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Intramyocellular Lipids and the Progression of Muscular Insulin Resistance

Description
Diabetes is a disease characterized by reduced insulin action and secretion, leading to elevated blood glucose. In the 1990s, studies showed that intravenous injection of fatty acids led to a sharp negative response in insulin action that subsided hours after the injection. The molecule associated with diminished insulin signalling response…

Diabetes is a disease characterized by reduced insulin action and secretion, leading to elevated blood glucose. In the 1990s, studies showed that intravenous injection of fatty acids led to a sharp negative response in insulin action that subsided hours after the injection. The molecule associated with diminished insulin signalling response was a byproduct of fatty acids, diacylglycerol. This dissertation is focused on the formulation of a model built around the known mechanisms of glucose and fatty acid storage and metabolism within myocytes, as well as downstream effects of diacylglycerol on insulin action. Data from euglycemic-hyperinsulinemic clamp with fatty acid infusion studies are used to validate the qualitative behavior of the model and estimate parameters. The model closely matches clinical data and suggests a new metric to determine quantitative measurements of insulin action downregulation. Analysis and numerical simulation of the long term, piecewise smooth system of ordinary differential equations demonstrates a discontinuous bifurcation implicating nutrient excess as a driver of muscular insulin resistance.
ContributorsBurkow, Daniel Harrison (Author) / Li, Jiaxu (Thesis advisor) / Castillo-Chavez, Carlos (Thesis advisor) / Kuang, Yang (Committee member) / Holechek, Susan (Committee member) / Arizona State University (Publisher)
Created2017
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Novel Aminoglycoside Polymers and Combination Treatments in Triple Negative Breast Cancer Studies

Description
In the United States, 12% of women are typically diagnosed with breast cancer, where 20-30% of these cases are identified as Triple Negative Breast Cancer (TNBC). In the state of Arizona, 810 deaths occur due to breast cancer and more than 4,600 cases are diagnosed every year (American Cancer Society). The lack…

In the United States, 12% of women are typically diagnosed with breast cancer, where 20-30% of these cases are identified as Triple Negative Breast Cancer (TNBC). In the state of Arizona, 810 deaths occur due to breast cancer and more than 4,600 cases are diagnosed every year (American Cancer Society). The lack of estrogen, progesterone, and HER2 receptors in TNBC makes discovery of targeted therapies further challenging. To tackle this issue, a novel multi-component drug vehicle is presented. Previously, we have shown that mitoxantrone, a DNA damaging drug, can sensitize TNBC cells to TRAIL, which is a protein that can selectively kill cancer cells. In this current study, we have formulated aminoglycoside-derived nanoparticles (liposomes) loaded with mitoxantrone, PARP inhibitors, for delivery to cancer cells. PARP inhibitors are helpful in preventing cancer cells from repairing their DNA following damage with other drugs (e.g. mitoxantrone). Various treatment liposome groups, consisting of lipid-containing polymers (lipopolymers) synthesized in our laboratory, were formulated and characterized for their size, surface charge, and stability. PARP inhibitors and treatment of cells for in-vitro and in-vivo experiments with these liposomes resulted in synergistic death of cancer cells. Finally, studies to evaluate the pre-clinical efficacy of these approaches using immuno-deficient mouse models of TNBC disease have been initiated.
ContributorsMuralikrishnan, Harini (Author) / Rege, Kaushal (Thesis advisor) / Holechek, Susan (Committee member) / Nannenga, Brent (Committee member) / Arizona State University (Publisher)
Created2018