Inflammatory Pathways Linked to Beta Cell Demise in Diabetes

Imai, Yumi; Morris, Margaret A.; Dobrian, Anca D.; Taylor‐Fishwick, David A.; Nadler, Jerry L.

doi:10.1007/978-94-007-6884-0_30-2

Cited by 1 publication

(1 citation statement)

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“…Review of 12-lipoxygenase and links to biological systems highlights the important role of 12-lipoxygenase in the development of type 1 diabetes [11,15,17,23,33,34]. Studies of mouse models with transgenic deletion of 12-lipoxygenase suggest that activity of the 12-lipoxygenase enzyme strongly associates with beta cell dysfunction [17,19,33].…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

et al. 2014

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Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-Shydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Results Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Conclusions/interpretation Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.

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