Level of serum IL-12 and its correlation with endothelial dysfunction, insulin resistance, proinflammatory cytokines and lipid profile in newly diagnosed type 2 diabetes

https://doi.org/10.1016/j.diabres.2011.07.037Get rights and content

Abstract

Aim

This study was an attempt to evaluate and correlate serum interleukin-12 (IL-12) with different circulating markers in newly diagnosed type-2 diabetes mellitus (T2DM) for possible progression of atherosclerosis.

Methods

For this study, we recruited 1968 family members of diabetics and 349 had abnormal glucose. Out of 349 subjects, 197 were T2DM as per American Diabetes Association guidelines and further investigated for cardiovascular abnormalities. 63 T2DM have high sensitive C-reactive protein (hsCRP) > 3.0 mg/l and cardiovascular complications. Overall, 150 subjects, 50 healthy, 50 T2DM (D1) and 50 T2DM with cardiovascular complications (D2) were enrolled and investigated for soluble markers.

Results

The levels of serum glucose, proinflammatory cytokines (IL-6, IL-12, tumor necrosis factor), endothelial dysfunction markers [vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-1 (ICAM-1), nitric oxide] and lipid abnormality were highest in D2 group. Correlation and regression study showed that IL-12 was dependent on hsCRP, insulin resistance, VCAM-1, ICAM-1 and lipids. The multivariate stepwise regression analysis demonstrates that hsCRP contributes significantly for variance of IL-12.

Conclusion

This study reveals that, even first-time diagnosis of T2DM, subjects with higher insulin resistance and abnormal lipids have elevated IL-12, endothelial dysfunction and proinflammatory markers. Further increased hsCRP enhance IL-12 which up-regulate cardiovascular disease progression.

Introduction

Diabetes mellitus is a devastating metabolic disorder and continues to be a cause of morbidity and mortality throughout the world [1]. This is a primary disease of carbohydrate metabolism due to deficient/absences of insulin has propensity towards vascular endothelial dysfunction resulting into micro and macroangiopathy. In the last two decades our understanding about hyperglycemia and its consequences has increased dramatically. The management of diabetes has changed from glucocentric to organo protective and specially the vascular endothelium, which could lead cardiovascular complications. In type-2 diabetes mellitus (T2DM), endothelial dysfunction with insulin resistance (IR) is significantly linked to the risk of initial or persistent cardiovascular malfunction [2]. Atherosclerosis in T2DM patients is multi-factorial and comprises intricate interaction of hyperglycemia, hyperlipidemia, hyperinsulinemia and oxidative stress. The sequel that leads from endothelial dysfunction to atherosclerosis is referred as an imbalance in the production of the mediators, which may hamper the endothelium homeostasis and predispose the endothelium to a pro-thrombotic and pro-atherogenic milieu [3], [4]. Hence, it is useful to measure markers of vascular endothelial function to provide insight into the evolution and prognosis of vascular diseases. Endothelial dysfunction has been documented in T2DM [5], [6], [7].

Interleukin-12 (IL-12) is an important cytokine produced by antigen presenting T cells, such as dendritic cells, macrophages and natural killer cells and it also plays a critical role in cell-mediated immunity. It has been observed that IL-12 plasma concentrations are elevated in T2DM, which may contributes to atherosclerotic plaque formation and accelerates the development of macrovascular complications [8], [9].

Taking into consideration the multi-factorial origins of endothelial dysfunction which further steps forward to cardiovascular complications in T2DM, the present study has conceived to explore the possible role of IL-12 in progression of cardiovascular disease and to know which factor is responsible for the alteration of IL-12.

Section snippets

Subjects and study design

This study was conducted at the authors’ Diabetic Clinic in the University Hospital. A total 1968 subjects from the diabetic family were included in this study. They were checked for fasting/random glucose levels. Out of 1968 subjects 349 participants have fasting blood sugar levels more than 5.6 mmol/l or random blood sugar level more than 7.8 mmol/l (impaired blood sugar). These 349 subjects were further checked for T2DM as per recent American Diabetes Association criteria i.e. fasting blood

Results

Table 1 summarizes the clinical, metabolic and soluble markers information of the participants included in this study.

T2DM patients with cardiovascular complications (D2) had highest serum fasting glucose, post-prandial glucose, HbA1c%, total cholesterol, LDL-C, VLDL-C and triglyceride concentrations than D1 and healthy groups (p < 0.001). The concentration of HDL-C was highest in healthy group than diabetic groups (p < 0.001). The level of VLDL-C was not significant among D1 and D2 groups. The

Discussion

Diabetes, characterized by chronic hyperglycemia, is associated with significant morbidity due to long-term complications, such as diabetic nephropathy, atherosclerosis, and hypertension. Endothelial dysfunction is regarded as a key event in the development and progression of atherosclerosis and thought to be the major cause of vascular disease due to hyperglycemia. High glucose has many toxic effects on endothelial cells, such as impaired endothelium-dependent relaxation, decreased nitric

Conflict of interest

There are no conflicts of interest.

Acknowledgements

The financial assistance extended by Banaras Hindu University is greatly acknowledged. M. Mishra is highly thankful to UGC for financial support as Dr. D.S. Kothari Postdoctoral fellowship {4-2/2006(BSR)/13-334/2010(BSR)}. Authors, H. Kumar and S. Bajpai are thankful to UGC and CSIR respectively for financial assistance as SRF.

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