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INVESTIGATION OF THE IMPACT OF HYPERGLYCEMIA ON THE IMMUNE SYSTEM IN TYPE 2 DIABETES
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|Title:||INVESTIGATION OF THE IMPACT OF HYPERGLYCEMIA ON THE IMMUNE SYSTEM IN TYPE 2 DIABETES|
|Authors:||Pang, Alina Psalm Soranaka|
|Contributors:||Corley, Michael J. (advisor)|
Cell and Molecular Biology (department)
show 2 moreimmunology
|Publisher:||University of Hawai'i at Manoa|
|Abstract:||Type 2 diabetes (T2D) is a prominent and chronic cardiometabolic disorder affecting the way the body processes glucose. There is a need for effective therapies as current options target symptoms of T2D in relation to glucose metabolism and hyperglycemia. However, a comprehensive understanding of the effects of hyperglycemia upon the immune system in the pathogenesis of T2D remain unknown. Insight into T2D impact on the immune system will provide a better understanding of related complications and comorbidities that relate to immune dysfunction and a weakened immune system that leads to poorer health outcomes in diabetes and uncover novel interventions to improve disease outcomes. In type 2 diabetes, hyperglycemia, or high blood sugar is a major clinical concern due to long-term complications due to untreated hyperglycemia. Hence, clinical treatments focus on controlling hyperglycemia with an achievable HbA1c target between 7%-8%; however, individuals with T2D vary dramatically in their achievable HbA1c. I hypothesize that hyperglycemia induces epigenetic, transcriptional, and metabolic alterations underlying immune dysfunction and inflammation and may contribute to poor treatment responses and exacerbation of complications. The goal of this dissertation centers on the identification of metabolic, immunological, and epigenetic aberrations in immune cells of individuals with T2D that associated with hyperglycemia to gain insight into biological mechanisms underlying immune dysfunction in T2D. I used real-time live-cell metabolic analyses to examine whether the most prescribed T2D medication to lower glycemia levels, metformin, impacted immune cell metabolism. Results identified that metformin treatment significantly and dose-dependently impacted human monocyte cell metabolism by inhibiting mitochondrial oxidative phosphorylation. In contrast, metformin did not drastically impact T cell metabolism. Next, we used flow cytometry profiling of monocyte, B cells, CD4 T cells, and CD8 T cell populations in 29 individuals, 25 T2D (HbA1c >7) and 4 healthy (HbA1c <7), and examined association with amount of time (years) a participant was diagnosed with T2D in 25 individuals and found that classical monocytes was associated with T2D duration. Epigenetic and transcriptomic assessment of DNA and RNA was isolated from purified cell sorted monocyte cells of T2D (n=25) and non-diabetic individuals (n=4) identified significant relationships between gene expression and DNA methylation states with glycemia. Genes associated with metabolic pathways, cell growth and monocyte immunometabolism were affected. Lastly, using single cell RNA-sequencing to assess the impact of glucose treatment on immune cells at single cell resolution, I identified conserved and differentially expressed immune regulatory, chemokine ligands, and ribosomal genes based on diabetic status. Altogether, this dissertation provides evidence for a dysregulation of molecular and epigenetic mechanisms in peripheral monocytes of individuals with T2D that relates to glycemia control. These novel findings may underlie the diabetes complications and weakened immune features of T2D as sustained hyperglycemia persist across time, possibly contribute to immune-based therapies for treating T2D, and provide insight into uncovering the immune dysfunction basis of T2D pathogenesis.|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
Ph.D. - Cell and Molecular Biology|
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