Graduation Semester and Year
2020
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Kinesiology
Department
Kinesiology
First Advisor
Paul J Fadel
Abstract
Currently, over 30 million adults in the United States have been diagnosed with Type 2 Diabetes mellitus (T2D). Importantly, T2D disproportionately augments the risk for the development of cardiovascular disease (CVD), which is currently the leading cause of morbidity and mortality in the United States. A hallmark characteristic of T2D is insulin resistance (IR), defined as a reduced tissue responsiveness to insulin stimulation, which contributes to prolonged periods of post-prandial hyperglycemia and is associated with a compensatory rise in pancreatic insulin secretion (hyperinsulinemia). Importantly, there is a well-known bi-directional association between the degree of IR/hyperinsulinemia and hypertension (HTN), with nearly 60% of all patients with T2D progressing to develop HTN. Yet, while this co-existence is well defined, the unifying mechanisms remain incompletely understood. A key pathogenic feature of both IR and HTN is peripheral vascular dysfunction, or dysregulated vascular endothelial cell signaling, typically attributable to greater vasoconstrictor and lesser vasodilator signaling. Beyond its metabolic actions, insulin exhibits both indirect (central nervous system) and direct (local vascular) actions that contribute to the regulation of peripheral vascular tone. In the central nervous system, insulin stimulates an increase in sympathetic nerve activity (SNA) which acts on vascular smooth muscle to confer vasoconstriction. Yet, while patients with T2D exhibit chronic hyperinsulinemia, and thus would be expected to exhibit marked sympatho-excitation, direct recordings of SNA have provided equivocal results. However, quantification of central sympathetic outflow alone represents only one aspect of sympathetic regulation, and much less is known regarding the ensuing vascular smooth muscle contractile response(s) following spontaneous bursts of MSNA (i.e., sympathetic transduction) in T2D. At the local vascular level, insulin signaling also directly stimulates an increase in skeletal muscle blood flow (vasodilation). Insulin-stimulated vasodilation is achieved through insulin binding its target receptor on endothelial cells, and the initiation of two distinct signaling cascades. The first pathway produces nitric oxide (vasodilator), while the second pathway produces endothelin-1 (ET-1; potent vasoconstrictor). Importantly, the skeletal muscle blood flow response to insulin is markedly reduced in patients with T2D, and preclinical animal models of IR/T2D suggest that a shift towards insulin-induced overproduction of ET-1 may be one putative mechanism. Accordingly, this dissertation has focused on further understanding how sympathetic, and ET-1 mediated vasoconstriction may contribute to T2D-associated vascular dysfunction in humans. First, using a novel spike-triggered averaging methodology developed and validated in the Fadel Laboratory, we quantified sympathetic transduction in patients with T2D (Chapter 2). Then, following the demonstration of an augmented sympathetic transduction in patients with T2D, we further set-out to understand the role that hyperinsulinemia may play in mediating this augmented sympathetic transduction by investigating the effect of acute hyperinsulinemia on sympathetic transduction in man (Chapter 3). Finally, we mechanistically probe the role that ET-1 plays in limiting insulin-stimulated vasodilation via blockade of the ET-1 receptors during hyperinsulinemia in patients with T2D (Chapter 4). In sum, the work contained herein supports role(s) for both greater sympathetic (via way of greater sympathetic transduction), and ET-1 mediated vasoconstriction in T2D-associated vascular dysfunction.
Keywords
Insulin, endothelial function, Sympathetic Nervous System, Endothelin-1, Nitric Oxide, Sympathetic Transduction, Blood Pressure, Vascular Conductance
Disciplines
Kinesiology | Life Sciences
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Young, Ben Earl, "Novel Mechanisms of Peripheral Vascular Dysfunction in Patients with Type 2 Diabetes" (2020). Kinesiology Dissertations. 42.
https://mavmatrix.uta.edu/kinesiology_dissertations/42
Comments
Degree granted by The University of Texas at Arlington