Type 2 diabetes (T2D) is characterized by chronic hyperglycemia and low-grade inflammation. Failure to expand β-cell mass in response to insulin resistance can lead to T2D. The hyperglycemia and chronic inflammation observed in T2D is associated with enhanced levels of prostaglandin E2 (PGE2) synthesis in pancreatic islets. Downstream effects of PGE2 signaling are carried out by four E-Prostanoid (EP) G-protein coupled receptors, EP1-4. Recent investigations by our lab demonstrated that EP3 and EP4 play opposing roles in pancreatic islets whereby EP3 activation inhibits β-cell proliferation and survival while EP4 activation stimulates β-cell mass expansion and reduces cytokine-induced cell death ex vivo. Preliminary data suggests that db/db mice (a model of T2D) treated with the EP3 antagonist, DG-041, exhibit enhanced levels of β-cell proliferation when compared to their vehicle-treated counterparts (3.04 ± 0.6% Ki67+/Ins+ β-cells and 1.67 ± 0.2%, respectively). Although differences in β-cell death between the vehicle- (0.09 ± 0.1% TUNEL+ β-cells) and DG-041-treated cohorts (0.23 ± 0.1%) did not reach statistical significance, treatment with the EP3 antagonist ultimately culminated in improved β-cell mass in db/db mice (1.57 ± 0.2 mg) compared to vehicle-treated controls (0.94 ± 0.2 mg). Additionally, preliminary results suggest that the EP3 antagonist-induced increase in β-cell proliferation in nondiabetic human cadaver donors occurs, in part, through PLCγ-1 whereby pretreatment of human islets with U-73122 (PLCγ-1 inhibitor) prior to DG-041 addition resulted in decreased β-cell proliferation (1.67 ± 0.2 fold of vehicle-treated control) when compared to the EP3 antagonist alone (2.30 ± 0.3 fold). Taken together, these results provide valuable foundational insight into the potential role of EP3 in the modulation of β-cell mass expansion.


S.R. Andrei: None. J.C. Dunn: None. A.A. Christensen: None. V.F. Ricciardi: None. W.A. Pace: None. R.M. Breyer: None. M. Gannon: None.

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