|Year : 2016 | Volume
| Issue : 1 | Page : 10-15
Serum levels of soluble receptor for advanced glycation end product in type 2 diabetic patients: possible association with urinary albumin excretion
Kamal M Okasha1, Samy A Khodeir1, Shaza A Madkour1, Heba A Mourad2
1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||09-Nov-2015|
|Date of Acceptance||20-Dec-2015|
|Date of Web Publication||22-Mar-2016|
Kamal M Okasha
MD, Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta
Source of Support: None, Conflict of Interest: None
Diabetes is now the major cause of end-stage renal failure worldwide, both in developing and in developed nations. Hyperglycemia is still considered the principal cause of complications of diabetes because of the formation of sugar-derived substances called advanced glycation end products. The formation of advanced glycation end product is markedly accelerated in diabetes because of the increased availability of glucose. The receptor for advanced glycation end products (RAGE) has been shown to be involved in the pathogenesis of diabetic complications. The aim of this work was to assess the possible association between soluble receptor for advanced glycation end products (sRAGE) and urinary albumin excretion in type 2 diabetic patients as an early predictor of microvascular complications such as diabetic nephropathy. The present study was carried on 70 individuals: 10 healthy individuals as control, 20 diabetic patients with normoalbuminuria, 20 diabetic patients with microalbuminuria, and 20 diabetic patients with macroalbuminuria. All participants were subjected to estimation of sRAGE by the sandwich enzyme-linked immunosorbent assay technique together with routine laboratory investigations. The results of this study showed that all diabetic patients had a low level of serum RAGE compared with the control group. Furthermore, a characteristic trend was observed whereas three groups of diabetic patients showed a decrease in RAGE in parallel with the severity of renal involvement. From this point of view, stimulation of sRAGE production should be considered a potential therapeutic target in diabetic patients.
Keywords: Advanced glycation end product, soluble receptor, type 2 diabetic, urinary albumin excretion
|How to cite this article:|
Okasha KM, Khodeir SA, Madkour SA, Mourad HA. Serum levels of soluble receptor for advanced glycation end product in type 2 diabetic patients: possible association with urinary albumin excretion. J Egypt Soc Nephrol Transplant 2016;16:10-5
|How to cite this URL:|
Okasha KM, Khodeir SA, Madkour SA, Mourad HA. Serum levels of soluble receptor for advanced glycation end product in type 2 diabetic patients: possible association with urinary albumin excretion. J Egypt Soc Nephrol Transplant [serial online] 2016 [cited 2018 Nov 15];16:10-5. Available from: http://www.jesnt.eg.net/text.asp?2016/16/1/10/179199
| Introduction|| |
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both . Chronic hyperglycemia is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels . Diabetic nephropathy is a clinical diagnosis that is made on the basis of the finding of proteinuria in a patient with diabetes and in whom there is no evidence of urinary tract infection. Overt nephropathy is characterized by protein excretion greater than 0.5 g/day. This is equivalent to albumin excretion of around 300 mg/day. It is preferable to assess proteinuria as albuminuria because it is a more sensitive marker for chronic kidney disease because of diabetes .
The first sign of renal involvement is the presence of persistent microalbuminuria (24-h urinary albumin excretion of 30-300 mg/day) and this stage is known as incipient nephropathy. This occurs in 20-40% of patients 10-15 years after the onset of diabetes. Progression to macroalbuminuria or proteinuria (urinary albumin excretion >300 mg/day) occurs in 20-40% of patients 15-20 years following the onset of diabetes and this stage is also known as overt nephropathy. Following this, the creatinine clearance deteriorates at an average rate of 10-12 ml/min/year in untreated patients and hypertension develops . In type 2 diabetes, the microalbuminuria is seldom reversible and is probably a sign of endothelial dysfunction that is not just confined to the kidney (91). No major difference has been identified between the nephropathies encountered in type 1 and type 2 diabetic patients either pathophysiologically or in terms of management. It should be kept in mind, however, that patients with type 2 diabetes tend to be older and more hypertensive, and thus more likely to have concomitant hypertensive and renovascular disease .
The normal urinary protein excretion rate is 30-299 mg/24 h, of which about 10% is albumin, equivalent/min, equivalent to a urine albumin creatinine ratio of 30-299 mg/g, which is defined as microalbuminuria as these levels are not detectable by conventional urine dipstick analysis. The onset of microalbuminuria is highly significant as its presence predicts the development of overt renal disease in both type 1 and type 2 diabetes. Furthermore, microalbuminuria is associated with an increased risk of cardiovascular and microvascular complications .
Diabetic control is the major factor that determines progression from normal albumin excretion to microalbuminuria. Good diabetic control reduces the risk of microalbuminuria . In the presence of microalbuminuria, the treatment of hypertension, irrespective of the agent used, exerted a beneficial effect on albuminuria . Both angiotensin converting enzyme (ACE) inhibitors and angitensin receptor blockade (ARBs) decrease the risk for diabetic nephropathy and reduce the occurrence of cardiovascular events .
Advanced glycation end products (AGEs) are produced by a nonenzymatic reaction between proteins and sugar in patients with long-term hyperglycemia. AGEs accumulate with time and are irreversibly deposited in various tissues of the body, contributing toward the development of diabetic complications, arteriosclerosis, and aging . In metabolic disorders, such as diabetes, there is a marked increase in a number of factors that promote the formation and accumulation of AGEs within various susceptible organs, in particular, the kidney. As a direct result of the hyperglycemic characteristic of diabetes, there is a marked increase in both carbonyl and oxidative stress, which promotes in-vivo AGE accumulation . Large AGE proteins that cannot enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix. Activation of receptor for advanced glycation end products (RAGE) induces the production of a variety of cytokines, including tumor necrosis factor-b, which mediates an inhibition of metalloproteinase and increases the production of mesangial matrix, leading to glomerulosclerosis and decreasing kidney function in patients with unusually high AGE levels .
RAGE is a member of the immunoglobulin superfamily that consists of three immunoglobulin-like regions, one v-domain and two c-domains, in addition to transmembrane and cytoplasmic regions . Generally, there are four main RAGE isoforms: full length (FL-RAGE), N-terminal truncated (Nt-RAGE), endogenous secretary (es-RAGE), and soluble (sRAGE) .
These observations support the important pathobiological effects of AGE-RAGE interaction through the modulation of a number of processes related to inflammation and oxidative stress, all of which have been implicated in the formation and progression of microvascular complications .
| Participants and methods|| |
This study was carried out on the following groups according to their urinary albumin concentration:
Group 1 included 20 patients of type 2 diabetes mellitus and normoalbuminuria.
Group 2 included 20 patients with type 2 diabetes mellitus and microalbuminuria.
Group 3 included 20 patients with type 2 diabetes mellitus and macroalbuminuria.
Group 4 included 10 healthy individuals as control group.
All patients and controls were subjected to the following: a full assessment of history, a thorough clinical examination, routine laboratory investigations [estimated glomerular filtration rate (eGFR), fasting and 2-h postprandial blood sugar, glycosylated hemoglobin, serum creatinine, blood urea, serum cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and C-reactive protein], and specific laboratory investigations (quantitative determination of serum level of sRAGE by the sandwich enzyme-linked immunosorbant assay technique).
| Results|| |
The statistical analysis of laboratory findings showed a significant increase in HbA1c in group III (diabetics and macroalbuminuria), mean ± SD value of 7.71 ± 3.69, than group II (diabetics with microalbuminuria), 7.62 ± 2.8, and higher than group I (diabetics with normoalbuminuria), mean ± SD = 7.15 ± 2.52, and all the values were higher than those in group IV (control group), mean ± SD = 5.25 ± 1.36, as shown in [Table 1] and [Figure 1].
The albumin creatinine ratio showed a significant increase in group III, mean ± SD value of 753.6 ± 75.6, higher than that of group II, 165.8 ± 40.6, and an increase in group II higher than that in group I, mean ± SD = 13.94 ± 3.25. All groups had values that were higher than those of group IV (healthy controls), mean ± SD = 8.63 ± 1.63, as shown in [Table 2] and [Figure 2].
|Figure 2: Comparison of albumin creatinine ratio (ACR) between the studied groups.|
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|Table 2: Comparison of albumin creatinine ratio between the studied groups|
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Serum creatinine showed a significant increase in group III, mean ± SD = 2.08 ± 0.63, group II, mean ± SD = 1.2 ± 0.23, than group I, mean ± SD = 0.84 ± 0.012, and all groups had higher values than those of group IV of healthy controls, which was mean ± SD = 0.75 ± 0.11, as shown in [Table 3] and [Figure 3].
Demonstration of eGFR between different studied groups: In group I, the mean value was 94 ± 7.8, in group II, the mean value 99.2 ± 7.9, in group III, the mean value 50.8 ± 4.6, and in group IV, the mean value 95.3 ± 5.36. The mean value of eGFR was significantly decreased in the macroalbuminuric group as shown in [Table 4] and [Figure 4].
|Figure 4: Comparison of estimated glomerular filtration rate (eGFR) between the studied groups.|
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Demonstration of serum sRAGE in different studied groups: In group I, the mean ± SD value was 1148 ± 302.2, in group II, the mean value was 768.6 ± 219.9, whereas in patients affected by overt diabetic nephropathy group III, the mean value was 462.8 ± 211.1, which was statistically lower than that of all the other groups. In healthy individuals (group IV), the mean value was 1495 ± 460.6. The mean value of serum RAGE was significantly decreased in all diabetic groups compared with the control group as shown in [Table 5] and [Figure 5],[Figure 6],[Figure 7] and [Figure 8].
|Figure 5: Comparison of serum soluble receptor for advanced glycation end products (sRAGE) between the studied groups.|
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|Figure 6: Correlation between the level of soluble receptor for advanced glycation end products (sRAGE) and creatinine.|
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|Figure 7: Correlation between the level of soluble receptor for advanced glycation end products (sRAGE) and albumin creatinine ratio.|
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|Figure 8: Correlation between the level of soluble receptor for advanced glycation end products (sRAGE) and estimated glomerular filtration rate (eGFR).|
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|Table 5: Comparison of serum soluble receptor for advanced glycation end products between the studied groups|
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| Discussion|| |
The present study showed a significant decrease in the serum level of sRAGE in the diabetic group compared with the control group (P < 0.001). This is in agreement with Grossin et al. , who found that patients with renal and retinal complications had significantly (P < 0.05) lower blood levels of sRAGE (1068 ± 136 pg/ml) compared with patients without complications (1575 ± 139 pg/ml). These findings are in agreement with another study carried out by Basta et al. , who studied 160 individuals, 84 patients with type 2 diabetes and 76 nondiabetic controls, and reported that plasma sRAGE was lower in diabetic patients than controls (P < 0.001) in their study.
The results are also in agreement with another study of Hesham et al.  carried out on 80 individuals, 60 type 2 diabetic patients and 20 healthy individuals, and found that sRAGE blood levels were lower in diabetic patients who had renal complications. The most sensitive and noninvasive indicator of the progression of diabetic nephropathy is albuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of the glomerules basement membranes are before albuminuria. Overall DM patients, 3.7% of type 2 diabetic patients progress every year to overt nephropathy .
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There are no conflicts of interest.
| References|| |
American Diabetic Association. Diagnosis and classification of DM. Diabet Care 2013; 36
Guyton AC, Hall JE. Insulin, glucagon, and diabetes mellitus, in textbook of medical physiology
. 11th ed. United Kingdom: Elsevier Saunders; 2006. 961-977.
Zerbini G, Gabellini D, Ruggieri D, Maestroni A. Dysfunction of cellular transporters and predisposition to diabetic nephropathy. Curr Diabetes Rev 2006; 2
Parving H. Diabetic nephropathy: prevention and treatment. Steno Diabetics Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Kidney Int 2001; 60
Lukas F, Sharon M, Firth J, et al.
Management of diabetic nephropathy. J R Soc Med 2001; 94
Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med 1997; 157
Jorge L, Gross NH, de Azevedo, et al.
Diabetic nephropathy: diagnosis, prevention and treatment. Diabetes Care 2005; 28
Lindlholm LH, Ibsen H, Dahlof B, et al.
Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomized trail against atenolol. Lancet 2002; 359
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355
Ono Y, Aoki S, Ohnishi K, et al.
Increased serum levels of advanced glycation end-products and diabetic complication. Diabetes Res Clin Pract 1998; 41
Miyata T, Ishikawa N, van Ypersele de Strihou C Carbonyl stress and diabetic complications. Clin Chem Lab Med 2003; 41
Yan HD, Li XZ, Xie JM, Li M. Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells. Chin Med J (Engl) 2007; 120
Talts JF, Andac Z, Göhring W, Brancaccio A, Timpl R Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. EMBO J 1999; 18
Younessi P, Yoonessi A. Advanced glycation end-products and their receptor-mediated roles: inflammation and oxidative stress. Iran J Med Sci 2011; 36
Vlassara H. Advanced glycation in health and disease: role of the modern environment. Ann N Y Acad Sci 2005; 1043
Grossin N, Wautier MP, Meas T, Guillausseau PJ, Massin P, Wautier JL Severity of diabetic microvascular complications is associated with a low soluble RAGE level, Diabetes Metab 2008; 34
(Pt 1): 392-395.
Basta G, Sironi AM, Lazzerini G, Del Turco S, Buzzigoli E, Casolaro A, et al
. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein, J Clin Endocrinol Metab 2006; 91
Hesham A, Osama S, Ahmed M, et al.
Soluble receptor for advanced glycation end products: a new biomarker in diagnosis of diabetic nephropathy, Clin Chem Pathol J Life Sci 2012; 9
Paczek L, Kropiewnicka HE, Senatorski G, Bart³omiejczyk I Urine TGF-beta1 concentration in patients with type II diabetes mellitus - prognostic values. Pol Arch Med Wewn 2002; 108
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]