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.
|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; Carter, Rickey E; Baker, Nathaniel L et al. (2012) High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in Type 1 diabetes. Nephrol Dial Transplant 27:1416-23|
|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|
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