Biomarkers of Vascular Disease Progression in Type 1 Diabetes Mellitus

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DESCRIPTION (provided by applicant): 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.