Human Islet Expression Levels of Prostaglandin E2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of β-Cell Function and Mass in Nondiabetic Obesity

Elevated islet production of prostaglandin E-2 (PGE(2)), an arachidonic acid metabolite, and expression of prostaglandin E-2 receptor subtype EP3 (EP3) are well-known contributors to the beta-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE(2) production and signaling pathway influences nondiabetic beta-cell function. In this work, plasma arachidonic acid and PGE(2) metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE 2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionally relevant upregulation of PGE(2) production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from nonobese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude that upregulated islet PGE 2 production may be part of the beta-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.

Automated summary

The production and signaling pathway of PGE(2) are associated with glycemic control, obesity, and systemic inflammation in both nondiabetic and type 2 diabetes subjects. Levels of IL-6 and COX-2 mRNA in islets show positive correlation with donor BMI, while IL-6 expression is strongly related to the expression of other PGE 2 synthetic pathway genes.