared with the control group.

Banu et al. [45], on the other hand, did not find any significant change in LDL between diabetic patients and control volunteers (P>0.05).

Another study by Pu et al. [37] did not show any significant difference between diabetic patients without IHD complications and diabetic individuals with IHD complications (P>0.05) regarding the LDL levels.

In this study, the mean urea values in group I, group II, and group III were 25.06±2.80, 26.24±2.45, and 26.88±1.27 mg/dl, respectively. Group III (P2<0.05) revealed a significant increase in comparison with group I. However, group II and group I did not display significant differences (P1>0.05), also group II and group III (P3>0.05) ([Table 6]). YKL-40 and urea did not show significant correlation in patients’ groups (r=0.244 and P>0.05) ([Table 7]).
Table 6 Mean(SD of kidney-function tests of the control group and patient subgroups (group II and group III)

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Table 7 Correlation of YKL-40 with laboratory parameters among studied groups

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These are consistent with the findings of Kumari et al. [1], who did not find any significant difference in urea between diabetic patients and the control group (P>0.05).

Paarivalavan et al. [30] did not agree with the results in our study as they reported that urea levels had a significant increase (P<0.05) in diabetes patients when compared with the control group, even though it was within the normal range physiological. It could explain that the T2DM individuals in the study were yet in the initial stages of diabetic nephropathy.

The mean creatinine levels in group I, group II, and group III were 0.62±0.06 0.95±0.16, and 1.00±0.12 mg/dl, respectively. Group II (P1<0.05) and group III (P2<0.05) revealed a significant increase in comparison with group I. However, group II and group III did not display significant differences ([Table 6]) (P3>0.05). YKL-40 and creatinine did not show significant correlation in patients’ groups (r=−0.087 and P >0.05).

Our results agree with EL-Attar et al. [34], who found that serum creatinine levels increased significantly (P<0.05) in diabetic patients with IHD compared with the control group. Furthermore, they noticed that YKL-40 and creatinine (P<0.05) had a significant positive correlation (P<0.05).

Yoo et al. [39] did not agree with the results in this study as they reported that creatinine levels (P>0.05) were not significantly different (P>0.05) between diabetic individuals with asymptomatic CAD and diabetic patients without CAD.

Limitations

Since it was a retrospective study, many patients’ data had to be eliminated because they were incomplete. In addition, collecting a sufficient number of suitable controls for a more efficient comparison was extremely difficult. As a result, the study sample may not be a realistic representation of the overall T2DM and IHD population. Furthermore, the occurrence of unrecorded illnesses and medications in the control group is a possibility.


  Conclusion Top


The results of this investigation revealed that type-2 diabetic patients had significantly higher levels of serum YKL-40, implying that it may have a role in diabetes pathogenesis.

In addition, this study found that patients with T2DM who had ischemic heart disease had higher serum levels of YKL-40 than T2DM patients who did not have ischemic heart disease, implying that YKL-40 could recognize effectively early stages of inflammation and endothelial dysfunction in T2DM patients.

As a result, we could use serum YKL-40 as a valuable diagnostic biomarker in T2DM to detect vascular complications.

Recommendations

In view of the above findings and discussion, we recommend:
  1. Further similar studies on YKL-40 with a larger sample size of Egyptian diabetic patients, both with and without cardiovascular, are needed to produce more generalized conclusions.
  2. Conducting a genetic study aiming at the discovery of possible polymorphisms in the YKL-40 gene among Egyptians that could influence its serum level and biological action .


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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