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Heterogeneous Distribution of Microv...

Mcclatchey, Penn Mason, Jr.

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Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes./
Author:	Mcclatchey, Penn Mason, Jr.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	170 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.
Contained By:	Dissertation Abstracts International78-10B(E).
Subject:	Biophysics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10272427
ISBN:	9781369774092

Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes.
Mcclatchey, Penn Mason, Jr.

Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 170 p.

Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.

Thesis (Ph.D.)--University of Colorado at Denver, 2017.

People with type 2 diabetes mellitus (T2DM) suffer excess morbidity and mortality. The strongest clinical predictor of morbidity and mortality in the general population is reduced aerobic exercise capacity. T2DM causes impaired exercise capacity, and traditional explanations for this impairment involve reduced blood flow and/or reduced mitochondrial capacity. However, recent studies indicate that exercise capacity may be impaired independently from either tissue demand or bulk blood flow. The most likely explanation for this disconnect is heterogeneous distribution of microvascular blood flow. Under conditions of heterogeneous blood flow, some capillaries are over-perfused and thus saturate their capacity for oxygen delivery, while others are under-perfused and thus cannot support local tissue demand. Local measures reveal excess skeletal muscle deoxygenation during exercise in T2DM despite normal limb blood flow, and skeletal muscle deoxygenation is more heterogeneous in T2DM than in overweight controls. Sensitivity analyses building from established principles in mass transport reveal that heterogeneous blood flow alone is sufficient to cause both impaired skeletal muscle oxygenation and insulin resistance in T2DM. A more detailed version of this model was applied to oxygen transport in the obese Zucker rat (OZR, a common animal model of T2DM), and accurately predicted the degree of perfusion heterogeneity observed in the OZR. A novel software technique for quantifying capillary blood flow and its distribution reveals that high fat feeding (an experimental model of insulin resistance) causes heterogeneous capillary blood flow in mice. Finally, a combined analysis drawing from both first principles in microfluidics and empirical measurements of blood viscosity reveals that diabetes-induced degradation of the endothelial glycocalyx (a gel-like layer of macromolecules lining the interior surface of blood vessels) can account for heterogeneous distribution of microvascular blood flow. Collectively, these findings help to explain impaired oxygen extraction despite reduced blood flow in T2DM, and also offer a potential explanation as to why exercise capacity would predict morbidity and mortality: the proposed mechanism could plausibly apply to all tissues, not just to skeletal muscle.

ISBN: 9781369774092Subjects--Topical Terms:

518360
Biophysics.

Heterogeneous Distribution of Microvascular Blood Flow Contributes to Impaired Skeletal Muscle Oxygenation in Diabetes.
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502 $a Thesis (Ph.D.)--University of Colorado at Denver, 2017.
520 $a People with type 2 diabetes mellitus (T2DM) suffer excess morbidity and mortality. The strongest clinical predictor of morbidity and mortality in the general population is reduced aerobic exercise capacity. T2DM causes impaired exercise capacity, and traditional explanations for this impairment involve reduced blood flow and/or reduced mitochondrial capacity. However, recent studies indicate that exercise capacity may be impaired independently from either tissue demand or bulk blood flow. The most likely explanation for this disconnect is heterogeneous distribution of microvascular blood flow. Under conditions of heterogeneous blood flow, some capillaries are over-perfused and thus saturate their capacity for oxygen delivery, while others are under-perfused and thus cannot support local tissue demand. Local measures reveal excess skeletal muscle deoxygenation during exercise in T2DM despite normal limb blood flow, and skeletal muscle deoxygenation is more heterogeneous in T2DM than in overweight controls. Sensitivity analyses building from established principles in mass transport reveal that heterogeneous blood flow alone is sufficient to cause both impaired skeletal muscle oxygenation and insulin resistance in T2DM. A more detailed version of this model was applied to oxygen transport in the obese Zucker rat (OZR, a common animal model of T2DM), and accurately predicted the degree of perfusion heterogeneity observed in the OZR. A novel software technique for quantifying capillary blood flow and its distribution reveals that high fat feeding (an experimental model of insulin resistance) causes heterogeneous capillary blood flow in mice. Finally, a combined analysis drawing from both first principles in microfluidics and empirical measurements of blood viscosity reveals that diabetes-induced degradation of the endothelial glycocalyx (a gel-like layer of macromolecules lining the interior surface of blood vessels) can account for heterogeneous distribution of microvascular blood flow. Collectively, these findings help to explain impaired oxygen extraction despite reduced blood flow in T2DM, and also offer a potential explanation as to why exercise capacity would predict morbidity and mortality: the proposed mechanism could plausibly apply to all tissues, not just to skeletal muscle.
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