Fig. 1.

Generation of lipid metabolites from arachidonic acid. Arachidonic acid [n-6 polyunsaturated fatty acid (20:4)] is generated from membrane phospholipids by phospholipase A₂. 12-Lipoxygenase (12-LO) converts arachidonic acid to 12(S)-hydroperoxyeicosatetraenoic acid [12(S)- H(p)ETE] through oxidation at carbon-12 (9th carbon from the ω tail). 12(S)-H(p)ETE is an unstable intermediate metabolite and is quickly converted to 12-S-HETE. The human enzyme most involved in generating 12-S-HETE in islets is 12-LO and is encoded by the ALOX12 gene. In mice, the products of both Alox12 and Alox15 (platelet 12-LO and leucocyte 12-LO, respectively) generate 12-S-HETE [9]. The enzymes 5-lipoxygenase (5-LO) and cyclo-oxygenase also metabolise arachidonic acid; the former produces leukotrienes, the latter produces prostaglandins. 12-S-HETE increases proinflammatory mediators including IL-12 [10], the phosphorylated form of p38 MAPK [23] and NOX1 [24], thus causing ER stress, mitochondrial stress, and oxidative stress, cumulatively contributing to the impairment in insulin secretion and beta cell death. Thus, the inhibitors of 12-LO, such as ML127 and ML355, hold therapeutic promise in the prevention and recovery of beta cell function in type 1 and type 2 diabetes