Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of ldl subfraction phenotype

BackgroundType 2 diabetes mellitus (T2D) is associated with higher cardiovascular risk partly related to an increase in inflammatory parameters. The aim of this study was to determine the association of inflammatory biomarkers with low-density lipoprotein (LDL) subfraction phenotype and glycemic control in subjects with T2D and poor glycemic control.MethodsA cross-sectional study was performed comparing 122 subjects with T2D (59 ± 11 years old, body mass index 30.2 ± 5.6 kg/m2) with 54 control subjects. Patients with T2D were classified according to their LDL subfraction phenotype and inflammatory biomarkers (C-reactive protein, Interleukin-6, Interleukin-8, Transforming growth factor β1, Monocyte chemotactic protein 1, Leptin, Adiponectin) were evaluated according to the degree of glycemic control, LDL phenotype and other clinical characteristics. Forty-two subjects with T2D were studied before and after 3 months of improving glycemic control by different strategies.ResultsPatients with T2D had higher C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP1) levels and lower adiponectin concentration, compared to controls. T2D subjects with body mass index ≥ 30 kg/m2 had higher CRP levels (5.2 ± 4.8 mg/l vs 3.7 ± 4.3 mg/l; p < 0.05). The presence of LDL phenotype B was related to higher levels of transforming growth factor-β1 (TGF-β1) (53.92 ± 52.82 ng/l vs 31.35 ± 33.74 ng/l; p < 0.05) and lower levels of adiponectin (3663 ± 3044 ng/l vs 2723 ± 1776 ng/l; p < 0.05). The reduction of HbA1c from 9.5 ± 1.8% at baseline to 7.4 ± 0.8% was associated with a significant reduction of TGF-β1 (41.86 ± 32.84 ng/l vs 26.64 ± 26.91 ng/l; p = 0.02).ConclusionsSubjects with T2D, especially those with LDL phenotype B and obesity, have higher levels of inflammatory biomarkers. Improvement of glycemic control reduces TGF-β1 levels, which may contribute partly to its renoprotective role.

[1]  Y. Aso,et al.  Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes. , 2004, Metabolism: clinical and experimental.

[2]  M. Volpe,et al.  Markers of inflammation and fibrosis are related to cardiovascular damage in hypertensive patients with metabolic syndrome. , 2007, American journal of hypertension.

[3]  C. Tanaseanu,et al.  Significance of platelet‐activating factor acetylhydrolase in patients with non‐insulin‐dependent (type 2) diabetes mellitus , 2002, Journal of cellular and molecular medicine.

[4]  J. Eckel,et al.  Monocyte chemotactic protein-1 and its role in insulin resistance , 2007, Current opinion in lipidology.

[5]  J. Ordóñez‐Llanos,et al.  Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects. , 2002, Journal of lipid research.

[6]  T. Funahashi,et al.  Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. , 2003, Diabetes care.

[7]  M. Taskinen,et al.  Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. , 2003, Atherosclerosis.

[8]  R. Barr,et al.  Inflammation and the Incidence of Type 2 Diabetes , 2010, Diabetes Care.

[9]  G. Wolf,et al.  Transforming growth factor-β and the progression of renal disease. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[10]  David M. Reboussin,et al.  A 1-Year Lifestyle Intervention for Weight Loss in Individuals With Type 2 Diabetes Reduces High C-Reactive Protein Levels and Identifies Metabolic Predictors of Change , 2010, Diabetes Care.

[11]  W. Rathmann,et al.  Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors , 2002, Diabetologia.

[12]  L. Luzi,et al.  Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality. , 2003, Diabetes care.

[13]  J. Pickup,et al.  Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. , 2000, Life sciences.

[14]  J. Pickup,et al.  Serum Sialic Acid Concentration and Coronary Heart Disease in NIDDM , 1995, Diabetes Care.

[15]  M. Sandhu,et al.  Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis , 2009, Diabetologia.

[16]  M. Suthanthiran,et al.  Transforming growth factor beta and progression of renal disease. , 2003, Kidney international. Supplement.

[17]  W. Rathmann,et al.  Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. , 2002, Diabetologia.

[18]  M. Fernandez,et al.  Inflammation and type 2 diabetes. , 2012, Diabetes & metabolism.

[19]  N. Cook,et al.  Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial. , 2009, JAMA.

[20]  M. Mauer,et al.  The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? , 2000, Diabetes.

[21]  S. Haffner,et al.  Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. , 2002, Diabetes.

[22]  A. Esteghamati,et al.  Association of oxidized low-density lipoprotein and transforming growth factor-beta in type 2 diabetic patients: a cross-sectional study. , 2009, Translational research : the journal of laboratory and clinical medicine.

[23]  K. Utsunomiya,et al.  Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report , 2013, Cardiovascular Diabetology.

[24]  Qingbo Xu,et al.  Endothelial lineage differentiation from induced pluripotent stem cells is regulated by microRNA-21 and transforming growth factor beta2 (TGF-β2) pathways , 2014 .

[25]  J. Ordóñez‐Llanos,et al.  Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution. , 2012, The American journal of cardiology.

[26]  J. Pickup.  Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. , 2004, Diabetes care.

[27]  S. Haffner,et al.  Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). , 2000, Circulation.

[28]  M. Isono,et al.  Stimulation of TGF-beta type II receptor by high glucose in mouse mesangial cells and in diabetic kidney. , 2000, American journal of physiology. Renal physiology.

[29]  K. Lam,et al.  Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus. , 2002, The Journal of clinical endocrinology and metabolism.

[30]  S. Coppack,et al.  C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[31]  S. Azar,et al.  Alterations in plasma transforming growth factor beta in normoalbuminuric type 1 and type 2 diabetic patients. , 2000, The Journal of clinical endocrinology and metabolism.

[32]  S. Möhlenkamp,et al.  Coronary aspirate TNFα reflects saphenous vein bypass graft restenosis risk in diabetic patients , 2013, Cardiovascular Diabetology.

[33]  J. Coresh,et al.  Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. , 2000, Kidney international.

[34]  A. Astrup,et al.  Redefining Type 2 diabetes: ‘Diabesity’ or ‘Obesity Dependent Diabetes Mellitus’? , 2000, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[35]  G. Tesch,et al.  Inflammation in Diabetic Nephropathy , 2012, Mediators of inflammation.

[36]  Jennifer L. Gay,et al.  Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. , 2012, Cytokine.

[37]  A. Wägner,et al.  Effect of statin and fibrate treatment on inflammation in type 2 diabetes. A randomized, cross-over study. , 2011, Diabetes research and clinical practice.

[38]  Antonio Pérez,et al.  Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes , 2013, Cardiovascular Diabetology.

[39]  S. Dooley,et al.  L-carnosine inhibits high-glucose-mediated matrix accumulation in human mesangial cells by interfering with TGF-β production and signalling. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[40]  M. Rodríguez-Moran,et al.  Increased levels of C-reactive protein in noncontrolled type II diabetic subjects. , 1999, Journal of diabetes and its complications.

[41]  E. Eschwège.  The dysmetabolic syndrome, insulin resistance and increased cardiovascular (CV) morbidity and mortality in type 2 diabetes: aetiological factors in the development of CV complications. , 2003, Diabetes & metabolism.

[42]  K. Kuboki,et al.  Small, dense LDL and high-sensitivity C-reactive protein (hs-CRP) in metabolic syndrome with type 2 diabetes mellitus. , 2010, Journal of atherosclerosis and thrombosis.