obesity in mouse models as a way to expand -cell mass. Human autopsy studies reveal that non-diabetic obese individuals have higher -cell mass than lean nondiabetic subjects. However, -cell mass is reduced in humans with T2D in both lean and obese settings. -Cell death is also increased in humans with T2D, which may contribute to failure to maintain proper -cell mass. Thus, it appears that expansion and regulation of -cell mass is an important feature in preventing T2D. In comparison to the literature on PGs and -cell function, less is known about their role in regulating -cell mass. Again, a majority of the available data focuses on PGE2 and its receptors. To our knowledge, there are no reports on PGD2 and -cell mass dynamics. Further, there is very little evidence to suggest a role for PGF2 in this process. In one study performed in rat islets, PGF2 had no effect on DNA synthesis. In this section, we will discuss the available information on PGI2, PGE2, and their receptors with regard to their roles in regulating -cell mass. PGI2 and regulation of -cell mass The PGI2 analog beraprost sodium improves islet viability during islet isolation in a canine model, suggesting that PGI2 may regulate -cell mass by enhancing -cell survival. Indeed, in multiple -cell lines, PGI2 and its receptor IP play a positive role in protecting against cell death. Overexpression of PGIS in the RINm5F -cell line improved cell viability following cytokine treatment. The PCI-32765 protective effect of PGIS overexpression corresponded with prevention of caspase-3, -12, and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19802338 -9 activation, decreased Chop expression, decreased activation of the transcription factor nuclear factor B, and blockade of the nitric oxide pathway. Interestingly, PGIS overexpression also prevented the cytokine-mediated reduction in cell proliferation. These data suggest that PGI2 may protect against cytokine toxicity by not only decreasing cell death and but also by maintaining normal proliferation levels. In the INS-1E -cell line, the IP antagonist CAY10441 decreases cell viability and cell proliferation in both control and PGIS-overexpressing cells. CAY10441 also induces caspase-3 activation in control cells while the IP agonist iloprost does not. Surprisingly, iloprost did not alter cell viability or proliferation PGs and regulation of -cell mass In addition to improving -cell function, expansion of -cell mass is another mechanism to increase insulin output in order to maintain euglycemia in the face of increased metabolic Prostaglandin signaling in beta cells 113 itself. Overexpression of PGIS also increased cell proliferation but only during high glucose conditions. Thus, high levels of PGI2 and signaling via the IP receptor play cytoprotective roles in -cell lines. Activation of the IP receptor also plays a protective role in vivo. As already discussed, the IP agonist selexipag augmented GSIS in response to STZ 
treatment. This can be in part attributed to a preservation of -cell mass in response to STZ. However, in the absence of STZ, twoweek administration of selexipag does not affect -cell mass. The in vivo mechanism for preservation of -cell mass in response to STZ is unknown; however, evidence from -cell lines suggest that it may be by protecting against cell death and maintaining proliferation. PGE2 and regulation of -cell mass PGE2 alters several mechanisms responsible for regulating cell mass, including replication and cell death. However, as discussed in the following section, PGE2 tre