Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2014  |  Volume : 27  |  Issue : 4  |  Page : 683-685

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

1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Artificial Kidney Department, Kom Hamada Hospital, Kom Hamada, Egypt

Date of Submission11-Sep-2013
Date of Acceptance17-Nov-2013
Date of Web Publication22-Jan-2015

Correspondence Address:
Amal Mohamed Salah Eldein Ahmed Anan
Gamaa Elfolly street, Shobra el Namla, Tanta, Gharbiya Governate
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-2098.149673

Rights and Permissions

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.
ICAM1 is most likely a useful biomarker for prediction of endothelial dysfunction in diabetes and diabetic nephropathy.

Keywords: Diabetic nephropathy, intercellular adhesion molecule 1, type 1 diabetes mellitus, type 2 diabetes mellitus

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;27:683-5

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 Sep 20];27:683-5. Available from: http://www.mmj.eg.net/text.asp?2014/27/4/683/149673

  Introduction Top

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 Top

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 Top

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 Top

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 Top

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 Top

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].

  Acknowledgements Top

Conflict of interest

There are no conflicts of interest.

  References Top

Gardner D, Shoback D. Greenspan′s basic & clinical endocrinology. New York: McGraw-Hill Medical; 2011.   Back to cited text no. 1
Lam DW, LeRoith D. The worldwide diabetes epidemic. Curr Opin Endocrinol Diabetes Obes 2012; 19 :93-96.  Back to cited text no. 2
Lightfoot YL, Chen J, Mathews CE. Immune-mediated b-cell death in type 1 diabetes: lessons from human b-cell lines. Eur J Clin Invest 2012; 42 :1244-1251.  Back to cited text no. 3
American Diabetes Association. Diabetes Care, January 2013;vol. 36 no. Supplement 1 S11-S66.  Back to cited text no. 4
Marshall SM. Diabetic nephropathy in type 1 diabetes: has the outlook improved since the 1980s? Diabetologia 2012; 55 : 2301-2306.  Back to cited text no. 5
Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne) 2013; 3 :179.   Back to cited text no. 6
Thomas MC, Groop PH. New approaches to the treatment of nephropathy in diabetes. Expert Opin Investig Drugs 2011; 20 :1057-1071.  Back to cited text no. 7
Ashcroft FM, Rorsman P. Diabetes mellitus and the b cell: the last ten years. Cell 2012; 148 :1160-1171.  Back to cited text no. 8
van de Stolpe A, van der Saag PT. Intercellular adhesion molecule-1. J Mol Med (Berl) 1996; 74 :13-33.  Back to cited text no. 9
Newman PJ, Berndt MC, Gorski J, White GC 2nd, Lyman S, Pad-dock C, Muller WA. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 1990; 247 :1219-1222.  Back to cited text no. 10
Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol 1999; 66 :876-888.  Back to cited text no. 11
Güler S, Cakir B, Demirbas B, Yönem A, Odabasi E, Onde U, et al. Plasma soluble intercellular adhesion molecule 1 levels are increased in type 2 diabetic patients with nephropathy. Horm Res 2002; 58 :67-70.  Back to cited text no. 12
Coimbra TM, Janssen U, Gröne HJ, Ostendorf T, Kunter U, Schmidt H, et al. Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int 2000; 57 :167-182.  Back to cited text no. 13
Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003; 52 :2586-2593.  Back to cited text no. 14
Mueller PW, Rogus JJ, Cleary PA, Zhao Y, Smiles AM, Steffes MW, et al. Genetics of kidneys in diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 2006; 17 :1782-1790.  Back to cited text no. 15
Ma J, Möllsten A, Prázny M, Falhammar H, Brismar K, Dahlquist G, et al. Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of type 1 diabetes and diabetic nephropathy. Diabet Med 2006; 23 :1093-1099.  Back to cited text no. 16
Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 2004; 13 :R57-R64.  Back to cited text no. 17
Nejentsev S, Guja C, McCormack R, Cooper J, Howson JM, Nutland S, et al. Association of intercellular adhesion molecule-1 gene with type 1 diabetes. Lancet 2003; 362 :1723-1724.  Back to cited text no. 18
Taki H, Kashiwagi A, Tanaka Y, Horiike K. Expression of intercellular adhesion molecules 1 (ICAM-1) via an osmotic effect in human umbilical vein endothelial cells exposed to high glucose medium. Life Sci 1996; 58 :1713-1721.  Back to cited text no. 19
Mastej K, Adamiec R. Neutrophil surface expression of CD11b and CD62L in diabetic microangiopathy. Acta Diabetol 2008; 45 :183-190.  Back to cited text no. 20
Watanabe N, Shikata K, Shikata Y, Sarai K, Omori K, Kodera R, et al. Involvement of MAPKs in ICAM-1 expression in glomerular endothelial cells in diabetic nephropathy. Acta Med Okayama 2011; 65 :247-257.  Back to cited text no. 21
Astrup AS, Tarnow L, Pietraszek L, Schalkwijk CG, Stehouwer CD, Parving HH, Rossing P. Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years: association with mortality and decline of glomerular filtration rate. Diabetes Care 2008; 31 :1170-1176.  Back to cited text no. 22
Rubio-Guerra AF, Vargas-Robles H, Ayala GV, Escalante-Acosta BA. Correlation between circulating adhesion molecule levels and albuminuria in type 2 diabetic normotensive patients. Med Sci Monit 2007; 13 :CR349-CR352.  Back to cited text no. 23
Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 1994; 70 :138-151.  Back to cited text no. 24
Renier G, Desfaits AC, Serri O. Effect of gliclazide on monocyte-endothelium interactions in diabetes. J Diabetes Complications 2000; 14 :215-223.  Back to cited text no. 25
Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011; 54 :965-978.  Back to cited text no. 26
Matsui T, Yamagishi S, Takeuchi M, Ueda S, Fukami K, Okuda S. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation. Biochem Biophys Res Commun 2010; 398 :326-330.  Back to cited text no. 27
Liu W, Zhang X, Liu P, Shen X, Lan T, Li W, et al. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol 2010; 638 :150-155.  Back to cited text no. 28


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Genomic DNA stru...
Linkage of The I...
Association of t...
Possible role of...
ICAM1 as a targe...

 Article Access Statistics
    PDF Downloaded154    
    Comments [Add]    

Recommend this journal