Lipids and immunoinflammatory pathways of beta cell destruction

Abstract

Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as ALOX12 in humans and 12-Lo in rodents in this manuscript) produces proinflammatory metabolites such as 12(S)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in 12-Lo expression and 12(S)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes. Subsequently, germline 12-Lo (-/-) was shown to prevent the development of hyperglycemia in mouse models of type 1 diabetes and in high-fat fed mice. More recently, beta cell-specific 12-Lo (-/-) was shown to protect mice against hyperglycaemia after streptozotocin and a high-fat diet. In humans, 12-LO expression is increased in pancreatic islets of autoantibody-positive, type 1 diabetic and type 2 diabetic organ donors. Interestingly, the high expression of ALOX12 is associated with the alteration in first-phase glucose-stimulated insulin secretion in human type 2 diabetic islets. To further clarify the role of islet 12-LO in diabetes and to validate 12-LO as a therapeutic target of diabetes, we have studied selective pharmacological inhibitors for 12-LO. The compounds we have identified show promise: they protect beta cell lines and human islets from apoptosis and preserve insulin secretion when challenged by proinflammatory cytokine mixture. Currently studies are underway to test the compounds in mouse models of diabetes. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied two other mini-reviews on topics from this symposium (by Simone Baltrusch, DOI: 10.1007/s00125-016-3891-x and Marc Donath, DOI: 10.1007/s00125-016-3873-z ) and a commentary by the Session Chair, Piero Marchetti (DOI: 10.1007/s00125-016-3875-x ).

Keywords: 12(S)-Hydroxyeicosatetraenoic acid; 12-Lipoxygenase; Review; Small molecule inhibitors; Type 1 diabetes; Type 2 diabetes.

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