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Characterization of risk factors for excessive cardiovascular diseases (CVD) from circulating and cardiovascular tissues of people with well-controlled chronic type 1 diabetes

Award Number: U01DK142331
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/7/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,020,124 )
2025	2025	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/3/2025	NON-COMPETING CONTINUATION	$1,020,124
2025	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/22/2025	NEW	$0
														Subtotal = $1,020,124

Issue Date FY: 2024 ( Subtotal = $1,009,308 )
2024	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/18/2024	NEW	$1,009,308
														Subtotal = $1,009,308

Grand Total All Awards = $2,029,432

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Characterization of risk factors for excessive cardiovascular diseases (CVD) from circulating and cardiovascular tissues of people with well-controlled chronic type 1 diabetes

Award Number: U01DK142331

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/18/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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