Menoufia Medical Journal

: 2014  |  Volume : 27  |  Issue : 4  |  Page : 683--685

Role of intercellular adhesion molecule 1 in development of diabetes and diabetic nephropathy

Sanaa Sayed Gazareen1, Ahmed Abd El-moneim Shoaib1, Amal Mohamed Salah Eldein Ahmed Anan2,  
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Artificial Kidney Department, Kom Hamada Hospital, Kom Hamada, Egypt

Correspondence Address:
Amal Mohamed Salah Eldein Ahmed Anan
Gamaa Elfolly street, Shobra el Namla, Tanta, Gharbiya Governate


Objective The present work aimed to discuss the association between intercellular adhesion molecule 1 (ICAM1) and development of both diabetes mellitus and diabetic nephropathy. Data sources They included English language citation in the last 20 years from the database of abstracts of reviews from 2005 to 2013 updates from expert reviews and literatures surveillance. Study selection Systematic reviews that addressed ICAM1 and studies that addressed the association of ICAM1 with development of both diabetes mellitus and diabetic nephropathy and mechanism of the benefit of inhibition of ICAM1 in treatment of diabetes mellitus and diabetic nephropathy were included. Data extraction Special search was performed at midline in the title of papers; all articles including review articles in the last 20 years were reviewed. In addition, a special search was performed at specific databases including science direct and genetic association studies of ICAM1 gene in diabetes mellitus and diabetic nephropathy used in midline search, and also studies in the last 20 years were included. Data synthesis The researcher reviewed each study independently and rebuilt obtained data in his own language according to his needs to know the role of ICAM1 in development of both diabetes mellitus and diabetic nephropathy through the article. Conclusion ICAM1 is most likely a useful biomarker for prediction of endothelial dysfunction in diabetes and diabetic nephropathy.

How to cite this article:
Gazareen SS, Shoaib AA, Eldein Ahmed Anan AM. Role of intercellular adhesion molecule 1 in development of diabetes and diabetic nephropathy.Menoufia Med J 2014;27:683-685

How to cite this URL:
Gazareen SS, Shoaib AA, Eldein Ahmed Anan AM. Role of intercellular adhesion molecule 1 in development of diabetes and diabetic nephropathy. Menoufia Med J [serial online] 2014 [cited 2020 Apr 10 ];27:683-685
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Diabetes mellitus is a group of metabolic diseases in which person has high blood sugar either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced [1]. On the basis of the figures today, at least 366 million people worldwide have diabetes. By the year 2030, this number is expected to be double [2]. There are two major types of diabetes. Type 1 diabetes mellitus, previously called juvenile diabetes or insulin-dependent diabetes, develops on the basis of autoimmune destruction of pancreatic b-cells, which results in insulin deficiency. It mostly affects young people (<20 years old) but occurs also in adults [3]. Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance [4]. Diabetes patients often develop macrovascular and/or microvascular complications. Diabetic nephropathy is one of serious complications and occurs in 30-40% of diabetic patients [5]. Diabetic nephropathy is the most common single cause of end-stage renal disease. This diabetic complication is characterized by pathophysiological changes such as glomerular hyperfiltration, renal hypertrophy, and then progresses to proteinuria and reduction of glomerular filtration rate [6]. Once overt diabetic nephropathy occurs, it progresses slowly or rapidly to the most advanced stage of chronic kidney disease, which needs dialysis or transplantation [7]. Diabetes and diabetic nephropathy are multifactorial diseases, which are influenced by both genetic and environmental factors [8]. Therefore, identification of the susceptibility genes in development of diabetes and diabetic complications is of greatest importance to provide useful information about prevention and medication programs. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein, expressed in endothelial cells and leukocytes in the immune system. This endothelial and leukocyte-associated transmembrane protein has been known for its importance in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Recently, the accumulating reports from genetic studies in diabetic patients with and without diabetic nephropathy and from biological studies with diabetic animal models have implicated that ICAM1 may play a role in the pathogenesis of diabetes and diabetic nephropathy [6].

 Genomic DNA structure, mRNA, and protein of ICAM1

The ICAM1 gene (GeneID:3383) is located in chromosome 19p13.2 and spans 15 775 base pairs along the short arm of this chromosome. Its aliases include cluster of differentiation 54 and cell surface glycoprotein P3.58 [6]. ICAM1 is a transmembrane glycoprotein molecule of the immunoglobulin superfamily and is characterized by five distinct immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail [9]. ICAM1 protein is 505 amino acids in length, and the molecule weighs between 80 and 114 kDa depending upon the levels of glycosylation, which varies among cell types and environments [10]. Interestingly, there are several transcription-binding proteins including NF (nuclear factor)-kappa B, NF-kappa B1, STAT3, dCREB, STAT1, STAT1a, and STAT1b, which may upregulate the ICAM1 gene activity [11].

 Linkage of The ICAM1 gene to diabetes and diabetic nephropathy

Both in type 1 and type 2 diabetes, the patients with nephropathy have elevated concentrations of ICAM1 compared with patients without renal injury, suggesting that this molecule can be of pathogenic importance for the development of renal injury [12]. Previous works in models of type 1 and type 2 diabetic nephropathy have shown increased ICAM1 expression in parallel with disease progression [13]. Furthermore, genetic-deficient mice studies have demonstrated that ICAM1 is critically involved in the pathogenesis of diabetic nephropathy in a model of type 1 diabetes because characteristic features of diabetic nephropathy, including glomerular hypertrophy, mesangial matrix expansion, and albuminuria, were significantly ameliorated in diabetic ICAM1 knockout mice [14].

 Association of the ICAM1 genetic polymorphisms with diabetes and diabetic nephropathy

It was found that K469E polymorphism in the ICAM1 is associated with diabetic nephropathy in type 1 diabetic patients of Americans of European descent [15]. Interestingly, we have observed that genotype distribution of K469E polymorphism in the ICAM1 gene presents a high heterozygous index (50%) [16]. In the human genome, there are segmental duplications (duplicons) with more than 90% sequences similarity between the copies, which may cause specific allelic and genotypic diversities, such as high heterozygous index in complex diseases [17]. Furthermore, it is demonstrated that another synonymous single nuclear polypeptide G241R in the ICAM1 gene was associated with type 1 diabetes mellitus [18].

 Possible role of ICAM1 in development of diabetes and diabetic nephropathy

There is increasing evidence that acute and chronic hyperglycemia induces activation of endothelial cells by upregulating levels of the adhesion molecules, such as vascular leukocytic antigen-4 (VLA-4) and ICAM1 [19]. Type 2 diabetic patients with diabetic microangiopathic complications have higher soluble ICAM1 levels in comparison with the diabetic group without microangiopathic complications and healthy control individuals [20]. Furthermore, evidence has indicated that ICAM1 is overexpressed in glomeruli diabetic rats [21]. Furthermore, it was reported that soluble ICAM1 levels are associated with all-caused mortality and cardiovascular morbidity in type 1 diabetic patients with diabetic nephropathy [22]. The similar findings have been observed in type 2 diabetic patients. Soluble ICAM1 levels are significantly correlated with albuminuria in type 2 diabetic patients [23]. Type 2 diabetic patients with diabetic microangiopathic complications have higher soluble ICAM1 levels in comparison with the diabetic group without microangiopathic complications and healthy control individuals [20]. The chronic hyperglycemia in diabetic patients leads to the development of so-called advanced glycation end products (AGEs) representing a heterogeneous group of metabolically altered substrates that accumulate during long-term hyperglycemia. These early glycated products are transformed into AGEs upon prolonged exposure to elevated plasma glucose levels and remain now irreversibly bound to proteins, lipids, and nucleic acids [24],[25]. Stimulation of endothelial cells with glycated albumin increases the expression of VCAM1, ICAM1, and E-selectin. AGEs together with inflammatory stimuli led to a higher expression of VCAM1, ICAM1, and E-selectin on cultured human endothelial cells. This is combined with a higher expression of the mRNA for the respective adhesion molecules. This result implicates that the combination of matrix glycation and inflammation upregulates the activation of the endothelial cell adhesion cascade.

 ICAM1 as a target for drug development

It is demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4, decreases the ICAM1 gene expression and ameliorates albuminuria, glomerular hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight [26].

Furthermore, Matsui et al. [27] have reported that nifedipine, a calcium-channel blocker, blocks the AGE-induced tubular damage and also inhibits ICAM1 gene activity in tubular cells, which may have benefits in treatment of diabetic nephropathy.

It is suggested that berberine, quaternary ammonium salt from the protobererine group of isoquinoline alkaloids, can ameliorate renal dysfunction in diabetic rats by decreasing ICAM1 gene expression and NF-kappaB activation. Taking together, the data from these studies suggest that ICAM1 may be a good candidate as target for drug development. Inhibition of ICAM1 gene activity may benefit in treatment of diabetes and diabetic nephropathy [28].


Conflict of interest

There are no conflicts of interest.


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