Biomarkers of Vascular Disease Progression in Type 1 Diabetes Mellitus

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DESCRIPTION (provided by applicant): The goal of the proposed research is to elucidate the value of selected biomarkers in predicting the development of micro- and macro-vascular complications in Type 1 diabetes and to determine if several risk factors, some unique to diabetes, may interact to augment vascular risk. We will measure three classes of biomarkers: i.) endothelial cell dysfunction - soluble ICAM-1, VCAM, and E selectin; ii.) inflammation-interleukin-6, CRP, and soluble TNF ?receptors; iii.) fibrinolytic and clotting system - fibrinogen, plasminogen activator inhibitor-1 and tissue plasminogen activator. We will assay these biomarkers longitudinally in samples, obtained from the well characterized DCCT/EDIC cohort of type 1 diabetes, at the DCCT baseline and closeout phases, and in years 3-5 and 9-12 of the EDIC phase of the study. We hypothesize that the pathogenic interaction between inflammation and endothelial cell/clotting/fibrinolytic dysfunction greatly contributes to the accelerated development of vascular complications in diabetes, and that selective clustering of the above biomarkers will predict patients at high risk to develop complications. Furthermore, we also hypothesize that the persistent, lower rate of complications observed in patients enrolled in the intensive glycemic control arm of the DCCT study even 10 years after the close-out of the DCCT is secondary to the effect of sustained glycemic control in one or more of the biomarkers we propose to measure. We will evaluate this hypothesis in three aims. Aim 1 will determine if concentrations of any biomarker or cluster of biomarkers, will predict the development of micro- or macro-vascular complications in this cohort and whether they predict a select group of complications, all vascular complications, or a single complication. Aim 2 will assess if levels of any of the biomarkers studied that remain similar, during the EDIC phase of the study, to those measured at DCCT close-out can explain the slower progression of complications observed in patients enrolled in the intensive glycemic control arm of the DCCT/EDIC study over the next decade of follow-up and, therefore, explain the "metabolic imprint" phenomenon postulated by the DCCT/EDIC group of investigators. Aim 3 will assess the value of the panel of novel biomarkers identified in Aim 1 to predict diabetic complications by assaying these biomarkers in samples collected at entry into the DCCT trial from patients not used to construct the biomarker risk algorithm.