Affiliation:
1. Laboratory of Pancreatic Islet Research Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
2. First Faculty of Medicine Charles University Prague Czech Republic
3. Faculty of Science Charles University Prague Czech Republic
4. Laboratory of Mitochondrial Physiology Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic
5. Department of Medical Chemistry and Biochemistry Palacký University Olomouc Czech Republic
Abstract
AbstractObjectiveBy exposing mice carrying a deletion of NADPH oxidase isoform 4, NOX4, specifically in pancreatic β cells (βNOX4−/−) to nutrient excess stimulated by a high‐fat diet (HFD), this study aimed to elucidate the role of β‐cell redox status in the development of meta‐inflammation within the diabetic phenotype.MethodsThe authors performed basic phenotyping of βNOX4−/− mice on HFD involving insulin and glycemic analyses, histochemistry of adipocytes, indirect calorimetry, and cytokine analyses. To characterize local inflammation, the study used caspase‐1 activity assay, interleukin‐1β immunochemistry, and real‐time polymerase chain reaction during coculturing of β cells with macrophages.ResultsThe phenotype of βNOX4−/− mice on HFD was not associated with hyperinsulinemia and hyperglycemia but showed accumulation of excessive lipids in epididymal fat and β cells. Surprisingly, mice showed significantly reduced systemic inflammation. Decreased interleukin‐1β protein levels and downregulated NLRP3‐inflammasome activity were observed on chronic glucose overload in βNOX4−/− isolated islets and NOX4‐silenced INS1‐E cells resulting in attenuated proinflammatory polarization of macrophages/monocytes in vitro and in situ and reduced local islet inflammation.ConclusionsExperimental evidence suggests that NOX4 pro‐oxidant activity in β cells is involved in NLRP3‐inflammasome activation during chronic nutrient overload and participates in local inflammatory signaling and perhaps toward peripheral tissues, contributing to a diabetic inflammatory phenotype.image
Funder
Grantová Agentura České Republiky
Grantová Agentura, Univerzita Karlova
Subject
Nutrition and Dietetics,Endocrinology,Endocrinology, Diabetes and Metabolism,Medicine (miscellaneous)