Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass

Abstract

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.

Keywords: arachidonic acid; beta-cell mass; eicosanoids; prostaglandins.

Figure 1

Eicosanoids derived from arachidonic acid (AA). Phospholipids containing AA are hydrolyzed by phospholipase A₂ (PLA₂), releasing free AA. AA can be subsequently metabolized by three enzymes and their associated pathways, cyclooxygenase (COX), lipoxygenase (LOX and cytochrome P450 (CYP)). These enzymes mediate the production of the eicosanoids, biologically active metabolites of AA including prostaglandins (PGs), thromboxane (TXA), hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs).

Figure 2

Model of EP3 and EP4 signaling in beta cells. In the presence of a proliferative or survival stimulus, when PGE₂ is bound, EP3 and EP4 exert opposing effects on adenylyl cyclase, with EP3 inhibiting cyclic AMP (cAMP) production through Gα_z signaling and EP4 promoting cAMP production through G_s signaling. EP3 acts through the downstream effector PLCγ1 to inhibit beta-cell proliferation and survival, while EP4 acts through PKA to promote beta-cell survival.