|Year : 2016 | Volume
| Issue : 2 | Page : 175-179
Immunoglobulin E is associated with markers of mast cell degranulation and microalbuminuria in obese subjects with type 2 diabetes
Olayiwola Popoola1, Oluwatoyin Epenusi2
1 Department of Medical Laboratory Science, College of Medicine, University of Lagos, Nigeria
2 Department of Medical Laboratory Sciences, College of Natural and Applied Sciences, Achievers University, Ondo State, Nigeria
|Date of Web Publication||20-Dec-2016|
Department of Medical Laboratory Sciences, College of Medicine, University of Lagos
Source of Support: None, Conflict of Interest: None
Background: Irrespective of the cause of kidney injury, development of renal fibrosis may likely result after prolong insult by the etiologic agent. Inflammatory process associated with an increase in number and activity of mast cell (MC) has been implicated in the development of renal fibrosis. Renal fibrosis occurs through the activation of MC by immunoglobulin E (IgE) binding to high-affinity receptor on its surface. After IgE binding, MC release inflammatory mediators such as histamine, MC protease, cytokines, and chemokines. Aim: This study was designed to investigate the possible role of IgE in the development of renal complication in subjects with Type 2 diabetes. Materials and Methods: A total number of 165 subjects comprising ninety obese diabetic cases (test group) and 75 nondiabetic controls were recruited in this study. The test group was further divided into those with poor glycemic control (n = 45) and those with good glycemic control (n = 45) using glycated hemoglobin (HbA1c). Urine microalbumin was determine using turbidimetry immunoassay, C-reactive protein (CRP) using latex-enhanced immunoturbidimetry assay, IgE, insulin, chymase, and tryptase were estimated using ELISA and HbA1c were estimated by high-performance liquid chromatography. Results: There was statistically significant difference in the mean values of microalbumin, IgE, CRP and HbA1c, chymase, and tryptase in the test group compared with controls (P < 0.01). We found a positive correlation between microalbumin excretion rate and IgE, HbA1c, tryptase, and chymase (P < 0.01). Conclusion: The findings of this study suggest that glycemic control associated inflammatory process involving MC degranulation may contribute to the development of diabetic nephropathy.
Keywords: Diabetic nephropathy, immunoglobulin E, mast cell, microalbuminuria, protease, Type 2 diabetes
|How to cite this article:|
Popoola O, Epenusi O. Immunoglobulin E is associated with markers of mast cell degranulation and microalbuminuria in obese subjects with type 2 diabetes. Arch Med Health Sci 2016;4:175-9
|How to cite this URL:|
Popoola O, Epenusi O. Immunoglobulin E is associated with markers of mast cell degranulation and microalbuminuria in obese subjects with type 2 diabetes. Arch Med Health Sci [serial online] 2016 [cited 2021 May 12];4:175-9. Available from: https://www.amhsjournal.org/text.asp?2016/4/2/175/196200
| Introduction|| |
Renal complications associated with diabetes mellitus (DM) is a major health problem worldwide. Out of the numerous theories proposed to be responsible for the development of diabetic nephropathy (DN), inflammation appears to be the critical pathway for the development and progression of this complication. DN affects more than one-third of patients with Type 1 DM and up to 25% of all patients with Type 2 DM, it is an extremely common complication of DM and profoundly contributes to patient morbidity and mortality.
DN is pathologically characterized by thickening of the glomerular basement membrane and mesangial expansion with progression into glomerulosclerosis, tubular necrosis, and interstitial fibrosis, which ultimately result in renal failure. DN is characterized by a progressive rise in urine albumin excretion, coupled with increasing blood pressure (BP). Although there are many risk factors responsible for the development of DN, the main factors responsible for its initiation and progression are sustained hyperglycemia and hypertension. Those affected will have progressive deterioration of renal function, declining of glomerular filtration and eventually end-stage renal disease (ESRD).,,,
Once renal function starts declining, it can result in a higher frequency of renal and extra-renal events, including cardiovascular events. Therefore, slowing renal function decline is one of the main areas of focus in DN research, and novel strategies are urgently needed to prevent diabetic kidney disease progression. Regardless of the type of injury and etiology, kidney fibrosis is the commonly the final outcome of progressive kidney diseases, and it results in significant destruction of normal kidney structure and accompanying functional deterioration.
In addition to mast cell (MC) involvement in asthma and allergic responses, recent evidence suggest their role in Type 2 DM and DN., Evidence provided by previous studies suggests that MCs contribute to renal diseases mainly by promoting tubular interstitial injury; however, evidence of the involvement of MCs in DN is still scarce, and their exact role remains poorly understood. The aim of the present study was to examine the association between immunoglobulin MC activation and development of renal complications in diabetic patients.
| Materials and Methods|| |
This study was conducted on diabetic patients attending metabolic clinic at Federal Medical Centre, Owo, Ondo State. This Medical Center is a tertiary health institution in Owo, Ondo State. A total number of 165 subjects were recruited in this study. Seventy-five apparently healthy individuals were used as control and ninety diabetic patients took part in the study. Ethical approval was obtained from the Hospital Ethics and Research committee (permission grant No. FMC/OWO/380/VOL.XXV/60), and a well-documented informed consent were obtained from all participants before specimen collection. Personal data and questionnaire include personal information such as name, age, gender, address, marital status, and lifestyle. All participants were fasted for 10–12 h to determine plasma glucose and insulin levels. A total of 5 ml of blood was collected from each participant. Two milliliters into ethylenediaminetetraacetic acid tubes for immunoglobulin E (IgE), glycated hemoglobin (HbA1c), two milliliters into plain bottle for C-reactive protein (CRP), chymase and tryptase while the remaining 1 ml was used for fasting glucose. A 24 h urine specimen was obtained in a clean wide-mouthed bottle containing preservative for microalbumin estimation.
Subjects with diabetes were grouped according to American Diabetes Association criteria. Diabetes was classified with a fasting plasma glucose ≥7.0 mmol/L or 2 h-oral glucose tolerance test ≥11.1 mmol/L. Control subjects were nondiabetic and nonhypertensive healthy controls. Glycemic control was defined according to the International Diabetes Federation as HbA1C <6.5%. All participants with a previous history of renal disease, asthma and/or allergic reactions were excluded from the study.
Height and weight were measured with the subjects wearing light underwear and without shoes. Body mass index (BMI) was calculated by dividing body weight in kilogram by height in m 2. Homeostatic model assessment for assessing insulin resistance (IR); homeostasis model assessment-IR (HOMA-IR) was determined using the formula (glucose [nmol/L] × insulin [µU/mL]/22.5). Quantitative estimation of IgE concentration was determined using solid phase ELISA method (kits produced by Leinco Technologies, Inc.). Urine albumin was analyzed using turbidimetric immunoassay and CRP by Latex enhanced immunoturbidimetry method both using kits from AGAPPE diagnostics with a reference range of 1–3 mg/l. Glycosylated hemoglobin was estimated using high-performance liquid chromatography, plasma chymase and tryptase levels were determined as described previously.
The SPSS (Statistical Package for Social Sciences) Developed by SPSS Inc. (Chicago, United States of America) was used for the statistical analysis. Values obtained from the study were expressed as mean ± standard deviation. Statistical difference between groups was expressed using one-way ANOVA and the association between variables was determined using bivariate correlation; P < 0.05 was regarded as statistically significant.
The anthropometric details of study participants are shown in [Table 1]. Of the total 165 participants 84 were female (50.9%), and 81 were male (49.1%). We recorded a significant difference in BMI, systolic and diastolic BP (P < 0.05) when diabetic patients were compared with controls.
[Table 2] shows the mean and standard deviation of biochemical parameters between groups, one-way ANOVA reveals a statistically significant difference in urinary albumin, fasting blood glucose (FBG), insulin, HOMA-IR, IgE, HbA1c, CRP, chymase, and tryptase. [Table 3] shows the result of Pearson correlation; A strong positive correlation was observed between urine albumin versus, IgE, HbA1c, tryptase, and chymase in the DPC group and between microalbumin and HbA1c only in the DGC group (P < 0.01).
|Table 3: Pearson correlation between microalbumin and mast cell protease in diabetic vs nondiabetic subjects|
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| Results and Discussion|| |
DN is becoming an increasingly important cause of morbidity and mortality worldwide, largely due to increase in the prevalence of Type 2 DM. Multiple mechanisms contribute to the development and outcomes of DN, such as an interaction between metabolic abnormalities, hemodynamic changes, genetic predisposition, inflammatory milieu and oxidative stress, constituting a continuous perpetuation of injurious factors for the initiation and progression of both of DM and DN. Poor glycemic control and elevated systolic BP further exacerbate the disease progression to proteinuria, nodular glomerulosclerosis, tubulointerstitial injury and a decline in glomerular filtration rate (GFR) which can eventually lead to ESRD.
Clinical DN develops in a sequence of stages beginning with initial increases in GFR and intraglomerular capillary pressure, glomerular hypertrophy, and albuminuria. Inflammation plays an essential role in the progression of DN. Recent evidence indicates that innate immunity, rather than adaptive immunity, is the major driving factor in the inflammatory response in diabetic kidneys. The increase in plasma concentration of inflammatory markers are associated with DM and DN.
Accumulating evidence indicates that age, sex, obesity, hypertension, IR, decreased β-cell sensitivity, hyperinsulinemia, HbA1c, and CRP are related to DM and its complications. Our result show as an increase in systolic BP, BMI and waist-hip ratio [Table 1] in diabetic groups when compared with controls. This further substantiates previous evidence supporting the role of obesity and BP in the development of DN., Our data further show that significant difference exists in biochemical parameters such as FBG, HbA1c, IgE, CRP, chymase, and tryptase in diabetic patient when compared with control [Table 2]. Although it is clear that human genetics represents an important factor in the development of DN as some patient often do not develop this complication despite poor glycemic control. Our result suggests poor glycemic control may play a crucial role in the development of DN and other complications associated with the disease.
Obesity and Type 2 DM are characterized by altered cytokine production and subsequent activation of inflammatory cytokines interleukin 4 (IL4). IgE production by normal human lymphocytes is induced by IL4 and inhibited by interferon gamma.
MCs, which are localized in various organs including the lungs, heart, and kidneys, play a central role in the pathogenesis of diabetic complications. MCs infiltrate the kidney and are degranulated in renal diseases, releasing pathologically active substances such as chymase and tryptase. Chymase is associated with accumulation of advanced glycation end product in the diabetic renal vasculature while tryptase is implicated in the development of renal interstitial fibrosis by increasing the production of extracellular matrix protein. Our result show an association between microalbuminuria (MAU), IgE, MC chymase, tryptase, and glycemic control when subject were compared with controls [Figure 1] and [Figure 2].
|Figure 1: Graphical representation of the relationship between glycated hemoglobin percentage, urinary microalbumin, tryptase, and chymase.|
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|Figure 2: Graphical representation of the relationship between immunoglobulin E, tryptase, and chymase.|
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The increased IgE observed in the study test group may likely be due to increased IL4 and proinflammatory activities that are further exacerbated by poor glycemic control. We want to stress the limitation to the data presented in this study although we determined insulin concentration to calculate HOMA-IR, we did not consider subject that were on insulin therapy. Further, still, the possible effect of other diabetic complication could have on the study parameters were not also prioritized.
The renin-angiotensin-aldosterone system (RAAS) is considered an endocrine system that produces renin in the kidney renin generates angiotensin I (Ang I) through angiotensinogen. Ang I produces Ang II through angiotensin-converting enzyme (ACE), the Ang II produced binds to specific receptors on the adrenal cortex, to initiate the release of aldosterone. Aldosterone is effector molecule of the RAAS, whose synthesis and secretion are stimulated by Ang II through the angiotensin Type 1 receptor in the adrenal cortex. Through specific actions on the distal nephron of the kidney, aldosterone promotes sodium reabsorption, water retention, and potassium and magnesium loss, thereby modulating extracellular space volume and BP. In MAU and proteinuric Type 1 and 2 diabetic patients, numerous studies have demonstrated that treatment of hypertension, irrespective of the agent used, produces a beneficial effect on albuminuria. Aggressive targets for BP control in diabetic patients have been shown to result in reduced development and retardation in the progression of incipient and overt nephropathy, as well as decreasing macrovascular events. The use of ACE inhibitors to slow down the progression of DN has been widely accepted in the clinical settings. About 85% of subjects in the diabetic group of our study were on antidiabetic and antihypertensive drugs. Some of the participants had a course to change therapy from one drug to another as prescribed by their physician but we do not have the details of the specific drugs.
The degree of urine albumin/protein is associated with the progression of kidney disease via the activation of tubular ACE inhibitors or inflammatory pathways. Strategies to decrease proteinuria with renin – angiotensin system (RAS) blockade have been shown to be partially renoprotective. However, 30% of DNs occur in the absence of significant proteinuria, suggesting that other pathways have a role in the pathogenesis of the condition, and recent clinical trials raise questions about the significance of strong RAS blockade using a combination of RAS inhibitors in DN patients.
| Conclusion|| |
Our result suggests that poor glycemic control and the inflammatory process may play a pathogenic role in the development of DN. Our data further supports the opinion that MC activation and release of tryptase and chymase are associated with renal damage in diabetic patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: The role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne) 2013;4:7.
Wu CC, Sytwu HK, Lu KC, Lin YF. Role of T cells in type 2 diabetic nephropathy. Exp Diabetes Res 2011;2011:514738.
Balakumar P, Arora MK, Ganti SS, Reddy J, Singh M. Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions. Pharmacol Res 2009;60:24-32.
Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 2005;28:164-76.
Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med 2002;346:1145-51.
Khatami Z, McIlveen DW, Nesbitt SG, Young IS. Screening for microalbuminuria by use of microproteinuria. East Mediterr Health J 2005;11:358-65.
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, et al.
Nephropathy in diabetes. Diabetes Care 2004;27 Suppl 1:S79-83.
Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: The role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne) 2013;4:7.
Zheng JM, Yao GH, Cheng Z, Wang R, Liu ZH. Pathogenic role of mast cells in the development of diabetic nephropathy: A study of patients at different stages of the disease. Diabetologia 2012;55:801-11.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9.
Wang Z, Zhang H, Shen XH, Jin KL, Ye GF, Qian L, et al.
Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus. PLoS One 2011;6:e28962.
Qu HQ, Li Q, Rentfro AR, Fisher-Hoch SP, McCormick JB. The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning. PLoS One 2011;6:e21041.
Nasir NM, Thevarajah M, Yean CY. Hemoglobin variants detected by hemoglobin A1c (HbA1c) analysis and the effects on HbA1c measurements. Int J Diabetes Dev Ctries 2010;30:86-90.
Xiang M, Sun J, Lin Y, Zhang J, Chen H, Yang D, et al.
Usefulness of serum tryptase level as an independent biomarker for coronary plaque instability in a Chinese population. Atherosclerosis 2011;215:494-9.
Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators Inflamm 2012;2012:146154.
Maric C, Hall JE. Obesity, metabolic syndrome and diabetic nephropathy. Contrib Nephrol 2011;170:28-35.
Fornoni A, Ijaz A, Tejada T, Lenz O. Role of inflammation in diabetic nephropathy. Curr Diabetes Rev 2008;4:10-7.
Chen HM, Shen WW, Ge YC, Zhang YD, Xie HL, Liu ZH. The relationship between obesity and diabetic nephropathy in China. BMC Nephrol 2013;14:69.
Van Buren PN, Toto R. Hypertension in diabetic nephropathy: Epidemiology, mechanisms, and management. Adv Chronic Kidney Dis 2011;18:28-41.
Fioretto P, Bruseghin M, Berto I, Gallina P, Manzato E, Mussap M. Renal protection in diabetes: Role of glycemic control. J Am Soc Nephrol 2006;17 4 Suppl 2:S86-9.
Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim Biophys Acta 2012;1822:14-20.
He A, Shi GP. Mast cell chymase and tryptase as targets for cardiovascular and metabolic diseases. Curr Pharm Des 2013;19:1114-25.
Shih Y, Ho L, Tsao C, Chang Y, Shiau M, Huang C, et al
. Role of cytokines in metabolism and type 2 diabetes mellitus. IJBLS 2013;2:1-6.
Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, et al.
Periodontitis and diabetes: A two-way relationship. Diabetologia 2012;55:21-31.
Pène J, Rousset F, Brière F, Chrétien I, Bonnefoy JY, Spits H, et al.
IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A 1988;85:6880-4.
Giunti S, Barit D, Cooper ME. Mechanisms of diabetic nephropathy: Role of hypertension. Hypertension 2006;48:519-26.
Spät A, Hunyady L. Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol Rev 2004;84:489-539.
Harris R. Angiotensin-converting enzyme inhibition in diabetic nephropathy: It's all the RAGE. J Am Soc Nephrol 2005;16:2251-3.
Baltatzi M, Savopoulos Ch, Hatzitolios A. Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results. Hippokratia 2011;15 Suppl 1:27-32.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]