In a recent study, butyrate administration to mice led to improved systemic insulin sensitivity

ressing cells. The mechanism underlying this PGIS-potentiated GSIS was not due to signaling via the cAMP-dependent protein kinase A pathway but rather through the cAMP-dependent exchange protein directly activated by cAMP -2 pathway . Epac2 converts inactive GDP-Rap1 to active GTP-Rap1, which initiates downstream signaling, and potentiates GSIS in a cAMPdependent manner in vivo, but no mechanism has been determined. EP3 couples to Gi proteins, including GaZ, which inhibit adenylyl cyclase and reduce islet cAMP levels. However, it is unclear if this is the mechanism responsible for alterations in GSIS and -cell mass dynamics. In cell lines and rodent islets, EP3 signaling can either inhibit phosphatidylinositol 3-kinase or activate c-Jun N-terminal kinase, which leads to dephosphorylation and inhibition of Akt. Akt normally phosphorylates and inhibits forkhead box O1, so upon EP3 signaling, FoxO1 is dephosphorylated and undergoes nuclear Insulin Secre on translocation. Pancreatic and duodenal homeobox-1 is important in regulating GSIS, -cell differentiation, and -cell PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19801058 mass dynamics, such as proliferation and cell death. FoxO1 and Pdx1 are mutually exclusive in the nucleus, thus providing a potential mechanism for EP3-induced decreases in GSIS and -cell proliferation. PGI2 via IP signaling results in GS-mediated activation of AC and increased islet cAMP levels. cAMP activates protein kinase A or Epac2. In -cell lines, IP signaling increases GSIS by either PKA activation and phosphorylation of Nephrin or by Epac2 signaling. The IP-induced downstream targets of Epac2 that increase GSIS have not been demonstrated. Dark gray symbols and bold lines indicate PGE2-EP3 signaling pathways. Outlined symbols and block arrows indicate PGI2-IP signaling pathways. Dashed gray symbols represent potential but not confirmed events 2013). Similarly, another IP agonist MRE-269 augmented GSIS in the MIN6 -cell line. The mechanism underlying this increase in GSIS involves PKAdependent phosphorylation of nephrin , distinct from what was observed in INS-1E cells. Nephrin is a transmembrane member of the immunoglobulin protein superfamily and has been shown to promote GSIS and induce -cell survival signaling pathways. The authors of the latter study did not measure Epac2, thus it is unclear if this pathway also contributes to the observed enhanced GSIS in MIN6 cells. These two studies differ in many aspects, including: 1. PGIS overexpression versus IP agonism; 2. incubation time with different PKA inhibitors; and, 3. stimulatory glucose conditions. These variations in experimental design may contribute to changes in signaling pathways that are altered in response to PGI2 signaling. Despite these differences, these data demonstrate that PGI2 can enhance insulin secretion in -cell lines, potentially via multiple signaling mechanisms. In agreement with the effects of PGI2/IP signaling observed in -cell lines, treatment with the IP agonist selexipag reduced the hyperglycemic effect of STZ injection in C57Bl/6 male mice. The decreased hyperglycemia in selexipag-treated mice was due to an increase in get PD-1/PD-L1 inhibitor 2 plasma insulin levels as observed during an intraperitoneal glucose tolerance test and maintenance of -cell mass. The signaling pathways contributing to this enhanced GSIS have yet to be determined. Intriguingly, seleixpag treatment in the absence of STZ had no effect on glucose tolerance or plasma insulin during an IP-GTT. Overall, the current literature on PGI2/IP sugge