# Apolipoprotein C3-loading of apolipoprotein B100 lipoproteins and cardiovascular disease in patients with type 1 diabetes

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $823,854

## Abstract

We recently showed that serum levels of apolipoprotein C3 (APOC3) predicted incident cardiovascular disease
(CVD) in CACTI, a prospective study of subjects with type 1 diabetes mellitus (T1DM). In complementary
mechanistic studies, we found that reducing APOC3 levels with an antisense oligonucleotide (ASO) prevented
lesion progression in a mouse model of T1DM and that apolipoprotein B (APOB)-containing lipoproteins were
driving accelerated diabetic atherosclerosis. These observations are important because they strongly support
the proposal that APOC3 promotes atherosclerosis in the setting of T1DM in both humans and mice. This is
particularly important because ASOs to APOC3 are under investigation in humans, raising the possibility that it
may be possible to reduce CVD risk in T1DM patients by lowering APOC3 levels.
 Our preliminary data strongly support the hypothesis that APOC3 accumulation in APOB100-containing
lipoproteins, intermediate-density lipoprotein (IDL) and LDL, makes these particles atherogenic in T1DM. To
test this hypothesis, and to lay the groundwork for a clinical trial of APOC3 ASO therapy in the prevention of
CVD in T1DM patients, we propose two specific aims.
 First, we will determine whether levels of APOC3 in IDL and/or LDL predict incident CVD risk in the
Pittsburgh Epidemiology of Diabetes Complications study, a large prospective study. Our proposed study is
well powered with ~550 T1DM patients and >30% rate of incident CVD. These studies will take advantage of a
state-of-the-art method we developedtermed calibrated ion mobility analysisthat quantifies molar
concentrations of APOB100-containing lipoprotein particles in blood. Our primary analysis will be to determine
if i) IDL-APOC3 and/or ii) LDL-APOC3 predict incident CVD.
 Second, we will perform detailed metabolic studies to determine how T1DM alters hepatic APOC3
production and VLDL turnover rates, and how this impacts the accumulation of APOC3 in LDL and IDL in
humans with and without T1DM. Based on our mouse studies, we hypothesize that T1DM promotes increased
levels of hepatic APOC3 production that impairs TG lipolysis, resulting in increased levels of IDL-APOC3
and/or LDL-APOC3. We will complement these analyses with comprehensive analyses of the metabolic factors
(e.g., body fat composition, liver triglycerides, hepatic sinusoidal insulin concentration) that might regulate the
concentration of APOC3 in LDL, IDL and VLDL.
 Identifying patients at increased risk for CVD should provide mechanistic insights into the pathogenesis of
accelerated atherosclerosis in T1DM. Moreover, it would lay the groundwork for a clinical study of APOC3
lowering therapy in T1DM because it could target patients at high risk of CVD.

## Key facts

- **NIH application ID:** 10757374
- **Project number:** 5R01HL161829-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JAY W HEINECKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $823,854
- **Award type:** 5
- **Project period:** 2022-01-05 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757374

## Citation

> US National Institutes of Health, RePORTER application 10757374, Apolipoprotein C3-loading of apolipoprotein B100 lipoproteins and cardiovascular disease in patients with type 1 diabetes (5R01HL161829-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757374. Licensed CC0.

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