Regulation of Beta-Cell Mass Expansion by Prostaglandin E2 Signaling

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.