Eicosanoids, β-cell function, and diabetes

Abstract

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in diverse diseases, including type 1 and type 2 diabetes. During the last 30 years, evidence has been accumulated that suggests important functions for eicosanoids in the control of pancreatic β-cell function and destruction. AA metabolites of the COX pathway, especially prostaglandin E(2) (PGE(2)), appear to be significant factors to β-cell dysfunction and destruction, participating in the pathogenesis of diabetes and its complications. Several elegant studies have contributed to the sorting out of the importance of 12-LOX eicosanoids in cytokine-mediated inflammation in pancreatic β cells. The role of CYP eicosanoids in diabetes is yet to be explored. A recent publication has demonstrated that stabilizing the levels of epoxyeicosatrienoic acids (EETs), CYP eicosanoids, by inhibiting or deleting soluble epoxide hydrolase (sEH) improves β-cell function and reduces β-cell apoptosis in diabetes. In this review we summarize recent findings implicating these eicosanoid pathways in diabetes and its complications. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of diabetes and its complications.

Figure 1

Bioactive eicosanoids derived from the arachidonic acid (AA) cascade. After trigging by inflammatory conditions such as the presence of cytokines and growth factors, AA-containing phospholipids are hydrolyzed by phospholipase A₂ (PLA₂) resulting in the release of free AA. AA can be further metabolized by three pathways, i.e., the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. AA cascade generates prostaglandins (PGs), thromboxane A₂ (TXA₂), and a series of hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs). The action of these bioactive eicosanoids is mediated through the binding of these substances to their receptors. However, an EET receptor has yet to be identified.

Figure 2

In pancreatic β cells, the uptake of glucose is mediated by glucose transporter, GLUT2. Within β-cells, glucose is further metabolized by the glycolysis and the citric acid cycle to generate NADH and FADH₂, which donate electrons to the mitochondrial electron-transport chain. Protons are pumped out by complexes I, III, and IV of the electron-transport chain creating a proton electrochemical gradient. Protons reenter the mitochondria via ATP synthase to generate ATP. In pancreatic β cells, increasing ATP inhibits the K⁺_ATP channel, causing plasma membrane depolarization, which opens voltage-gated Ca²⁺ channels. Increasing the intracellular Ca²⁺ concentration contributes to the release of insulin. UCP2 acts as a negative regulator of GSIS by decreasing ATP levels.