Faculty Grants

Division of Endocrinology & Metabolism
GRANTS

During FY 2015,  new grant-supported research conducted by Endocrinology faculty members included the following:

PI: Stacey Anderson, MD

– Medtronic Minimed Inc., CEP272, “In-Clinic Evaluation of the Predictive Low Glucose Management (PLGM) System in Adult and Pediatric Insulin Requiring Patients with Diabetes using the Enlite™ 3 Sensor”
Aim: To evaluate the safety of the PLGM System and its algorithm with the Enlite 3 Sensor.

– InSpark Technologies Inc., “Human Factors and Home Use Study of the Vigilant™ Diabetes Management Application”
Aim: To confirm that subjects with diabetes (T1DM or T2DM) and their caregivers understand feedback received from Vigilant™ about their blood glucose levels and patterns and that the decisions made in response to device feedback does not cause unintended harm.

– Medtronic Minimed Inc., CEP273, “In-Clinic Feasibility Study to Observe the Closed Loop System”
Aim: To demonstrate that the closed loop system is safe to be used in a bridging study.

PI: Eugene Barrett, MD, PhD

– National Institutes of Health R01, “Reversing Vascular Dysfunction in Type 1 Diabetes”

Large and small cerebral, coronary and peripheral arterial disease is the major cause of morbidity/mortality in type 1 diabetes (DM1). This begins early as indicated by evidence for arterial dysfunction in DM1 adolescents. Multicenter trials testing efficacy of vascular interventions to improve cardiovascular disease (CVD) outcomes in DM1 are lacking. Our general hypothesis is that DM1 impairs vascular function at multiple levels of the arterial vasculature and arterial vessels are resistant to insulin-induced vascular relaxation.

We further hypothesize that mineralocorticoid receptor (MCR) blockade and/or enhanced fitness will improve DM1 arterial dysfunction. We will use non-invasive methods (i.e. pulse wave velocity and augmentation index) to assess arterial stiffness in conduit vessels. We will measure flow-mediated dilation and post-ischemic flow velocity to assess endothelial function in conduit and resistance vessels and contrast-enhanced ultrasound to assess microvascular function.

Aim 1: We will measure pan-arterial vascular function in 18- to 50-year-olds. DM1 and healthy age/gender matched controls in both the basal and insulin-stimulated state. Aim 1 will define whether the entire arterial tree is adversely affected by DM1 and whether vascular insulin sensitivity is impaired. It may also indicate which specific tests provide greatest discrimination between DM1 and controls. Duration of DM1, glycemic control, lipid profile, hypertension and evidence of inflammation will be co-variates in this analysis.

Aim 2: We will test whether basal or insulin-responsive pan-arterial function in 18- to 50-year-olds. DM1 responds to a 12 week lifestyle (fitness training) or pharmacologic (eplerenone) intervention or combined fitness plus eplerenone. Fitness and eplerenone have beneficial vascular effects in other populations. If these hypotheses prove correct, they will indicate: (a) whether in the basal or insulin treated state there is pan-arterial vascular dysfunction or is it restricted to one or another vascular level; (b) whether insulin’s vascular action (or resistance) contributes to the linkage between DM 1 and CVD; (c) a compelling rationale for further emphasizing diet/exercise interventions or early pharmacologic interventions to avoid CVD. In addition, the approach used here may suggest that early assessment pan-arterial function can afford a platform to improve selection of drug candidates for later hard endpoint clinical trials in DM1.

Co-PIs: Leon Farhi, PhD, and Susanna Keller, MD

– UVA School of Medicine research and development grant, “Novel Molecular Pathways Regulating Glucagon Secretion”

The goal is to unite the complementary expertise of Farhi and Keller in signaling and regulation of membrane trafficking and system-level paracrine regulation in order to identify molecular pathways to repair the abnormal glucagon regulation in diabetes.

PI: Zhenqi Liu, MD

– American Diabetes Association, “GLP-1R Regulation of Muscle Microvascular and Metabolic Insulin Actions in Humans”

Patients with Type 2 diabetes have microvascular insulin resistance and dysfunction; both contribute to metabolic insulin resistance and cardiovascular complications. Microvascular insulin resistance plays important roles in the pathogenesis of metabolic insulin resistance. Glucagon-like peptide 1 (GLP-1) potently recruits muscle microvasculature and increases muscle delivery and action of insulin, likely via a protein kinase A (PKA)-nitric oxide (NO)-dependent pathway in laboratory animals.

In the proposed studies, we will test in human subjects an overarching hypothesis that sustained activation of the GLP-1 receptor (GLP-1R) enhances muscle microvascular perfusion and improves muscle microvascular response to insulin, which leads to increased muscle insulin delivery and action in humans. We will examine whether sustained GLP-1R activation (1) increases basal muscle microvascular perfusion and enhances muscle microvascular and metabolic responses to insulin in healthy humans; (2) restores muscle insulin sensitivity in the setting of acute insulin resistance, by recruiting muscle microvasculature and enhancing insulin delivery to muscle in healthy humans; and (3) increases muscle microvascular perfusion and attenuates muscle microvascular and metabolic insulin resistance in patients with pre-diabetes.

We will use a state-of-the-art technique — contrast-enhanced ultrasound — in combination with forearm arteriovenous balance, muscle biopsy and insulin clamp, in order to quantify the effects of sustained GLP-1R activation on microvascular and metabolic responses to insulin in humans with or without insulin resistance, and open a new avenue for future mechanistic and/or therapeutic studies. By understanding the regulation of muscle microvasculature, it may be possible to correct vascular, and ameliorate metabolic, insulin resistance and prevent diabetes.