Physiology Commons^™

Exploring Β-Cell Function And Heterogeneity In Obese Sm/J Mice, Mario Alejandro Miranda

Arts & Sciences Electronic Theses and Dissertations

Pancreatic β-cells perform glucose-stimulated insulin secretion, a process required to maintain systemic glucose homeostasis. Obesity promotes glycemic and inflammatory stress, causing β-cell death and dysfunction, resulting in diabetes. Efforts to improve β-cell function in obesity have been hampered by observations that β-cells are highly heterogeneous, varying in morphology, function, and gene expression. There is great need to understand the breadth of β-cell heterogeneity in health and obesity to improve diabetic therapies.High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we show that as they resolve hyperglycemia, obese SM/J …

The Impact Of Age/Rage Signaling On Oxidative Stress Under Diabetic Conditions In Cardiac Fibroblasts, Christopher Dorroh

Honors Theses

Diabetes is a major health concern in the United States, with 1.5 million new cases diagnosed each year. Patients who suffer from diabetes have an increased risk of developing heart failure, a form of cardiovascular disease. Heart failure has been shown to result from increased left ventricular stiffness, which in turn is caused by increased remodeling of the extracellular matrix (ECM). This increase in ECM remodeling is a result of AGE/RAGE signaling, which occurs at a heightened level in the cardiac fibroblast cells of diabetics. Studies have shown that diabetics have elevated levels of AGEs (Advanced Glycation End-Products), which bind …

Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon

Dissertations & Theses (Open Access)

Salt inducible kinase 1 (SIK1) has been considered a stress-inducible kinase since it was first cloned in 1999. Continued efforts since this time have been dedicated to characterizing the structure and function of SIK1. Such research has laid the ground work for our understanding of SIK1 action and regulation in tissue and stimuli dependent manners. The fundamental findings of this dissertation continue in this tradition and include investigations of SIK1 regulatory mechanisms in skeletal muscle cells, the cellular and physiological effects of SIK1 loss of function in vitro and in vivo, and intracellular metabolic and mitochondrial regulation by this …

The Role Of Receptors For Advanced Glycation End-Products (Rage) And Ceramide In Cardiovascular Disease, Michael Bruce Nelson

Theses and Dissertations

Type 2 diabetes and cigarette smoke exposure are associated with an increased risk of cardiovascular complications. The role of advanced glycation end-products (AGEs) is already well-established in numerous comorbidities including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with carboxy-methyl lysine-BSA, followed by mitochondrial respiration assessment. We found that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when co-treated with myriocin, an inhibitor of de novo …

The Role Of C-Kit Receptor Tyrosine Kinase In Beta-Cell Proliferation, Function And Survival, Zhi Chao Feng

Electronic Thesis and Dissertation Repository

c-Kit, a receptor tyrosine kinase, interacts with Stem Cell Factor (SCF), mediating cell differentiation, function, and survival. c-Kit is critical for the development and maintenance of beta-cell function in both rodents and humans. The mutation of c-Kit at W locus (c-Kit^Wv/+) in mice results in an early onset of diabetes. However, the underlying mechanisms by which c-Kit deficiency leads to beta-cell failure are unknown. Therefore, studying SCF/c-Kit downstream signaling pathways is essential to understanding the precise mechanism by which c-Kit regulates beta-cell survival and function in vivo.

We identified that dysregulated Akt/Glycogen synthase kinase 3β (Gsk3β)/cyclin …

Islet Regenerative Properties Of Ex Vivo Expanded Hematopoietic Progenitor Cells, Ayesh K. Seneviratne

Electronic Thesis and Dissertation Repository

Human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDH^hi), can stimulate endogenous islet regeneration after transplantation into mice with steptozotocin (STZ)-induced diabetes. However, UCB ALDH^hi cell are extremely rare, and expansion will be required to develop cell-mediated strategies to treat patients with diabetes. To increase the number of progenitor cells available for clinical application, we expanded ALDH^hi UCB cells under clinically applicable, serum-free hematopoietic-restricted conditions. 6 day expansion resulted in a 15-fold increase in total cell number, and a 3-fold increase in the number of HPC retaining high ALDH (ALDH^hi HPC) …

The Role Of Integrins In Support Of Pancreatic Function, Survival And Maturation, Matthew Riopel

Electronic Thesis and Dissertation Repository

The pancreas is a glandular organ composed of endocrine and exocrine compartments. Integrins are cell adhesion molecules that connect cells to the extracellular matrix (ECM). Integrins modulate a variety of cellular effects, yet their mechanism of action in the developed pancreas is not well understood. Fibrin is a provisional ECM protein that contains ligands for integrin receptors. Fibrin is capable of supporting islet health, but it is unclear how fibrin exerts its effects. The objective of this thesis is to understand the role of integrin receptors on in vivo pancreatic cell function, survival, and proliferation. In addition, this thesis investigates …