Ceramide Accumulation in the Alpha Cell Drives Glucagon Secretion and Hyperglycemia
| dc.contributor.advisor | McDonald, Jeffrey | en |
| dc.contributor.committeeMember | Scherer, Philipp | en |
| dc.contributor.committeeMember | Holland, William L. | en |
| dc.contributor.committeeMember | Roth, Michael G. | en |
| dc.contributor.committeeMember | Unger, Roger | en |
| dc.creator | Pearson, Mackenzie Jo | en |
| dc.creator.orcid | 0000-0002-8659-0659 | |
| dc.date.accessioned | 2017-11-21T19:37:39Z | |
| dc.date.available | 2017-11-21T19:37:39Z | |
| dc.date.created | 2017-08 | |
| dc.date.issued | 2017-06-14 | |
| dc.date.submitted | August 2017 | |
| dc.date.updated | 2017-11-21T19:36:28Z | |
| dc.description.abstract | Lipids were not always considered to be biologically active compounds. For many years, researchers believed they served two purposes -- to act as building blocks of membranes and to serve as an energy source. Yet, it wasn't until the early 1960's that Bergstrom, Samuelsson and others, discovered that the hormone-like prostaglandins were derived from arachidonate -- an essential free fatty acid. Since this biosynthetic precursor has many roles in metabolic processes, researchers gained interest in the functions that lipids and their metabolites might play in other cellular processes (William W. Christie AOCS Lipid Library). In 1994 that Roger Unger and collaborators coined the term "lipotoxicity". Their research described a lipid overload in pancreatic beta-cells that results in a lipid-induced dysfunction that ultimately leads to programmed cell death (1). More importantly, their later research in ZDF diabetic fatty rats showed an increase in serine palmitoyl transferase, the rate limiting enzyme in ceramide synthesis, in islets of obese fa/fa ZDF rats compared to lean mice of the same age (2). Blockade of ceramide synthesis in these islets demonstrated a decrease in lipid mediated apoptosis. Further studies have shown that aberrant deposition of ectopic lipid in peripheral tissues has been correlated to many metabolic disorders, cancers, heart disease, and atherosclerosis. In 1998, Summers and group were able to show that de novo ceramide synthesis inhibits insulin stimulated glucose uptake in cultured adipocytes. From this study, they were able to show indirect inhibition of AKT to promote insulin resistance in a ceramide dependent manner (3). However, does ceramide accumulation specfically within the alpha-cell play a role in the diabetic phenotype? In 1975, Drs. Unger and Orci proposed a bihormonal-abnormality hypothesis. To perpetuate hyperglycemia in the diabetic state, not only must there be deficient amounts of insulin available, but also excessive amounts of glucagon present. They were the first to provide evidence that hyperglucagonemia in type 2 diabetes mellitus may result from insulin resistant alpha-cells, since patients' circulating glucagon levels were poorly suppressed by exogenous insulin. Additionally, the Kulkarni group demonstrated that in vitro and in vivo deletion of the insulin receptors within alpha-cells caused insulin resistance, facilitated hyperglucagonemia, and perpetuated hyperglycemia. I hypothesize that ablating ceramide accumulation within the alpha-cell can improve insulin signaling or regulate glucagon secretion in this cell type. To investigate the possible mechanisms by which glucagon is regulated, three mouse models have been generated. Acid ceramidase (AC) overexpression, adiponectin receptor 2 (AdipoR2) overexpression, and FGF21 signaling impairment by deletion of its coreceptor beta-klotho are the three novel approaches outlined in this body of work to elucidate the effects of ceramides on glucagon secretion. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1012493133 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/4246 | |
| dc.language.iso | en | en |
| dc.subject | Ceramides | en |
| dc.subject | Glucagon | en |
| dc.subject | Hyperglycemia | en |
| dc.title | Ceramide Accumulation in the Alpha Cell Drives Glucagon Secretion and Hyperglycemia | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Integrative Biology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |