Tuesday, February 4, 2025
2/4/2025
PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is markedly elevated in type 1 diabetes (T1D), and two prevalent conditions in T1D, insulin resistance and endothelial dysfunction, precede and predict CVD. In health, insulin action at the endothelial cell dilates blood vessels, which promotes glucose and insulin delivery to muscle for glucose uptake. We recently showed, in adults with uncomplicated T1D, insulin commonly fails to enhance muscle microvascular perfusion, indicating microvascular insulin resistance, and even youth with T1D have apparent microvascular endothelial dysfunction. This is significant since the microvasculature is critical for muscle health as the direct supplier and exchange site of substrates. Possibly due to impaired muscle health from microvascular dysfunction, the T1D population has diminished cardiorespiratory fitness, even when matched for activity. Mechanisms of microvascular dysfunction in T1D remain ill-defined, but oxidative stress (OS) contributes to endothelial dysfunction at large arteries and likely the microvasculature as well. OS is clearly amplified in T1D. Adjuvant treatments to improve endothelial function and fitness are critically needed in T1D, and such therapies have potential to prevent CVD in future studies. Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RA) improve: microvascular function in insulin resistant states, OS outside of glucose effects, cardiorespiratory fitness, and CVD outcomes in type 2 diabetes (T2D). Exercise attenuates large artery endothelial function and OS in T1D, and it improves microvascular endothelial function in T2D. Whether GLP- 1RA or exercise training improve muscle microvascular endothelial function in T1D is unknown. This project will test the hypothesis that, in adults with T1D, GLP-1RA and exercise training each enhance insulin-stimulated muscle microvascular perfusion via attenuating endothelial OS and improving endothelial cell function. Using cutting-edge contrast enhanced ultrasound before and after randomization to 14-wks of: 1) GLP-1RA, 2) exercise training, or 3) placebo, this study will assess whether GLP-1R agonism (Aim 1) or exercise training (Aim 2) improves insulin-mediated microvascular perfusion and muscle function in adults with T1D. Finally, harvesting and analyzing endothelial cells using an innovative technique will assess whether these therapies attenuate endothelial cell OS and improve endothelial function in vivo (Aim 3). Significantly, completion of the proposed studies will increase mechanistic knowledge of microvascular endothelial dysfunction in T1D and ascertain if larger studies examining GLP-1RA and exercise alone/combined are merited and feasible. The proposed research and training will support the candidate’s long-term goal to conduct larger clinical studies in T1D aiming to reverse endothelial dysfunction/prevent CVD. Preparing for that end, goals for this award are training in T1D- focused clinical trial work, human endothelial cell harvesting + cell biology, and biostatistics + data management. A robust mentorship team, with complementary expertise, and abundant institutional resources will ensure successful project completion and facilitate the promising candidate’s future independent research career.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).