Vascular disease is the major cause of morbidity and mortality in persons with Type 1 Diabetes Mellitus (T1DM). T1DM patients experience earlier onset of cardiovascular disease (CVD) by several decades and have a greater CVD mortality rate compared to the general population. Tight glycemic control modestly improves CVD outcomes in this population, but the pathogenesis of accelerated atherosclerosis in T1DM cannot be fully explained by hyperglycemia or typical cardiovascular risk factors. Given the markedly increased CVD risk in T1DM, a greater understanding of vascular dysfunction in T1DM is urgently needed. Metabolic insulin resistance increases CVD risk, and T1DM patients are insulin resistant compared to matched controls. Insulin is a vasoactive hormone and vascular insulin resistance, manifest as impaired vasodilatory effects of insulin on the arterial vasculature, accompanies metabolic insulin resistance in Type 2 Diabetes (T2DM) and obesity. It is unclear whether this similarly occurs in T1DM. Endothelial dysfunction and increased vascular stiffness occur early in the genesis of atherosclerosis and predict CVD risk in obesity, T2DM and peripheral vascular disease. Neither baseline nor post-insulin vascular function has ever been systematically studied across the entirety of the arterial tree (i.e. in conduit arteries resistance arterioles, and arteriolar micro vascular vessels) in T1DM. We hypothesize that baseline and insulin-responsive pan-arterial vascular function is impaired in young adults with T1DM compared to healthy controls. Young adults are targeted as vascular inflammation and abnormal vascular function which contribute to CVD pathogenesis begin early, long before the development of clinical disease. Early intervention may significantly improve outcomes through the identification, prevention, stabilization or reversal of such pathology. This hypothesis will b tested by measurement of conduit artery, resistance arteriolar, skeletal and myocardial micro vascular function in both the basal state and under conditions of a euglycemic insulin clamp in T1DM and aged matched healthy controls. Results from this study will increase our understanding of vascular function in T1DM by determining whether: 1) baseline vascular function is impaired;2) vascular insulin resistance accompanies metabolic insulin resistance in T1DM (as is found in obesity and T2DM) and is present throughout the arterial tree in young persons with T1DM. The results of this work may facilitate development of a non-invasive "biomarker" of vascular health which can then be used in T1DM to: 1) investigate potential therapies targeting vascular dysfunction;2) improve cardiovascular risk stratification;and 3) better identify those persons likely to respond to treatment, thereby enabling personalization of therapeutic strategies. These insights are critical steps toward our ultimate goal of improving cardiovascular outcomes in T1DM.

Public Health Relevance

Vascular disease is the major cause of morbidity and mortality in persons with Type 1 diabetes. This project will identify whether large, medium or very small arteries function normally in type 1 diabetes before they develop clinical vascular disease, and whether vascular inflammation and/or insulin resistance contributes to vascular dysfunction. The outcomes of this study will provide a model for testing therapies aimed at improving cardiovascular outcomes in this population.

National Institute of Health (NIH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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