Elevated
islet production of prostaglandin E2 (PGE2),
an arachidonic acid metabolite, and expression of prostaglandin
E2 receptor subtype EP3 (EP3) are well-known contributors
to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many
of the same pathophysiological conditions exist in obesity, and little
is known about how the PGE2 production and signaling pathway
influences nondiabetic β-cell function. In this work, plasma
arachidonic acid and PGE2 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 PGE2 synthetic pathway
genes. Insulin secretion assays using an EP3-specific antagonist confirmed
functionally relevant upregulation of PGE2 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 PGE2 production may be part of the β-cell
adaption response to obesity and insulin resistance that only becomes
dysfunctional when both ligand and receptor are highly expressed in
T2D.
Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes.
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