Characterization of risk factors for excessive cardiovascular diseases (CVD) from circulating and cardiovascular tissues of people with well-controlled chronic type 1 diabetes - Abstract
People with Type 1 diabetes (T1D) have excessive risks for cardiovascular diseases (CVD),
even when they have well-controlled traditional CVD risk factors, such as hypertension,
hyperlipidemia, and hyperglycemia, without nephropathy (DN) or significant systemic insulin
resistance (IR). The presence of chronic autoimmunity in T1D may play a role since many
autoimmune diseases are associated with increased CVD risk. The lack of knowledge regarding
the pathologies of CVD in T1D is partially due to the difficulty of obtaining cardiovascular tissues
from people with T1D and the lack of true mice models of T1D and atherosclerosis. However,
the availability of arteries from T1D, T2D and non-diabetic subjects from the CaRe-T1D and
Medalists’ (T1D for >50 years) repositories have made it possible to have detailed comparative
analysis of potential differences amongst them. CVD studies of Medalists by history and
Coronary Artery Calcium (CAC) score showed accelerated atherosclerosis despite well-
managed diabetes and absence of DN. Advanced glycation end-products (AGEs) and
inflammatory cytokines, IL1β and interferon-γ correlated to CVD history Novel autoantibodies
(AAbs) to NFkBIB and loss of insulin signaling were found in arteries in both people and mice
(ApoE-/-/NOD) with T1D. Plasma metabolomics showed different and opposite changes in T1D
and T2D, in pathways related to adaptive immunity and CVD. Single cell sequencing (scRNA) of
aorta from diabetic mouse models of atherosclerosis due to deletion of insulin receptors showed
elevated inflammatory vascular smooth muscle cells. We postulated the novel idea that chronic
autoimmunity in T1D can promote inflammatory processes in the arterial wall, causing selective
insulin resistance only in the arteries to accelerate atherosclerosis. To test this hypothesis, we
propose: Sp. Aim 1:To compare the pathologies, cellular composition (using spatial
transcriptomics) and insulin signaling of the atherosclerotic plaques from people T1D, vs T2D
and non-DM using tissues from the CaRe-T1D. Sp. Aim 2: To characterize differences in
circulatory novel anti-vascular autoantibodies, inflammatory cytokines and metabolites of people
with T1D, monogenic DM, T2D and non-DM which can be correlated to severity of CAC or CVD
history. Sp. Aim 3: To test definitely whether enhancing insulin actions targeted to endothelial
cells (EC) can decrease innate and adaptive immunity induced inflammation at the arterial wall
and atherosclerosis, using T1D mouse, ECIRS1-/-/ApoE-/-/NOD mice.
