International Conference on Pure and Applied Sciences (ICPAS 2018) 69

Some Cardiac Marker Levels and Cytokines in Diabetic Patients

Esmail S. Kakey1 and Shahen S. Hussen2

1Department of Radiology, Erbil Polytechnic University, Koya Technical Institute, Erbil Polytechnic University, Kurdistan, Region – Iraq 2Department of Biology, Koya University, Daniel Mitterrand Boulevard, Koya KOY45 AB64, Kurdistan Region – Iraq

Abstract–This study conducted 80 diabetic males and females effects on in the adipose tissue and probably patients hospitalized in Surgical specialty Hospital/Erbil also in other organs. Cytokines, which release from adipose Governorate their ages ranging from 40 to 80 years, and 40 tissue appears to be stimulated by inflammatory stimuli and nondiabetic persons as a control. The study aimed to assess also by catecholamines and β--adrenergic stimulation. A cardiac markers, leptin, and cytokine marker levels in diabetic study reported that concentrations of TNF-α and IL-6 patients with cardiovascular complications. Blood samples were collected from patients and control subjects for further analysis. are elevated in insulin resistance and T2DM [3]. Cytokine Fully automated ELISA system was used for the determination is factors have effects on many physiological functions of cytokine markers, leptin, and cardiotropic-1 (CT-1) level. The including, appetite, energy expenditure, insulin sensitivity, results of the current study revealed that the cytokine parameter inflammation, and coagulation [4]. Interleukine-6 and TNF-α levels, human interleukin-6, and tumor necrosis factor-α and (CT-1) are adipocytokines that induce insulin resistance, and their were showed significantly higher levels in diabetic patients of both concentrations are increased in patients with T2DM [5]. sexes. Moreover, the results of the current study revealed that leptin Adipokines such as adiponectin, leptin, and resistin level was significantly higher in diabetic patients of both sexes. are bioactive mediators that have a significant role in With respect to the cardiac marker levels, T high sensitive the regulation of lipid and carbohydrate metabolism, and (TNT-hs), the results showed significantly higher levels of TNT-hs and - creatine kinase-myoglobin creatine contributed in the inflammatory responses [6]. Adipokines, kinase-myoglobin in diabetic patients of both sexes. in general, regulate the lipid and glucose metabolism, high insulin sensitivity, arrange food intake and body weight, Index Terms—Cardiac markers, Cytokines, Diabetes, Leptin. also protect from chronic inflammation in adipose tissue [7]. Adipocytokines can play a role in the observed link between obesity and its associated morbidities, such as coronary I. Introduction artery disease and insulin resistance, therefore, dysregulation of adipocytokines caused by dysfunctional adipocytes that in diabetes is associated with increased could involve to the pathogenesis of various complications risks of , increase in hemoglobin A1c (HbA1c) of obesity [8]. Leptin level in patients with longstanding DM is associated with an 8% increased the relative risk of did not differ from normal, but it was significantly lower in heart failure. Despite a consistent association between patients newly diagnosed with DM, it has been shown that hyperglycemia and heart failure, no causal relationship has low level of leptin inhibit insulin release, and higher levels been proven [1]. Cardiovascular disease (CVD) is the principal have a stimulating effect on this, this could explain some complication occurring in patients with type 2 diabetes conflicting results regarding the effect of leptin in T2DM [9]. mellitus (T2DM). Diabetes leads to elevation of many CV risk factors. The insulin resistance in the DM contributes to the elevation of CVD risk factors in DM patients [2]. II. Procedure Adipose tissue also synthesizes cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), that have In this study, a case–control design was used for the investigation of some biochemical parameters including leptin and some cytokines, cardiac markers in diabetic Pure and Applied Science Conference | Koya University subjects with CV complications. The current study included Paper ID: ICPAS2018.BPH26, 5 pages 80 diabetic subjects (40 males and 40 females) with CV DOI: 10.14500/icpas2018.bph26 complications were hospitalized in surgical specialty hospital Received 18 February 2018; Accepted 27 March 2018 cardiac center/Erbil Governorate. Patients ages were ranging Conference paper: Published 01 August 2018 from 40 to 80 years. Furthermore, the control group was 40 Conference track: Biotechnology and Physiology (BPH) Corresponding author’s e-mail: [email protected] nondiabetic healthy persons of both sexes. Blood samples Copyright © 2018 Esmail S. Kakey, Shahen S. Hussen. This is were collected from the cases and control individuals, an open access article distributed under the Creative Commons serum samples were obtained by centrifugation of blood for Attribution License. biochemical parameters assay.

DOI: http://dx.doi.org/10.14500/icpas2018 70 International Conference on Pure and Applied Sciences (ICPAS 2018)

A. Biochemical Assay The results of the current study showed significant immunoassay method “sandwich type” was used increased (P<0.05) in the level of serum leptin in diabetic for the quantitative determination of leptin level in human patients (20.99 ± 1.366 mg/L and 23.63 ± 1.854 mg/L), serum by Solarbio ELISA Kit (China), and fully automated respectively, as compared with controls (17.56 ± 2.710 mg/L ELISA system (DS2™ - Automated ELISA System). The and 14.59 ± 0.963 mg/L), respectively (Table III). serum leptin was measured by Solar bio human superoxide dismutase assay kit. 96-well ELx 800 absorbance microplate Reader (Biotech, USA). IV. Discussion The serum IL-6 was measured by Solar bio human protein The results of the current study showed a significant increase carbonyl assay kit. 96-well ELx 800 absorbance microplate in the level of serum leptin in men and women diabetic cases. Reader (Biotech, USA). These results confirmed the previous study which reported Enzyme immunoassay method “sandwich type” was used that increased leptin level is associated with DM [10]. for the quantitative determination of IL-6 level in human Furthermore, the data presented in this study revealed that serum using the solar bio ELISA Kit (China), and fully the average level of leptin was increased in diabetic patients, automated ELISA system (DS2™ - Automated ELISA this finding coincided with previous results which found an System). increased level of leptin in diabetic patients compared to The serum cardiotrophin-1 (CT-1) was measured by Solar none diabetics. The age-related differences in leptin level bio human superoxide dismutase assay kit. 96-well ELx 800 may be explained by that in addition to an increase in fat absorbance microplate Reader (Biotech, USA). mass; aging is associated with a redistribution of adipose The serum TNF–α was measured by the Solar bio human tissue from peripheral to central fat depots and also with total antioxidant capacity assay kit. 96-well ELx 800 endocrine changes [11,12]. Obesity is a major risk factor for absorbance microplate Reader (Biotech, USA). diabetes, which can expect to find an increased level of leptin Cardiac markers, troponin T high sensitive (TNT-hs) and in obesity-related diabetic patients compared to controls. creatine kinase-myoglobin (CK-MB) were estimated using Many researchers found an increase in the leptin level in Cobas diagnostic kit (Roche/COBAS e 411 INTEGRA), type 2 diabetic patients with diabetic cardiopathy [13,14]. with the fully automated chemical analyzer. The activated Results of different studies conducted on diabetes and (TNT - hs and CK-MB) method was used for this research. leptin have been inconsistent. For instance, some studies demonstrated an association between diabetes and leptin levels. Since leptin has a restraining effect on normal insulin III. Results secretion by the , it has been proposed that in DM, The results of the current study showed significant elevation (P < 0.05) in the level of serum interleukin-6 TABLE I (IL-6) in diabetic patients (133.4 ± 4.762 ng/L and 132.1 ± Cytokine Parameters in Diabetic Patients 15.83 ng/L) in both sexes, respectively, as compared with Parameters Sex Control Case P nondiabetic controls (104.9 ± 11.79 ng/L and 93.54 ± IL‑6 (ng/L) Male 104.9±11.79 133.4±4.762 0.013 8.932 ng/L), respectively. The results of the current study Female 93.54±8.932 132.1±15.83 0.005 showed significant elevation (P < 0.05) in the level of serum TNF-α (pg/m) Male 108.6±9.202 164.3±12.92 0.006 (TNF-α) in diabetic patients (164.3 ± 12.92 pg/ml and 132.7 Female 87.58±8.073 132.7±9.062 0.007 ± 9.062 pg/ml) in both sexes, respectively, as compared with CT‑1 (pg/ml) Male 36.03±9.354 71.57±8.024 0.015 Female 38.43±9.258 65.28±5.353 0.032 nondiabetic men and women controls (108.6 ± 9.202 pg/ml Results expressed as mean±SEM. SEM: Standard error mean, IL‑6: Interleukin‑6, and 87.58 ± 8.073 pg/ml), respectively. The results of the TNF‑α: Tumor necrosis factor‑α, CT‑1: Cardiotrophine‑1 current study showed significant elevation (P < 0.05) in the levels of serum CT-1 in diabetic men and women cases TABLE II (71.57 ± 8.024 pg/ml and 60.50±6.530 pg/ml) in both sexes, Cardiac Biomarkers in Diabetic Patients respectively, as compared with nondiabetic male controls Parameters Sex Control Case P (36.03 ± 9.354 pg/ml and 38.34 ± 13.73 pg/ml), respectively TNT‑hs (ng/mL) Male 0.207±0.084 0.432±0.108 0.046 (Table I). Female 0.208±0.171 0.388±0.124 0.030 The results of the current study showed significant elevation CK‑MB (ng/mL) Male 0.941±0.184 3.338±0.805 0.048 (P > 0.05) in the level of serum troponin T-hs (TNT-hs) in Female 0.492±0.122 1.252±0.186 0.010 diabetic patients (0.200 ± 0.138 ng/mL and 0.202 ± 0.174 ng/ Results expressed as mean±SEM. SEM: Standard error mean, CK‑MB: Creatine mL) in both sexes, respectively, as compared with nondiabetic kinase‑myoglobin, TNT‑hs: Troponin T high sensitive control groups (0.003 ± 0.000 ng/mL and 0.003 ± 0.000 ng/ mL), respectively. The results showed significant increased TABLE III (P < 0.05) in the level of serum CK-MB in diabetic patients Leptin Level in Diabetic Patients (3.338 ± 0.805 ng/mL and 1.252 ± 0.186 ng/mL) in both Parameters Sex Control Case P sexes, respectively, as compared with the concentrations in Leptin (mg/L) Male 17.56±2.710 20.99±1.366 0.035 the nondiabetic controls (0.941 ± 0.184 ng/mL and 0.492 ± Female 14.59±0.963 23.63±1.854 0.008 0.122 ng/mL), respectively (Table II). Results expressed as Mean±SEM

DOI: http://dx.doi.org/10.14500/icpas2018 International Conference on Pure and Applied Sciences (ICPAS 2018) 71 leptin resistance might occur in b-cells that may worsen of adipose tissue is associated with increased number of hyperinsulinemia observed in DM subjects. Given that adipose tissue macrophages, which are responsible for obesity can be a result of leptin resistance, leptin resistance increases in serum concentration of pro-inflammatory is likely to be involved in the development of the disease. cytokines, especially IL-6 and TNF-α expression [28]. The Like leptin resistance, leptin deficiency is significant in the elevation in the levels of IL-6 and TNF-α in the current pathogenesis of severe insulin resistance in uncontrolled study might be caused by the relationship between insulin insulin-deficient diabetes mellitus [15]. resistance IR and each of the pro-inflammatory cytokines Leptin is also increased in T2DM which is strongly studies associated with DM [29]. Several studies have shown associated with obesity and insulin resistance. Whereas that increased adipocyte size is associated with insulin leptin may be increased in both diabetes and obesity, it resistance. Enlarged fat cells secrete increased amounts of is not the cause of either disease. It has been suggested adipokines include TNF-α and IL-6 which could contribute that leptin mediates insulin resistance and as such may be to insulin resistance. Moreover, high HbA1c level was a possible treatment for insulin resistance. Diet-induced associated with both TNF-α and IL-6 high levels, also high leptin resistance can be reversed through dietary changes, insulin resistance was associated with TNF-α, with IL-6 and its administration can be effective in combating insulin high levels [30]. TNF-α level is associated with IR, and this resistance. Leptin levels may also decrease with increased cytokine promotes serine phosphorylation of insulin receptor exercise [16,17]. substrate that impairs insulin signaling, resulting in insulin The leptin-deficient mice also develop hyperinsulinemia, resistance [31]. These pro-inflammatory cytokines appear in often times leading to DM. These effects can be reversed the early stage of T2DM, and they are found to be capable to through the administration of the leptin [18]. Meek and increase IR directly in adipocytes, muscle and hepatic cells his team suggested that leptin is implicated in glycemic leading to augmentation of the systemic IR [32]. tolerance independent of its effect on energy balance. It was Recently reported that pro-inflammatory cytokines, such reported that systematic infusion of leptin reversed insulin as TNF-α, IL-6 contribute significantly to the pathogenesis resistance in congenital lipodystrophic mice characterized by of T2DM, and increased in TNF-α, and IL-6 levels lead to hyperinsulinemia and hyperglycemia. Similar results were increased IR in overweight individuals and subsequently obtained from patients with severe lipodystrophy in which results in T2DM [33]. Pro-inflammatory cytokines such as chronic leptin treatment improved hepatic and peripheral IL-6 and TNF-α have been reported to play a critical role insulin resistance [19]. The associations of leptin levels with in IR and the pathogenesis of T2DM. These cytokines exert insulin resistance and diabetes are overall inconsistent as the cytotoxic, cytostatic through inhibition of the synthesis and positive, inverse, and null associations have been reported secretion of insulin, or cytocidal action on the pancreatic previously [20]. islands, stimulating the production of nitric oxide. Serum level of leptin was inversely associated with Together these cytokines can induce an acute inflammatory the β-cell function, which is also associated with insulin process [34]. Finally, the increased levels of IL-6 and TNF- α resistance. These effects of adipocytokines overall persisted were associated with increased levels of glucose in T2DM, after adjustment for the components of metabolic syndrome. also increased levels of IL-6 and TNF-α were also found to It should be pointed out that serum leptin was no longer predict CV events with diabetes [35]. significantly associated with β-cell function when insulin The results of the current study, showed a significant resistance was additionally controlled for the multiple linear increase in the level of serum CT-1 in both sexes of diabetic regression analysis. The findings of the present study are patients when compared with the concentrations in the improved understanding of the role of leptin in the etiology, normal nondiabetic controls. The results of the current study pathogenesis, and prevention of pre-diabetics and diabetics were in agreement with previous studies [36,37]. if they can be replicated in other populations with low These results demonstrated that the CT-1 level is a risk prevalence of overweight and obesity [21]. factor that increases risks of CV complications, hypertension Leptin suppresses insulins ability to slow down in DM patients, vascular damage, diastolic dysfunction, left gluconeogenesis, and increased blood sugar levels [22]. ventricular hypertrophy LVH, and ischemia may all be factor Increased leptin in obese individuals, related to the fat stimulating the high release of CT-1 from myocytes [38]. production rate of leptin. Some obese people may make leptin Increases in serum CT-1 level are strongly associated to at a greater rate to compensate for faulty signaling process or the intensity of several parameters associated to target organ action that influence eating behaviors and energy use to cause damage which is associated with CV injury in DM patients, obesity [23,24]. In diabetic patients, the stimulatory effect of and that is regarded as an important of CV injury insulin on leptin production in humans is more inert than in in diabetic patients [39,40]. normal persons, and the incorporation of glucose into adipose The results of the current study showed a significant tissue is more active process in humans [25]. increase in the level of serum TNT-hs in diabetic patients The results of the current study showed a significant of both sexes when compared with the concentrations in increase in the level of serum (TNF-α and IL-6) in diabetic the normal nondiabetic controls. The result of the current patients. It has been reported that TNF-α and IL-6 levels study was in agreement with the previous investigation, are significantly increased in T2DM patients compared to which reported elevation in troponin T values in diabetic nondiabetics [26,27]. It has been confirmed that enlargement populations with established CV complications [41].

DOI: http://dx.doi.org/10.14500/icpas2018 72 International Conference on Pure and Applied Sciences (ICPAS 2018)

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DOI: http://dx.doi.org/10.14500/icpas2018