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Title page for ETD etd-08152017-102047


Type of Document Dissertation
Author Carboneau, Bethany Ann
URN etd-08152017-102047
Title Regulation of Beta-Cell Mass Expansion by Prostaglandin E2 Signaling
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Dr. David Jacobson Committee Chair
Dr. Laura Dugan Committee Member
Dr. Richard Breyer Committee Member
Dr. Roger Colbran Committee Member
Dr. Wenbiao Chen Committee Member
Keywords
  • pancreatic beta cell
  • prostaglandins
  • proliferation
  • cell death
  • beta-cell mass
Date of Defense 2017-08-08
Availability unrestricted
Abstract
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.

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