Bridging the gap between basic and clinical research to prevent cardiovascular disease in diabetes

About This Grant

Abstract Currently, over 11% of the US population (nearly 40 million people) are affected by type 1 or type 2 diabetes (T1D or T2D), with T2D representing >90% of diabetes cases. In addition, 97.6 million youth and adults have pre-diabetes and are therefore at high risk of developing T2D and associated vascular complications. Alarmingly, T2D is rapidly increasing in youth, with incidence projected by some models to rise by 700% between 2017 and 2060. Youth-onset T2D is characterized by more severe insulin resistance than adult-onset T2D, and a substantial incidence of arterial stiffening—an early marker of atherosclerotic cardiovascular disease (CVD). Since both T1D and T2D markedly increase the risk of CVD, and because CVD events occur at younger ages in people with diabetes, it is critical to understand how diabetes increases CVD risk and how CVD can be prevented. Preventive strategies likely need to start early in youth. Although LDL-cholesterol lowering for CVD risk reduction is recommended for children >10 years of age as in adults with high CVD risk, a substantial residual CVD risk remains. This residual CVD risk in individuals with diabetes is linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs). Size-distributions and concentrations of TRL particle subpopulations and their partly-lipolyzed remnant lipoprotein particles (RLPs) are governed in part by apolipoprotein C3 (APOC3) and may predict CVD risk in adults and youth with diabetes. We hypothesize that increased hepatic APOC3 production resulting from adipose tissue insulin resistance in both T2D and T1D causes accumulation of a mid-sized atherogenic TRL particle subpopulation. These particles promote CVD by increasing vascular inflammation, with changes occurring early in youth at risk for CVD. This research program will ask three overarching questions to address this hypothesis: i) Does increased plasma APOC3 associate with accumulation of a mid-sized TRL particle population and worsened trajectories of insulin resistance and arterial stiffness in youth with T1D or T2D?; ii) How do TRL/RLP subpopulations differ structurally and functionally?; and iii) Does dysfunction in the hepatic sortilin 1-APOB100 secretion pathway explain the increased APOC3 secretion and atherosclerosis in diabetes? By combining longitudinal and mechanistic studies in youth with diabetes with investigation of mouse models of diabetes-accelerated atherosclerosis and cell systems, we believe we are in an excellent position to fill an important and clinically significant gap in our understanding of how diabetes promotes CVD risk and to identify new treatment and prevention strategies.