Journal article
Lipids and immunoinflammatory pathways of beta cell destruction
Diabetologia, Vol.59(4), pp.673-678
04/2016
DOI: 10.1007/s00125-016-3890-y
PMCID: PMC4779407
PMID: 26868492
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 ).
Details
- Title: Subtitle
- Lipids and immunoinflammatory pathways of beta cell destruction
- Creators
- Yumi Imai - Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23507, USA. Imaiy@evms.eduAnca D Dobrian - Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USAMargaret A Morris - Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USADavid A Taylor-Fishwick - Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USAJerry L Nadler - Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23507, USA. NadlerJL@evms.edu
- Resource Type
- Journal article
- Publication Details
- Diabetologia, Vol.59(4), pp.673-678
- DOI
- 10.1007/s00125-016-3890-y
- PMID
- 26868492
- PMCID
- PMC4779407
- ISSN
- 0012-186X
- eISSN
- 1432-0428
- Grant note
- R01 DK090490 / NIDDK NIH HHS R01-DK090490 / NIDDK NIH HHS R01-DK105588 / NIDDK NIH HHS R01-HL112605 / NHLBI NIH HHS R15-HL114062 / NHLBI NIH HHS R15 HL114062 / NHLBI NIH HHS R01 DK105588 / NIDDK NIH HHS R01 HL112605 / NHLBI NIH HHS
- Language
- English
- Date published
- 04/2016
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094752302771
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