1. Academic Validation
  2. Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

  • Diabetes. 2017 Nov;66(11):2875-2887. doi: 10.2337/db17-0215.
Marimar Hernandez-Perez 1 Gaurav Chopra 2 Jonathan Fine 2 Abass M Conteh 3 Ryan M Anderson 1 4 Amelia K Linnemann 1 3 4 Chanelle Benjamin 1 Jennifer B Nelson 1 Kara S Benninger 1 Jerry L Nadler 5 David J Maloney 6 Sarah A Tersey 1 Raghavendra G Mirmira 7 3 4 8
Affiliations

Affiliations

  • 1 Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN.
  • 2 Department of Chemistry, Purdue Institute for Drug Discovery; Purdue Center for Cancer Research; Purdue Institute for Inflammation, Immunology and Infectious Disease; and Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN.
  • 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
  • 4 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
  • 5 Department of Medicine, Eastern Virginia Medical School, Norfolk, VA.
  • 6 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
  • 7 Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN rmirmira@iu.edu stersey@iu.edu.
  • 8 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
Abstract

Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated Insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of Reactive Oxygen Species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

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