The NIH has announced the availability of Recovery Act Funds for Competitive Revision Applications (NOT-OD-09-058). The goal of our parent RO1 is to establish a panel of biomarkers for endothelial cell dysfunction/ inflammation/ fibrinolysis that may identify patients with type 1 diabetes at high risk to develop complications. To accomplish this goal, we are measuring circulating levels of cell adhesion molecules (CAM), IL6, TNF, CRP, PAI-1, and fibrinogen in samples from the DCCT/EDIC cohort, collected longitudinally over 20 years. One of the limitations of this work is the lack of a control group that will allow us to establish the normal values for this population. We recently learned that a healthy age and gender matched group was recruited within the 28 centers of the DCCT/EDIC study to serve as a control for the carotid ultrasound studies performed in the cohort. We received serum/plasma samples from these subjects (N=620) and we now propose as Aim 1 of this Competitive Revision to measure VCAM-1, ICAM-1, E-selectin, PAI-1, fibrinogen, CRP, IL-6, and soluble tumor necrosis factor receptors in these samples. We will compare the concentrations of the biomarkers measured in this group of control subjects with those of a matched group of subjects with type 1 diabetes from the DCCT/EDIC cohort without and with diabetes complications that are being measured in the parent RO1. This will enable us to compare the distribution of biomarkers between a population with and without type 1 diabetes as well as with the subgroup of subjects with type 1 diabetes and complications. While knowledge of the levels of these important bioanalytes in both diabetic patients and controls is critical to evaluate their role as biomarkers, we would also like to expand our previous studies to include determination of two recently identified biomarkers, sphingosine-1-phospate (S1P) and lipoprotein-associated phospholipase A2 (Lp- PLA2) which are known to affect the clotting/fibrinolytic pathways and adhesion molecules/inflammation, respectively, and are independent of the level of other biomarkers. Therefore, in Aim 2, we propose to determine the circulating levels of S1P and Lp-PLA2 in the baseline samples of the subgroup of 636 patients enrolled in the DCCT/EDIC cohort in whom longitudinal measurements of biomarkers will not be performed but who will be used to test/validate the predictive value of the biomarkers risk algorithm developed in the remaining cohort. We will determine whether quantitation of either of these newly discovered biomarkers will increase the predictive power of the algorithm developed in Aim 1 of our parent RO1 and better predict the development of micro- and macrovascular complications in this cohort.

Public Health Relevance

Diabetes is associated with an increased incidence of heart disease and limb amputation and it is also one of the major contributors to blindness and kidney disease. These complications of diabetes markedly increase the cost of health care and lead to enormous suffering both to the patients and their families. We do not know how to predict the development of these complications in order to intervene earlier in the course of the disease and prevent their development. These studies will determine if blood levels of selected biomarkers (proteins that are associated with well known metabolic abnormalities in diabetes) can predict which diabetic patients will develop diabetic complications and, thus, identify those patients who will require early intervention to prevent the development of complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK081352-02S1
Application #
7810292
Study Section
Special Emphasis Panel (ZDK1-GRB-R (O3))
Program Officer
Jones, Teresa L Z
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2009-09-25
Budget End
2011-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$410,125
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Rajab, Hussein A; Baker, Nathaniel L; Hunt, Kelly J et al. (2015) The predictive role of markers of Inflammation and endothelial dysfunction on the course of diabetic retinopathy in type 1 diabetes. J Diabetes Complications 29:108-14
Hunt, Kelly J; Baker, Nathaniel L; Cleary, Patricia A et al. (2015) Longitudinal Association Between Endothelial Dysfunction, Inflammation, and Clotting Biomarkers With Subclinical Atherosclerosis in Type 1 Diabetes: An Evaluation of the DCCT/EDIC Cohort. Diabetes Care 38:1281-9
Klein, Richard L; Hammad, Samar M; Baker, Nathaniel L et al. (2014) Decreased plasma levels of select very long chain ceramide species are associated with the development of nephropathy in type 1 diabetes. Metabolism 63:1287-95
Lopes-Virella, Maria F; Baker, Nathaniel L; Hunt, Kelly J et al. (2014) Response to comment on Lopes-Virella et al. Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes care 2013;36:2317-2323. Diabetes Care 37:e108-9
Lopes-Virella, Maria F; Baker, Nathaniel L; Hunt, Kelly J et al. (2013) Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes Care 36:2317-23
Hunt, Kelly J; Baker, Nathaniel; Cleary, Patricia et al. (2013) Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes. Atherosclerosis 231:315-22
Lopes-Virella, Maria F; Baker, Nathaniel L; Hunt, Kelly J et al. (2012) High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. Diabetes Care 35:1333-40
Lu, Zhongyang; Li, Yanchun; Jin, Junfei et al. (2012) Toll-like receptor 4 activation in microvascular endothelial cells triggers a robust inflammatory response and cross talk with mononuclear cells via interleukin-6. Arterioscler Thromb Vasc Biol 32:1696-706
Truman, Jean-Philip; Al Gadban, Mohammed M; Smith, Kent J et al. (2012) Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release. Immunology 136:30-45
Lopes-Virella, Maria F; Hunt, Kelly J; Baker, Nathaniel L et al. (2012) The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study. Atherosclerosis 224:526-31

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