Characterization of cardiovascular diseases (CVD) in people with long duration Type 1 diabetes

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Abstract Cardiovascular disease (CVD) is the major cause of mortality in Type 1 diabetes (T1D). Some CVD risk factors are shared between people with T1D and Type 2 diabetes (T2D). However, differences in dyslipidemia, severity of insulin resistance, disease onset, responses to glycemic control, and presence of autoimmunity suggest that the pathogenesis of CVD may differ between T1D and T2D. Diabetic nephropathy (DN) is a major risk factor for CVD in T1D; but while it occurs in 40% of those with T1D, CVD is still the major cause of mortality in those without DN. Autoimmunity may also contribute to CVD, since the risks of atherosclerosis are elevated in several autoimmune diseases. Understanding the pathogenesis of CVD in TID is hampered also by the lack of comparative pathological studies of coronary vessels of aging people with T1D versus T2D and non-diabetic subjects. Preliminary studies from the Medalist Study, a large cohort (n=1019) with >50 years of insulin-dependent T1D, showed that while only 13% have DN, 40% exhibited significant CVD history, which correlated with coronary artery calcium (CAC) scores by CT and myocardial dysfunction by cardiac MRI (CMR). While >90% of Medalists possess high-risk HLA alleles for classic autoimmune T1D, 8% also have known genes for monogenic diabetes. The Medalist biobank includes plasma/serum samples and postmortem organ specimens (hearts with coronary vessels, aortae, kidney, pancreases and others). Pilot studies in Medalists provide the first extensive characterizations of inflammatory and metabolomics profiles of T1D and their associations with CAC scores and CMR parameters, which may indicate differences with published data on T2D. Pilot morphological studies of Medalists’ coronary vessels clearly identified immune cell infiltrates, including CD3+ T-cells. The role of autoimmunity in exacerbating atherosclerosis is clearly demonstrated by studies using newly-created ApoE-/-/NOD mice with autoimmune diabetes closely mimicking T1D, which exhibited significantly more atherosclerotic plaques containing elevated subsets of pro-inflammatory T-cells and less regulatory T-cells than in non-diabetic ApoE-/-/CongNOD control mice. In this proposal, we aim to characterize CVD in T1D by clinical, biochemical, imaging, metabolomic and pathological studies, and their associations with autoimmunity, via comparative studies of the Medalist cohort with T2D, monogenic diabetes and non-diabetic subjects. Our specific aims are as follows: Sp. Aim 1: To characterize atherosclerosis and myocardial structure and function in type 1 diabetes of long duration (Joslin Medalist Study) by CVD history and imaging, presence of autoimmunity, beta cell function, inflammatory and metabolomics markers, metabolic control and microvascular diseases. Sp. Aim 2: To compare the plaque characteristics and composition of immune cells, including monocytes, macrophages, B-cells and T-cells (CD3+, CD4+ and CD8+ T cells) and subtypes of T-cells (Treg, Tfh, Th1 and Th17) in the atherosclerotic plaques of the coronary vessels and peripheral arteries from patients with T1D, T2D, monogenic diabetes and no DM.