Identifying new strategies for prevention of cardiovascular complications of diabetes

确定预防糖尿病心血管并发症的新策略

• 批准号: 10591588
• 负责人: Karin E. Bornfeldt
• 金额: $ 102.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591588
• 关键词: Acceleration; Adult; Age; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Child; Chylomicrons; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic mouse; Event; Flow Cytometry; Glycolysis; Goals; Health; Human; Hypertriglyceridemia; Incidence; Insulin-Dependent Diabetes Mellitus; LDL Cholesterol Lipoproteins; Lesion; Link; Lipoproteins; Macrophage; Methods; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Patients; Persons; Plasma; Population; Positioning Attribute; Prediabetes syndrome; Prevalence; Prevention strategy; Prospective Studies; Proteomics; Reporting; Residual state; Risk Factors; Serum; Severities; Stroke; Time; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; cardiovascular disorder risk; cardiovascular risk factor; clinically significant; endoplasmic reticulum stress; novel; novel therapeutic intervention; particle; prevent; risk prediction; single-cell RNA sequencing; targeted treatment; treatment strategy

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.

目前，近10%的美国人口（超过3000万人）患有1型或2型糖尿病