Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 ).
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PMID:Lipids and immunoinflammatory pathways of beta cell destruction. 2686 92

Natural killer (NK) cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of type 1 diabetes (T1D) in at least a portion of patients. NK cells recognize their target cells through a delicate balance of inhibitory and stimulatory receptors on their surface. If unbalanced, NK cells have great potential to wreak havoc in the pancreas due to the beta cell expression of the as-yet-defined NKp46 ligand through interactions with the activating NKp46 receptor found on the surface of most NK cells. Blocking interactions between NKp46 and its ligand protects mice from STZ-induced diabetes, but differential expression non-diabetic and diabetic donor samples have not been tested. Additional studies have shown that peripheral blood NK cells from human T1D patients have altered phenotypes that reduce the lytic and functional ability of the NK cells. Investigations of humanT1D pancreas tissues have indicated that the presence of NK cells may be beneficial despite their infrequent detection. In non-obese diabetic (NOD) mice, we have noted that NK cells express high levels of the proinflammatory mediator 12/15-lipoxygenase (12/15-LO), and decreased levels of stimulatory receptors. Conversely, NK cells of 12/15-LO deficient NOD mice, which are protected from diabetes development, express significantly higher levels of stimulatory receptors. Furthermore, the human NK92 cell line expresses the ALOX12 protein [human 12-lipoxygenase (12-LO), related to mouse 12/15-LO] via Western blotting. Human 12-LO is upregulated in the pancreas of both T1D and T2D human donors with insulin-containing islets, showing a link between 12-LO expression and diabetes progression. Therefore, our hypothesis is that NK cells in those susceptible to developing T1D are unable to function properly during viral infections of pancreatic beta cells due to increased 12-LO expression and activation, which contributes to increased interferon-gamma production and an imbalance in activating and inhibitory NK cell receptors, and may contribute to downstream autoimmune T cell responses. The work presented here outlines evidence from our lab, as well as published literature, supporting our hypothesis, including novel data.
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PMID:The Four-Way Stop Sign: Viruses, 12-Lipoxygenase, Islets, and Natural Killer Cells in Type 1 Diabetes Progression. 2899 59