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Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
- Source :
- Diabetes
- Publication Year :
- 2017
- Publisher :
- American Diabetes Association, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Blood Glucose
medicine.medical_specialty
Programmed cell death
endocrine system diseases
Endocrinology, Diabetes and Metabolism
Thiophenes
Biology
Naphthalenes
medicine.disease_cause
Arachidonate 12-Lipoxygenase
Proinflammatory cytokine
03 medical and health sciences
Mice
Mice, Inbred NOD
Diabetes mellitus
Internal medicine
Insulin-Secreting Cells
Internal Medicine
medicine
Animals
Arachidonate 15-Lipoxygenase
Humans
Computer Simulation
Lipoxygenase Inhibitors
Cells, Cultured
chemistry.chemical_classification
Reactive oxygen species
geography
Type 1 diabetes
geography.geographical_feature_category
Molecular Structure
Isoxazoles
medicine.disease
Islet
Pharmacology and Therapeutics
3. Good health
Oxidative Stress
030104 developmental biology
Endocrinology
Diabetes Mellitus, Type 1
chemistry
Hydroxyquinolines
Female
Insulitis
Oxidative stress
Software
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 1939327X and 00121797
- Volume :
- 66
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....ee7cc2934faba5b310b3af548fd2670c