Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

Abstract

Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-Shydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Results Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Conclusions/interpretation Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes

“…This supports earlier findings that CB 1 R promotes CCL2 secretion via p38MAPK (43), but documents for the first time show the selective role of the p38MAPKα isoform in this effect. Whereas the above findings indicate that inflammatory macrophages are an important source of CCL2, we could also detect this chemokine in β-cells, which is in agreement with evidence for CCL2 secretion by islet β-cells (31,32). It is possible that in the early stages of diabetic insulitis, β-cell–derived CCL2 initiates the transmigration of macrophages, which then amplify the production of this chemotactic signal.…”

“…4 E ). β-Cells in ZDF islets produce CCL2 (31,32) (Supplementary Fig. 2 B ), whereas the dramatically higher CCL2 expression in islets of ZDF rats transplanted with wild-type compared with Cnr1 −/− BM (Fig.…”

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…12-LO is expressed in metabolically active tissues including insulin secreting beta cells (Laybutt et al, 2002). Analyses of mouse beta cell lines and mouse and human islets exposed to inflammatory cytokines, obesityinduced oxidative stress or hyperglycemia revealed upregulation of 12-LO expression and subsequent generation of 12-HETE (Natarajan et al, 1993;Shannon et al, 1992;Taylor-Fishwick et al, 2015;Tersey et al, 2014). Less is known about 15-LO expression in rodent and human beta cells.…”

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…These observations suggest that modulation of immune cell function may be a mechanism by which iPLA 2 ␤ and iPLA 2 ␤ -derived lipid signals participate in autoimmune-mediated ␤ -cell death. In support of involvement of iPLA 2 ␤ -derived lipid signals is the recent observation that 12-LO products contribute to pro-infl ammatory cytokine-mediated ␤ -cell dysfunction and apoptosis ( 284 ).…”