Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes

The pathogenesis and natural history of type 1 diabetes (T1D) and type 2 diabetes (T2D) are fundamentally
different, but the two diseases result in many common long-term complications. Most notably, cardiovascular
disease (CVD) is the leading cause of death for individuals with diabetes, resulting in a shortened life expectancy.
While rigorous blood glucose management reduces the risk for CVD development, the vast majority of diabetes
patients are unable to meet recommended HbA1c targets. Given the high prevalence of diabetes (10.5%) and
pre-diabetes (33%) in the United States (U.S.), it is imperative to understand diabetes-related CVD pathogenesis
to support the development of optimal intervention and treatment strategies. However, studies comparing CVD
mechanisms in T1D versus T2D are critically lacking. To address this, we propose to establish a Cardiovascular
Repository-Type 1 Diabetes (CARE-T1D) program to facilitate collaboration and multi-modal data acquisition
across a large network of investigators. Through our leadership of 6 organ procurement and biospecimen sharing
research programs, we have 15 consecutive years of operational experience and well-established programmatic
infrastructure for collecting and distributing 16 different types of transplant-quality tissue from human organ
donors, including a recently concluded kidney project and current heart pilot program. We will leverage our
productive relationships with all 57 U.S. Organ Procurement Organizations, centralized 24/7/365 Call Center and
Organ Processing and Pathology Core to procure, to swiftly process and bank a complete CVD-related tissue
panel (heart, kidney, vasculature, blood) from 60 donors with CVD, evenly distributed across three groups (T1D,
T2D, age/sex-matched no-diabetes controls). Following whole organ radiology and calcium scoring, anatomical
dissection will be systematically performed by our highly experienced staff to prepare biospecimens in a variety
of formats (e.g., FFPE blocks, OCT blocks, flash-frozen), with protocols evolving to support emerging needs for
research applications. Each case will be subjected to tissue-specific stains with histopathologic examination by
board certified pathologists and QA/QC analysis. Resulting data will be made available alongside de-identified
donor information and medical records in a secure searchable Data Portal to aid investigators in selecting sample
sets for their research. We propose to establish a Scientific Advisory Board to evaluate research proposals and
sample requests, modeled after our existing Tissue Prioritization Committee. We will distribute biosamples to
approved researchers seeking to apply multimodal approaches for deep phenotyping of specimens to study CVD
progression in T1D vs T2D. The Data Portal will also support visualization and sharing of all externally generated
data types. Finally, we will organize annual meetings to promote collaboration across the Cardiovascular
Biorepository Consortium. In sum, we expect the proposed CARE-T1D program will support discovery and
mechanistic research, conducted by a collaborative network of investigators, that will increase our understanding
of CVD in diabetes, leading to early detection as well as novel treatments specific for both T1D and T2D.

Grant Number: 5U24DK133700-04
NIH Institute/Center: NIH
Principal Investigator: MARK ATKINSON