Type 2 diabetes is a major healthcare concern and is characterized by chronic hyperglycemia and low-grade inflammation. Hyperglycemia and systemic inflammation can induce the production of Prostaglandin E2 (PGE2) in islets. PGE2 signals through its four receptors, termed E-Prostanoid (EP) 1-4, to modulate many physiological functions, including insulin secretion and systemic inflammation. EP3 and EP4 often play opposing roles due to signaling through different G proteins, resulting in Gi inhibition (EP3) or Gs stimulation (EP4) of adenylyl cyclase. Previous work from our group revealed that Ptger4 (EP4) is increased while Ptger3 (EP3) is decreased in a mouse model of enhanced beta-cell proliferation and survival. Additional evidence from our lab suggests that EP3 inhibits mouse beta-cell proliferation in the setting of insulin resistance. Using ex vivo assays, we have determined that EP3 and EP4 play opposing roles in regulating beta-cell proliferation and survival in mouse and human islets: EP3 inhibits beta-cell proliferation via inhibition of PLC-gamma1 and enhances beta-cell death whereas EP4 activates beta-cell proliferation and promotes beta-cell survival in a PKA-dependent mechanism.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08152017-102047 |
| Date | 16 August 2017 |
| Creators | Carboneau, Bethany Ann |
| Contributors | Dr. David Jacobson, Dr. Wenbiao Chen, Dr. Roger Colbran, Dr. Richard Breyer, Dr. Laura Dugan |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08152017-102047/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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