# Identifying new strategies for prevention of cardiovascular complications of diabetes

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2020 · $1,037,755

## Abstract

Currently, almost 10% of the US population (over 30 million people) suffer from type 1 or type 2 diabetes
mellitus (T1DM or T2DM) and more than 30% have pre-diabetes. Approximately 1.4 million children and adults
have T1DM. Because the prevalence of diabetes continues to rise, because both T1DM and T2DM markedly
increase the risk of cardiovascular disease (CVD), and because CVD events occur at younger ages in patients
with diabetes, it is critical to understand how diabetes increases CVD risk and how CVD can be prevented.
Patients with increased CVD risk are generally treated with statins to lower LDL cholesterol. However, even
with statin treatment, patients with diabetes have residual CVD risk and a greater incidence of heart attack and
stroke than subjects without diabetes. This residual CVD risk in patients with T2DM and elevated triglycerides
(TGs) has been linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs). However, TG levels are
normal in most T1DM patients, and current dogma maintains that TRLs do not drive CVD risk in these patients.
We hypothesize that plasma TGs do not accurately reflect levels of the atherogenic remnant lipoprotein
particles (RLPs) derived from VLDL or chylomicrons because RLPs and small VLDL contain much less TG
than do TRLs. We have developed a new method to quantify RLPs and small VLDL. Furthermore, our data
show that elevated serum apolipoprotein C3 (APOC3) levels predict CVD events in subjects with T1DM when
adjusted for diabetes severity and other traditional risk factors; this correlation was found in subjects with
normal TGs. APOC3 increases levels of TRLs and RLPs. We have previously reported that TRLs contribute to
atherosclerotic plaque instability in mouse models of diabetes. We have also found that diabetes leads to
suppression of glycolysis in macrophages, and that this in turn is linked to ER stress and plaque instability.
During the next 7 years, this project will reveal mechanisms behind increased CVD risk in humans, focusing on
RLPs and APOC3 as CVD risk factors in patients with T1DM and T2DM and TG levels in the normal range. By
using our mechanistic mouse models of diabetes-accelerated atherosclerosis, we will also clarify the diabetes-
induced mechanisms that promote early and advanced atherosclerosis. As part of these mechanistic studies,
we will reveal how diabetes, APOC3 and RLPs alter lesion macrophages, by using proteomics, single cell
RNA-sequencing, flow cytometry, and functional assays. By combining prospective studies on CVD risk in
humans with diabetes and our mechanistic mouse models of diabetes-accelerated atherosclerosis, we believe
we are in an excellent position to fill an important and clinically significant gap in our understanding of how
diabetes promotes CVD and to identify new treatment and prevention strategies.

## Key facts

- **NIH application ID:** 9893203
- **Project number:** 1R35HL150754-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Karin E Bornfeldt
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,037,755
- **Award type:** 1
- **Project period:** 2020-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893203

## Citation

> US National Institutes of Health, RePORTER application 9893203, Identifying new strategies for prevention of cardiovascular complications of diabetes (1R35HL150754-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893203. Licensed CC0.

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