Mimicking the Diabetic State in the Non‐Diabetic β‐cell to Elucidate Critical Pathways in β‐cell Dysfunction

Abstract

EP3, a receptor for prostaglandin E2 (PGE2), plays a key role in the β‐cell dysfunction of diabetes. We demonstrated EP3 expression and PGE2 production are increased in islets isolated from diabetic mice and humans, and targeting this pathway in vitro restores proper β‐cell function. Yet, the mechanisms involved in the pathogenesis of β‐cell dysfunction upstream and downstream of EP3 remain elusive. The INS‐1 832/3 cell line has high EP3 expression, just as in diabetic islets. Interestingly, even though EP3 expression is high, PGE2 production is not; thus, an EP3 antagonist has no effect on β‐cell function. We hypothesized one or more of the multitude of insults β‐cells encounter in the diabetic state are necessary to stimulate PGE2 production and resulting β‐cell dysfunction. We mimicked diet by enriching INS‐1 cells with arachidonic acid (AA), an ω‐6 polyunsaturated fatty acid and PGE2 precursor, and inflammation by IL‐1β treatment. This combination significantly increased PGE2 production, blunting insulin secretion. Further, β‐cell function could be restored by an EP3 antagonist. In islets isolated from non‐diabetic mice and humans, AA and IL‐1β had a strong effect on PGE2 synthetic enzyme expression, but EP3 itself was relatively unchanged, and EP3‐mediated β‐cell dysfunction minimal. We hypothesized that high glucose or free fatty acids are responsible for the dysfunctional up‐regulation of β‐cell EP3 in vivo. Finally, we demonstrate the relevance of targeting this pathway in vivo, as mice lacking the EP3 effector, Gαz, specifically in the β‐cell are protected from the β‐cell dysfunction induced by inflammation.