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.