The origin of circulating CD36 in type 2 diabetes

Objective:Elevated plasma levels of the fatty acid transporter, CD36, have been shown to constitute a novel biomarker for type 2 diabetes mellitus (T2DM). We recently reported such circulating CD36 to be entirely associated with cellular microparticles (MPs) and aim here to determine the absolute levels and cellular origin(s) of these CD36+MPs in persons with T2DM.Design:An ex vivo case-control study was conducted using plasma samples from 33 obese individuals with T2DM (body mass index (BMI)=39.9±6.4 kg m−2; age=57±9 years; 18 male:15 female) and age- and gender-matched lean and obese non-T2DM controls (BMI=23.6±1.8 kg m−2 and 33.5±5.9 kg m−2, respectively). Flow cytometry was used to analyse surface expression of CD36 together with tissue-specific markers: CD41, CD235a, CD14, CD105 and phosphatidyl serine on plasma MPs. An enzyme-linked immunosorbent assay was used to quantify absolute CD36 protein concentrations.Results:CD36+MP levels were significantly higher in obese people with T2DM (P<0.00001) and were primarily derived from erythrocytes (CD235a+=35.8±14.6%); although this did not correlate with haemoglobin A1c. By contrast, the main source of CD36+MPs in non-T2DM individuals was endothelial cells (CD105+=40.9±8.3% and 33.9±8.3% for lean and obese controls, respectively). Across the entire cohort, plasma CD36 protein concentration varied from undetectable to 22.9 μg ml−1 and was positively correlated with CD36+MPs measured by flow cytometry (P=0.0006) but only weakly associated with the distribution of controls and T2DM (P=0.021). Multivariate analysis confirmed that plasma CD36+MP levels were a much better biomarker for diabetes than CD36 protein concentration (P=0.009 vs P=0.398, respectively).Conclusions:Both the levels and cellular profile of CD36+MPs differ in T2DM compared with controls, suggesting that these specific vesicles could represent distinct biological vectors contributing to the pathology of the disease.

[1]  Timothy McCaffrey,et al.  A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation , 2001, Nature Medicine.

[2]  P. Stenvinkel,et al.  Serum soluble CD36, assessed by a novel monoclonal antibody-based sandwich ELISA, predicts cardiovascular mortality in dialysis patients. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[3]  M. Connelly,et al.  Common CD36 SNPs reduce protein expression and may contribute to a protective atherogenic profile. , 2011, Human molecular genetics.

[4]  A. Tedgui,et al.  Microparticles and type 2 diabetes. , 2008, Diabetes & metabolism.

[5]  J. Barnard,et al.  Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms. , 2011, Blood.

[6]  J. Freyssinet,et al.  Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. , 2000, Circulation.

[7]  Christian Weber,et al.  Microparticles: Protagonists of a Novel Communication Network for Intercellular Information Exchange , 2010, Circulation research.

[8]  D. Giugliano,et al.  Pioglitazone reduces endothelial microparticles in the metabolic syndrome. , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[9]  N. Egberg,et al.  Release of endothelial microparticles in vivo during atorvastatin treatment; a randomized double-blind placebo-controlled study. , 2012, Thrombosis research.

[10]  C. Bogardus,et al.  Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. , 1995, Obesity research.

[11]  J. Lovegrove,et al.  Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress. , 2011, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[12]  Kumar Sharma,et al.  Multiple Metabolic Hits Converge on CD36 as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic Nephropathy , 2005, PLoS medicine.

[13]  J. Dekker,et al.  Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population , 2012, Journal of internal medicine.

[14]  A. Handberg,et al.  Soluble CD36 (sCD36) clusters with markers of insulin resistance, and high sCD36 is associated with increased type 2 diabetes risk. , 2010, The Journal of clinical endocrinology and metabolism.

[15]  J Ratajczak,et al.  Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication , 2006, Leukemia.

[16]  B. D. de Pauw,et al.  Erythrocyte vesiculation: a self‐protective mechanism? , 2008, British journal of haematology.

[17]  M. Kelm,et al.  Impaired Red Blood Cell Deformability in Patients with Coronary Artery Disease and Diabetes Mellitus , 2011, Hormone and Metabolic Research.

[18]  C. Meldrum,et al.  CD36 forms covalently associated dimers and multimers in platelets and transfected COS-7 cells. , 1997, Biochemical and biophysical research communications.

[19]  E. Lasonder,et al.  Comparative proteomics of erythrocyte aging in vivo and in vitro. , 2010, Journal of proteomics.

[20]  L. Ragolia,et al.  Circulating Endothelial Microparticles in Diabetes Mellitus , 2010, Mediators of inflammation.

[21]  T. Iwasaka,et al.  Detection of monocyte-derived microparticles in patients with Type II diabetes mellitus , 2002, Diabetologia.

[22]  J. Dixon,et al.  Obesity and the White Blood Cell Count: Changes with Sustained Weight Loss , 2006, Obesity surgery.

[23]  Patrice Darmon,et al.  Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. , 2002, Diabetes.

[24]  F. Bosch,et al.  Quantification of loss of haemoglobin components from the circulating red blood cell in vivo , 1997, European journal of haematology.

[25]  Kristina M. Little,et al.  The plasma microparticle proteome. , 2010, Seminars in thrombosis and hemostasis.

[26]  F. Ortega,et al.  Circulating soluble CD36 is a novel marker of liver injury in subjects with altered glucose tolerance. , 2009, The Journal of nutritional biochemistry.

[27]  H. Lim,et al.  Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[28]  S. Filetti,et al.  Atorvastatin Downregulates Monocyte CD36 Expression, Nuclear NFκB and TNFα Levels in Type 2 Diabetes , 2010 .

[29]  Kylie J. Ralston,et al.  CD36 is a receptor for oxidized high density lipoprotein: Implications for the development of atherosclerosis , 2007, FEBS letters.

[30]  A. Dahl,et al.  Soluble CD36 in Plasma Is Increased in Patients With Symptomatic Atherosclerotic Carotid Plaques and Is Related to Plaque Instability , 2008, Stroke.

[31]  J. Roh,et al.  Risk of Macrovascular Complications in Type 2 Diabetes Mellitus: Endothelial Microparticle Profiles , 2011, Cerebrovascular Diseases.

[32]  R. Silverstein,et al.  CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. , 2001, The Journal of clinical investigation.

[33]  S. Filetti,et al.  Atorvastatin downregulates monocyte CD36 expression, nuclear NFkappaB and TNFalpha levels in type 2 diabetes. , 2010, Journal of atherosclerosis and thrombosis.

[34]  G. Leftheriotis,et al.  Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. , 2008, The American journal of pathology.

[35]  R Lacroix,et al.  Standardization of platelet‐derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop , 2010, Journal of thrombosis and haemostasis : JTH.

[36]  P. Fontana,et al.  Cell-derived microparticles in haemostasis and vascular medicine , 2009, Thrombosis and Haemostasis.

[37]  Nizar M. Mhaidat,et al.  The putative diabetic plasma marker, soluble CD36, is non‐cleaved, non‐soluble and entirely associated with microparticles , 2011, Journal of thrombosis and haemostasis : JTH.

[38]  C. Vrints,et al.  Flow cytometric detection of endothelial microparticles (EMP): effects of centrifugation and storage alter with the phenotype studied. , 2010, Thrombosis research.

[39]  K. Højlund,et al.  Identification of the Oxidized Low-Density Lipoprotein Scavenger Receptor CD36 in Plasma: A Novel Marker of Insulin Resistance , 2006, Circulation.

[40]  W. Jy,et al.  Elevated plasma endothelial microparticles: preeclampsia versus gestational hypertension. , 2004, American journal of obstetrics and gynecology.

[41]  R. Silverstein.  Infl ammation , atherosclerosis , and arterial thrombosis : Role of the scavenger receptor CD 36 , 2022 .

[42]  Ariel Roguin,et al.  Involvement of microparticles in diabetic vascular complications , 2011, Thrombosis and Haemostasis.

[43]  L. Horstman,et al.  Platelet microparticles: a wide-angle perspective. , 1999, Critical reviews in oncology/hematology.

[44]  R. Nieuwland,et al.  Elevated Numbers of Tissue-Factor Exposing Microparticles Correlate With Components of the Metabolic Syndrome in Uncomplicated Type 2 Diabetes Mellitus , 2002, Circulation.

[45]  M. Alessio,et al.  CD36 is a ditopic glycoprotein with the N-terminal domain implicated in intracellular transport. , 2000, Biochemical and biophysical research communications.

[46]  B. Goichot,et al.  Circulating procoagulant microparticles in obesity. , 2006, Diabetes & metabolism.

[47]  R. M. Oliart Ros,et al.  Induction of Cd36 expression elicited by fish oil PUFA in spontaneously hypertensive rats. , 2006, The Journal of nutritional biochemistry.

[48]  R. Silverstein.  Inflammation, atherosclerosis, and arterial thrombosis: Role of the scavenger receptor CD36 , 2009, Cleveland Clinic Journal of Medicine.

[49]  L. Arnaud,et al.  Standardization of platelet‐derived microparticle counting using calibrated beads and a Cytomics FC500 routine flow cytometer: a first step towards multicenter studies? , 2009, Journal of thrombosis and haemostasis : JTH.

[50]  M. McMichael,et al.  Microparticles in health and disease. , 2013, Journal of veterinary internal medicine.