HUMAN CARTILAGE GLYCOPROTEIN 39 (YKL-40): A VIEW IN TYPE 2 DIABETES MELLITUS

HUMAN CARTILAGE GLYCOPROTEIN 39 (YKL-40): A VIEW IN TYPE 2 DIABETES MELLITUS

Rekha Kumari D. ^*1, Farid Babu M. ¹ and Balu Mahendran K. ²

Department of Biochemistry ¹, Konaseema Institute of Medical Sciences & Research Foundation, Amalapuram, Andhra Pradesh, India.

Division of Biochemistry ², Rajah Muthiah Medical College and Hospital, Annamalai University, Annamalainagar, Tamil Nadu, India.

ABSTRACT: Background:  Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes causes the combination of resistance to insulin action and an inadequate compensatory insulin secretory response. The degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected.  Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with type 2 diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular complications. Aim: The aim of this study was to determine the association between plasma human cartilage glycoprotein 39 (YKL-40) and glycated hemoglobin (HbA1C) in type 2 diabetic patients. Materials and methods: Thirty type 2 diabetic patients with the age group of 35 to 50 years were selected for this study and 30 age matched healthy individuals were selected as a control group. Plasma YKL-40 was assessed by ELISA method and routine investigations was done fully automated analyzer. Results: The mean levels of Plasma YKL-40 was significantly increased in diabetic patients compared with controls. Plasma YKL-40 was positively correlated with HbA1c. Conclusion:  Plasma YKL-40 might be useful to detect early stages of inflammation and endothelial dysfunction in T2DM patients. Hence measurement of plasma YKL-40 could be useful diagnostic marker for the assessment of vascular complications in type 2 diabetic patients.

Diabetes mellitus (DM),

Human cartilage glycoprotein 39 (YKL-40), Glycated hemoglobin (HbA1c)

INTRODUCTION: Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

Type 2 diabetes which accounts for 90–95% of those with diabetes, previously referred to as non–insulin-dependent diabetes, or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency.

An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia ¹. The risk of each of the microvascular and macrovascular complications of type 2 diabetes associated with hyperglycemia ². In patients with type 2 diabetes previous prospective studies have shown an association between the degree of hyperglycemia and increased risk of microvascular complications, sensory neuropathy, myocardial infarction, stroke, macrovascular mortality, and all-cause mortality ^3-10.

Human cartilageglycoprotein – 39 (YKL-40, chitinase-3-like-1 [CHI3L1], is a heparin-, chitin-, and collagen-binding lectin) produced by immunologically active cells such as macrophages ¹¹ and neutrophils ¹². YKL-40 is a member of the mammalian chitinase-like proteins and is a phylogenetically highly conserved serum protein ^13-15. Other cells shown to produce YKL-40 are vascular smooth muscle and endothelial cells ^16-18, arthritic chondrocytes ¹³, and cancer cells ¹⁹. YKL-40 was found to act as an inflammatory marker in relation to both acute and chronic inflammation as well as participate in the processes during the early stages of atherosclerosis ^{20, 21, 22}. So in this view the aim of the present study was to determine association between plasma YKL-40 levels and HbA1c in subjects with type 2 diabetes mellitus compared with normal subjects.

MATERIALS AND METHODS:  

A total of 30 type 2 diabetic patients of both sexes aged between 35-50 years on oral hypoglycemic drugs, attending diabetic out-patient department of Konaseema Institute of Medical Sciences &Research foundation, Amalapuram, Andhra Pradesh, India, were selected for our study after approval of Institutional Human ethics committee. We excluded the patients based on the following criteria: Patients on insulin, Smokers, Alcoholics, Tobacco chewers, abnormal urinary sediment, urinary tract infection, history of other active or chronic persistent infection or inflammatory disorders, neoplastic disorders, uncontrolled thyroid disorders, severe liver dysfunction, history of acute myocardial infarction, stroke, and occlusive peripheral vascular disease. Thirty healthy individual age, sex matched subjects were selected as control. Experiments were done in accordance with Helsinki declaration of 1975.

Biochemical analysis:

A fasting blood samples were obtained from the subjects immediately after enrolment. Blood samples were centrifuged at 2000×g for 10 min. Samples were analyzed for routine investigations blood sugar, lipid profile (Total Cholesterol, HDL,Triglycerides), glycosylated hemoglobin (HbA1C). Plasma YKL-40, insulin assessed by ELISA and the 2 hour post prandial venous plasma glucose (PPBS) estimation was also done.

Statistical analysis: Statistical analyses were carried out with SPSS 20.0. Values were expressed as mean ± standard deviation, p value < 0.05 was considered statistically significant. Normally distributed data were analyzed by using one-way ANOVA. The Pearson correlation test was used for correlation analysis.

RESULTS:

TABLE 1: COMPARISON OF BASELINE CHARACTERISTICS BETWEEN CONTROL AND TYPE 2 DIABETIC SUBJECTS.

Data are expressed as mean ±SD, p value <0.05 was considered statistically significant.

TABLE 2: COMPARISON OF BIOCHEMICAL PARAMETERS BETWEEN CONTROL AND TYPE 2 DIABETIC SUBJECTS.

Data are expressed as mean ±SD, p value <0.05 was considered statistically significant.

TABLE 3: CORRELATION BETWEEN PLASMA YKL-40 &MEASURED PARAMETERS

**Correlation is significant at the 0.01 level (2-tailed).

DISCUSSION: Glycemic exposure, i.e. the extent and duration of hyperglycemia, is a major risk factor for both micro and macrovascular complications of diabetes. Glycemic variability comprises “glucose variability” and “HbA1c variability”. Glucose variability relates to within day fluctuations of glycemia, especially as a consequence of post-prandial hyperglycemia ²³, which may eventually reflect in HbA1c levels above the normal range. Conversely, HbA1c variability relates to changes in glycaemia over longer periods of time ²⁴. However, three retrospective analyses of the Diabetes Control and Complications Trial (DCCT) found that within-day glucose variability does not contribute to the development of microvascular complications ^25-27. Recently, microvascular complications were shown to be predicted by HbA1c variability from one visit to the next, independently of average HbA1c  and known risk factors for microangiopathy, both in type 1 ^28-30 and type 2 ^31-33 diabetes.

Micro- and macrovascular complications are known to decrease the quality of life as well as shortens the life in diabetic patients. Despite intensive research in the pathological mechanisms resulting in improved and intensified treatment of diabetes and its vascular risk factors and complications, there is still a need for supplementary risk markers to understand the pathogenesis and predict the development of micro and macrovascular disease. So the measurement various inflammatory markers in biologic fluids might be useful for detection vascular complications in diabetic patients.

In the present study, we observed that plasma YKL-40 levels were significantly increased in type 2 diabetic patients. It therefore seems to be reasonable that it is the low-grade inflammation and endothelial dysfunction that account for the elevated YKL-40 levels in diabetic patients. And also our study shows that plasma YKL-40 levels show strong positive correlation with HbA1C and HOMA-IR.  Chronic hyperglycemia produces reactive oxygen species (ROS), protein glycation reactions which leads to the formation of advanced glycation end products (AGEs) and activates inflammatory signaling cascades, that leads inflammatory changes ^{34, 35}. Consequently, AGEs have key roles in the pathogenesis of vascular complications ³⁵In addition, our study shows that Plasma YKL-40 levels shows strong positive correlation with LDL, TGL and negative correlation with HDL. AGEs may promote atherogenesis by oxidizing low density lipoproteins (LDL) and causing changes in the intimal collagen ³⁶. The cellular effects of AGEs are mediated by specific receptors, one of which is the receptor for AGE (RAGE). The presence of RAGE has been demonstrated in all cells relevant to the atherosclerotic process including monocytes, macrophages, endothelial cells, and smooth muscle cells ³⁷. These vascular cells do not express significant amounts of RAGE under physiological conditions but can be induced to express RAGE in situations where either ligands accumulate and/or various transcription factors regulating RAGE are activated ³⁸. In the diabetic vasculature, cells expressing high levels of RAGE are often proximal to or co-localized in areas in which AGEs are abundant ^{39, 40}.

Aside from AGEs, tumor necrosis factor-α (TNF-α), S100/calgranulins, β-amyloid, amphoterin, and oxidative stress can upregulate RAGE expression, thus rendering these cells more susceptible to the effects of AGEs and chronic inflammation ^{38, 41, 42}.

Cell and animal studies suggest that limiting RAGE expression in vascular cells could modulate expression of various proinflammatory mediators and prevent atherosclerosis development ^{43, 44}. So therefore all these factors along with chronic hyperglycemia, low-grade inflammation and endothelial dysfunction may contribute the elevated YKL-40 levels in diabetic patients. Some other studies shown that patients that YKL-40 levels are associated with the presence and extent of CAD, are even higher in patients with MI and are associated with all-cause as well as cardiovascular mortality ^{45, 46}.  In this view, the precise role of YKL-40 remains elusive, but our study suggest that YKL-40 might be involved vascular complications of type 2 diabetic patients.

In conclusion plasma YKL-40 might be useful to detect early stages of inflammation and endothelial dysfunction in T2DM patients. Hence measurement of plasma YKL-40 could be potentially useful diagnostic marker for the assessment of vascular complications in type 2 diabetic patients.

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    How to cite this article:

    Kumari DR, Babu MF and Mahendran KB: Human Cartilage Glycoprotein 39 (YKL-40): A View in Type 2 Diabetes Mellitus. Int J Pharm Sci Res 2015; 6(11): 4852-56.doi: 10.13040/IJPSR.0975-8232.6(11).4852-56.

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