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Cystine/Glutamate antiporter System Xc- in Beta cell and Macrophage function

de Baat, Axel. Cystine/Glutamate antiporter System Xc- in Beta cell and Macrophage function. 2022, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/92097/

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Abstract

Hormonal regulation of blood glucose is a complex dynamic process in which insulin is a
major player. Beta cells are the insulin producing cells located in the pancreatic islets of Langerhans. These cells are optimized to be the perfect glucose sensors because of their specialized glucose metabolism. This optimization comes at the cost of sensitivity to reactive oxygen species, a by-product of metabolism, through relative lack of buffering capacity and high metabolic rate. Cells have systems for mitigating oxidative insults, mostly involving redox chemistry using sulphur peptides as co-factors. Upon oxidative stress, cells upregulate the light chain of system Xc-, encoded by Slc7a11. This non-sodium dependent antiporter exports glutamate and imports cystine, the oxidized dimeric form of the semi-essential sulphur amino acid cysteine. When cysteine enters the cell, it is immediately reduced and accessible for incorporation into thiol peptides such as glutathione, used as co-factors for redox maintenance. In this study we describe the metabolic implications of Slc7a11 deficiency in both whole body and macrophage specific knockout mice. Lack of Slc7a11 leads to drastically lowered glutathione levels in the pancreatic islets and a defect in insulin secretion both in vitro and in vivo. We also observe a compensatory increase in insulin sensitivity that is abrogated upon dietary challenge. We find system Xc is rapid upregulation in response to lipopolysaccharides in addition to a defective cytokine production in Slc7a11 deficient macrophages in vitro. We did not find a decrease in insulin secretion during myeloid specific deletion of Slc7a11, which excludes macrophages from driving earlier reported excitotoxicity. These findings suggest an important role for cysteine and glutathione in beta cell biology and macrophage function, with macrophage Slc7a11 not playing a major role in the islet micro-environment.
Advisors:Donath, Marc Y. and Hess, Christoph and Konrad, Daniel
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie > Endokrinologie, Diabetologie und Metabolismus (Donath)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie > Endokrinologie, Diabetologie und Metabolismus (Donath)
05 Faculty of Science
UniBasel Contributors:Hess, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14925
Thesis status:Complete
Number of Pages:58
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss149259
edoc DOI:
Last Modified:01 Jan 2024 02:30
Deposited On:03 Feb 2023 15:19

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