Prostaglandin E2 Receptor, EP3, Is Induced in Diabetic Islets and Negatively Regulates Glucose- and Hormone-Stimulated Insulin Secretion

Abstract

BTBR mice develop severe diabetes in response to genetically induced obesity due to a failure of the β-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that Pgter3, the gene for the prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 receptor is stimulated by prostaglandin E2 (PGE2) and couples to G-proteins of the Gi subfamily to decrease intracellular cAMP, blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to β-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide (GLP)-1 receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for β-cell dysfunction in T2D.

Group X Secretory Phospholipase A2 Regulates Insulin Secretion through a Cyclooxygenase-2-dependent Mechanism

“…Inhibition of COX-2 enhances GSIS in C57BL/6 mice with a parallel reduction in PGE2 production, consistent with a role for PGE2 in suppressing GSIS (20). The increase in diabetes susceptibility in the BTBR mouse strain has recently been attributed to elevated PGE2 production and EP3 receptor expression in pancreatic beta cells (13). Islets from T2D humans produce significantly more PGE2 compared with islets from non-diabetic donors (13).…”

“…Islets from T2D humans produce significantly more PGE2 compared with islets from non-diabetic donors (13). Furthermore, L-798,106, a specific EP3 receptor antago-* This work was supported in whole or in part by National Institutes of Health nist significantly enhanced GSIS only in islets from T2D donors and not non-diabetic donors, suggesting that the PGE2/EP3 axis contributes to beta cell dysfunction in humans (13). Hyperglycemic conditions increase COX-2 expression and hence PGE2 production in beta cells, suggesting a mechanism by which hyperglycemia contributes to beta cell dysfunction (21).…”

“…PGE2 exerts its effects by interacting with one or more of its four PGE2 (EP) receptors, EP1, EP2, EP3, and EP4 (14). EP3 is the most abundant PGE2 receptor expressed in islets (13,15). Upon binding to the EP3 receptor subtype, PGE2 decreases adenylyl cyclase activity with a subsequent reduction in cAMP (16), a known potentiator of GSIS (17).…”

“…The increase in diabetes susceptibility in the BTBR mouse strain has recently been attributed to elevated PGE2 production and EP3 receptor expression in pancreatic beta cells (13). Islets from T2D humans produce significantly more PGE2 compared with islets from non-diabetic donors (13). Furthermore, L-798,106, a specific EP3 receptor antago-* This work was supported in whole or in part by National Institutes of Health nist significantly enhanced GSIS only in islets from T2D donors and not non-diabetic donors, suggesting that the PGE2/EP3 axis contributes to beta cell dysfunction in humans (13).…”

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

“…With significant evidence that rapamycin impairs beta cell function (Barlow et al ., 2013), we decided to investigate the impact of rapamycin dosing on islet function more closely. We isolated pancreatic islets from mice after 8 weeks of rapamycin treatment and performed an ex vivo glucose‐stimulated insulin secretion assay (Kimple et al ., 2013) (Fig. 2F–H).…”