New Biomarker For Diabetes Nephropathy Biology Essay


Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and derangement in protein and fat metabolism. The worldwide prevalence of diabetes was approximately 2.8% in 2000 and is estimated to grow to 4.4% by 2030. The main risk factors for the development of diabetes are ethnic variations, changes in the food habits, obesity and altered lifestyles. Diabetes mellitus (DM) is the most frequent cause of chronic kidney failure in both developed and developing countries. The incidence of renal complications in type 2 diabetes showed uprising because type 2 diabetes accounts for at least 90% of all patients with diabetes. Diabetic nephropathy is responsible for 30%-40% of all CKD cases and approximately 45% of end-stage renal disease (ESRD) cases in the KSA. There are no data available on the incidence of diabetic renal disease in Saudi diabetics. What is known is that the vast majority of Saudi diabetics entering dialysis (96%) are of Type II. In a study of a diabetic outpatient clinic, 12.8% of patients had dipstick proteinuria and of the remaining patients 41.3% had microalbuminuria The rate of progression of renal disease in diabetics differs from one ethnic group to another. British Asians have a more rapid course than Caribbeans or Caucasians . In Caucasians with microalbuminuria, 20-40% develop overt nephropathy over a 6‐year period whereas 37-40% of Pima Indians do so over 4-5 years. If Saudi diabetics behave in a similar fashion as Pima Indians, with aggressive course of their diabetes as seems the case, this would indicate that we are going to face a 'medical disaster' in dialysis units. The Saudi government spending more than 15% of total budget in the health sector, Unfortunately, the current economic environment and the increasing number of nephropathic patient's number indicate that our resources will be unable to meet the growing needs of this population in near future.

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Early identification of diabetic nephropathy via the use of meaningful biomarkers and prompt intervention to delay CKD progression are therefore crucial measures to prevent the continuing rise in CKD prevalence.

Detection of microalbuminuria identifies not only individuals who are at risk of developing renal diseases but also cardiovascular events and death in these patients. Up to 30% of people with newly diagnosed type 2 diabetes will already have abnormally high urine albumin levels I.e. macroalbuminuria which indicates that many may have overt diabetic nephropathy at the time of diagnosis.

Renal disease is strongly linked to heart disease and the presence of microalbuminuria is a predictor of worse outcomes for both in renal and cardiac patients. Microalbuminuria does not directly cause cardiovascular events; it serves as a marker for identifying those who may be at increased risk. Microalbuminuria is caused by glomerular capillary injury and so may be a marker for diffuse endothelial dysfunction. According to Steno hypothesis, albuminuria might reflect a general vascular dysfunction and leakage of albumin and other plasma macromolecules such as low density lipoproteins into the vessel wall that may lead to inflammatory responses and in turn start the atherosclerotic process.

Diabetic Nephropethic marker

Cell adhesion molecules

The accumulation of extracellular matrix (ECM) components and the development of fibrosis are fundamental processes that occur in response to chronic hyperglycemia, intraglomerular and systemic hypertension, dyslipidemia, and oxidative stress. These processes initiate expression of growth factors, cytokines, mediators, and modulators that perpetuate the overproduction of matrix proteins and families of cell adhesion molecules (CAMs). CAM families include intercellular adhesion molemolecules (ICAMs) and vascular adhesion molecules (VCAMs) produced by endothelial cells; integrins produced by mesangial, endothelial, and epithelial cells; and osteopontin and some laminins, which are matrix glycoproteins.

Under normal physiologic conditions, these components provide the structural support and communication necessary between resident cells and their environment for homeostasis, but under the chronic influence of the diabetic milieu, their altered expression becomes pathologic. Targeted remodeling of the ECM is currently thought to be an important therapeutic strategy to both delay the progression and induce regression of established lesions of CKD. The renin-angiotensin-aldosterone system (RAAS) plays an important contributory role in this remodeling

(Am J Nephrol. 2004;24:549- 556), because blockade of components of the RAAS with the use

of an ACE inhibitor, a type I angiotensin receptor blocker (ARB), or a direct renin inhibitor (DRI) have proven utility in delaying disease progression (Vasc Health Risk Manag. 2009;5:411-427).

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Accumulation of glomerular ECM components has two underlying causes. The first is an imbalance of cytokines (transforming growth factor- β; TGF-β‚) and growth factors, including insulin-like growth factor (IGF), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), plateletderived growth factor-β (PDGF), fibroblastic growth factor (FGF), epithelial growth factor (EGF) and bone morphogenetic proteins (BMPs), especially BMP-7. The other cause of ECM accumulation is an altered protease system consisting of matrixmetalloproteinases (MMPs) and plasminogen activator inhibitor-1 (PAI-1) which are expressed by mesangial and endothelial cells and podocytes (See figure on opposite page). In several studies, these mediators have been shown to directly influence the turnover of ECM proteins in the development of diabetic nephropathy; their expression may be altered with blockade of the RAAS. In particular, CAMs are im-portant participants in mediating interactions between renal cells, the basement membrane, and matrix proteins and also play an important role in renal morphogenesis, renal health, nephropathy, and tissue repair. ICAM-1 and VCAM-1 Endothelial cells are important players in promoting the microvascular disease that defines some of the pathologic lesions of diabetic nephropathy.

Endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) is augmented when cells are exposed to serum from diabetic patients, and the enhanced levels correlate well with worsening albuminuria. Soluble forms of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) are produced either de novo or as cleavage products from established cellular lesions, and their plasma levels correlate with the severity of diabetic nephropathy.

Notably, ACE inhibitor and ARB therapies can significantly reduce circulating sVCAM-1 levels while statins can re-duce sICAM levels in patients with type 2 diabetes. Thus, ICAM-1 and VCAM-1 are potentially useful as biomarkers in diabetic nephropathy.

Integrins. Integrins are cell surface receptors, consisting of approximately 25α- and β-heterodimeric complexes that recognize and adhere to specific ECM proteins (Nephron Exp Nephrol. 2003;94:e77-e84). Thus, integrins sense and transmit the external cellular environment. Their role in renal development has been highlighted by in vitro and in vivo gene mutational studies and by the use of function blocking antibodies that demonstrate abnormal or absent renal morphogenesis and induce significant renal diseases.

In the diabetic kidney, expression of specific integrin subunits and their respective ligand ECM proteins correlates with disease severity (J Am Soc Nephrol. 1996;7:2636-2645). Studies also suggest that blockade of certain integrin functions may alter the course of diabetic nephropathy. Thus, the monitoring of integrin function and expression may be an early and predictable biomarker of diabetic nephropathy, and these cell adhesion molecules may be appropriate targets in matrix remodeling.


Resistin or resistance to insulin named for its ability to resist (interfere with) insulin action (Steppan et al; 2001). Resistin is also found in inflammatory zone 3 and adepocyte-secreted factor (Schinke et al; 2004). Many cell types known to express resistin include such as adepocytes, mononuclear leukocytes, macrophages, spleen and bone marrow cells , intestinal epithelium and skeletal muscles cells ( Raja et al; 2002, Nogueiras et al; 2003). Its primarily produced by cell populations other than adipocytes, which include peripheral blood mononuclear cells(PBMCs), macrophages and bone marrow cell (Patel et al; 2003). Changes accompanying renal dysfunction are associated with increased serum resistin (Bauers S et al; 2011). Resistin that affect inflammation and subsequent deregulation of cell function in renal glomeruli that leads to pathological changes (Tang J et al; 2012). The renal failure with DM patient higher concentrations of resistin was recorded (Rasic D et al; 2010). Elevated resistin level is significantly associated with the likelihood of chronic kidney disease in the general Japanese population (Kawamura R et al; 2010). In type 2 diabetes mellitus and in chronic kidney disease, the serum concentration of resistin is increased (Cohen G et al; 2009). The independent association of resistin with eGFR suggests involvement of resistin in the progression of kidney damage in the early stages of hypertension (Dimitriadis K et al; 2009). The serum levels of resistin a protein primarily expressed in inflammatory cells in humans, are increased in patients with chronic kidney disease and those with diabetes mellitus (Cohen G et al; 2006).; Serum resistin levels are markedly elevated in chronic kidney disease probably due to decreased renal excretion (Axeisson J et al; 2006). Resistin levels were increased in the children with chronic renal impairment (Buyan N et al; 2006). Circulating resistin levels are strongly associated with both glomerular filtration rate inflammatory biomarkers in chronic disease (Axelssor et al; 2006).

Research Objective:

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The aim of this case - control study to assess the relationship between elevations of resistin in Saudi type 2 diabetes Subjects with and without nephropathy complications.

Research Methodology:

Methods: The study involved Saudi type 2 diabetes 200 subjects with and 200 without diabetic nephropathy complications .

Study Setting: The subjects will be required at outpatient's clinic of nephropathy, University Diabetes Center, King Abdul Aziz University Diabetes Center, King Saud University, Riyadh.

Inclusion Criteria: Patients will be included in the study only Albumin/ creatinine ratio is < 30mg/g of creatinine adequately established. Serum creatinine levels with normal reference values 0.7 to 1.2 mg/dl.

Exclusion Criteria: Patients with a diagnosis of reduced renal function, proteinuria (≥300 mg/dl) and creatinine levels (≥2mg/dl), history of alcohol intake or smoking.

Research design: With the approval of the protocol by the Institutional Review Board (IRB) of college of Medicine, King Saud University, after obtaining patients informed consent , a cross sectional study will be started from September 2012.

A cross sectional study, 200 Saudi type 2 diabetes nephropathy complications (cases) and 200 Saudi type 2 diabetics without nephropathy complications (control) will be recruited from an outpatient's nephropathy clinic of the University Diabetes Center.

Height (cm) and weight (kg) will be measured using standard methods. Body mass index (BMI) will be calculated as weight (in kilograms) divided by height (in meter) squared. Waist circumference will be taken at minimum circumference at the umbilical level. Liver function tests (,AST,ALT,Gamma GT,bilirubin total ,Bilirubin direct,Total protein, Albumin and alkaline phosphatase ) were measured in serum by calorimetric methods using the A25 Bio-system chemistry analyzer. Lipid profile (cholesterol, HDL, LDL, and triglycerides) were measured in serum by calorimetric methods using the A25 Bio-system chemistry analyzer and Bio-system reagents kits. Resistin will be analyze by Sandwich enzyme immunoassay (Resistin-ELISA, DIASource, Belgium). Electrolyte profile (Na+,k+ and Cl¯)were measured in serum by 9180 Electrolyte analyzer and reagents ,(Roche).

All the biochemical analysis will be carried out in the Biochemistry laboratory of the Strategic Center for Diabetes Research, King Saud University.

Sample Collection: Blood sample will be drawn after an overnight fast by nurse at the Clinic Laboratory of University Diabetes Center using 10 ml plastic disposable syringe with a 21 gauge needle, 5 ml blood will be transferred into plain tube (Venoject), and about 5 ml into a tube containing EDTA as anticoagulant. After collection of the whole blood ,allow the blood to clot by leaving it undisturbed at room temperature.Remove the clot by centrifuging at 1000-2000 x g for 10 minutes in a refrigerated centrifuge. The resulting supernatant was designated serum. Immediately transfer the serum into a clean polypropylene tube using a pasteur pipette. Serum stored at -20Ëšc freezer.

Statistical Analysis: Differences between two groups (Type 2 diabetes with nephropathy complication and without nephropathy complication) will be assessed using unpaired Student t test or Mann-Whitney U test or chi-square test.

The relationship between serum resistin levels and type 2 diabetes nephropathy will be determined by calculating the odd ratio (OR) using logestic regression analysis. Data will be analyzed using SPSS 19.0 statistic package (SPSS, Inc, Chicago, IL, U.S.A.).

Research Problem: Diabetes is an expensive disease. Most of the expenses in curried could be attributed to the morbid complications. Treatment of diabetic complications constitutes the highest cost. The expenses include both direct cost of treatment and indirect cost due to man hours lost in loss of productivity .Medical expenditure for a diabetic is estimated to be two to five times more than a non diabetic subjects. This imposes a heavy burden both at the individual and at the societal level in Saudi Arabia. This underscores the need for early detection of nephropathy complications of diabetes.

Research Significance: Diabetic nephropathy is a substantial health problem in the Saudi Arabia. It also comprises a significant financial burden. Resistin marker in Saudi with type 2 diabetes and to evaluate the relationship between diabetic nephropathy and serum level of resistin. The onset and course of diabetic nephropathy can be ameliorated to a very significant degree by several interventions, but these interventions have their greatest impact if instituted at a point very early in the course of the development of this nephropathy complication.