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Principal Investigator: Kaitlin M Love
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $192,031
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <21+ years old><Active Oxygen><Address><Adjuvant Therapy><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Agonist><Antioxidants><Arteries><Attenuated><Award><Biometrics><Biometry><Biostatistics><Blood Plasma><Blood Vessels><Body Tissues><Brittle Diabetes Mellitus><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cessation of life><Chronic><Clinical Research><Clinical Study><Clinical Trials><D-Glucose><Data><Data Analyses><Data Analysis><Death><Dextrose><Disease Outcome><ENOS><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelial Nitric Oxide Synthase><Endothelium><Endothelium-Derived Nitric Oxide><Ensure><Exercise><Exercise Tolerance><Exhibits><Future><GLP-1><GLP-1 receptor><GLP-I receptor><Glucose><Goals><Harvest><Health><Heart failure><Human><Humulin R><Hyperglycemia><IDDM><Impairment><Individual><Institution><Insulin><Insulin Resistance><Insulin-Dependent Diabetes Mellitus><Interval training><Intracellular Communication and Signaling><Investigation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Knowledge><Link><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Mentors><Mentorship><Methodology><Microvascular Dysfunction><Modality><Modern Man><Mononitrogen Monoxide><Muscle><Muscle Tissue><Muscle function><NIDDM><NIH><NOS3><NOS3 gene><National Institutes of Health><Nitric Oxide><Nitric Oxide Synthase 3><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><O element><O2 element><Obesity><Outcome><Oxidative Stress><Oxidative Stress Induction><Oxygen><Oxygen Radicals><Participant><Pathway interactions><Perfusion><Persons><Phosphorylation><Physical activity><Physiologic><Physiological><Pilot Projects><Placebos><Plasma><Plasma Serum><Play><Population><Pro-Oxidants><Production><Protein Phosphorylation><Public Health><Randomized><Reactive Oxygen Species><Regular Insulin><Research><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Role><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Staining method><Stains><Stimulus><Subcellular Process><Sudden-Onset Diabetes Mellitus><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Techniques><Testing><Therapeutic><Tissues><Training><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Type III nitric oxide synthase><United States National Institutes of Health><VO2 max><VO2max><Vascular Endothelium><Vasodilatation><Vasodilation><Vasorelaxation><Voluntary Muscle><Work><Youth><Youth 10-21><adiposity><adjuvant treatment><adult onset diabetes><adulthood><attenuate><attenuates><biological signal transduction><cardiac failure><cardiorespiratory fitness><cardiorespiratory health><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular effects><career><cell biology><contrast enhanced><corpulence><data interpretation><data management><endothelial cell derived relaxing factor><endothelial dysfunction><exercise adherence><exercise training><fitness><glucagon-like peptide 1><glucagon-like peptide-1 receptor><glucose uptake><hyperglycemic><improved><improved outcome><in vivo><innovate><innovation><innovative><insight><insulin dependent diabetes><insulin dependent type 1><insulin resistant><insulin tolerance><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><maturity onset diabetes><maximal oxygen uptake><microvascular complications><microvascular disease><muscular><pathway><pilot study><post intervention><prevent><preventing><randomisation><randomization><randomly assigned><response><sham therapy><small vessel disease><social role><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><ultrasound><uptake><vascular><vascular endothelial dysfunction>