title: 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 ).
authors: Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23507, USA. Imaiy@evms.edu.
authors: Yumi
authors: Y
authors: Imai
authors: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA.
authors: Anca D
authors: AD
authors: Dobrian
authors: Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23507, USA.|Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
authors: Margaret A
authors: MA
authors: Morris
authors: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
authors: David A
authors: DA
authors: Taylor-Fishwick
authors: Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23507, USA. NadlerJL@evms.edu.
authors: Jerry L
authors: JL
authors: Nadler
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008055:Lipids
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D008055:Lipids; D001092:Arachidonate 12-Lipoxygenase
keywords: 12(S)-Hydroxyeicosatetraenoic acid; 12-Lipoxygenase; Review; Small molecule inhibitors; Type 1 diabetes; Type 2 diabetes