Dokument: Investigating the role of very long chain sphingolipids in pancreatic beta cell demise
| Titel: | Investigating the role of very long chain sphingolipids in pancreatic beta cell demise | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=55053 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20230119-094845-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Grieß, Kerstin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Lammert, Eckhard [Gutachter] PD Dr. Burkart, Volker [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Type 2 diabetes (T2D) is characterized by dysfunctional insulin secretion from pancreatic beta cells. Ceramides are suggested to be involved in the development of T2D and might be implicated in beta cell failure. Six individual ceramide synthases (CERS1-6) exist, which attach fatty acids with a specific chain length to a sphingoid base backbone and thus generate distinct ceramide species possessing different biophysical and biochemical properties. Previous studies demonstrated that pharmacological inhibition of ceramide de novo synthesis might be a potential therapy to treat metabolic diseases, such as obesity and T2D. However, the role of distinct ceramide species in pancreatic beta cells has not been investigated.
In this thesis, alterations in the sphingolipidome of diabetic pancreatic islets of db/db mice were analyzed using untargeted lipidomics. While long and very long chain ceramide species were elevated in islets from db/db mice, more complex sphingolipids, such as sphingomyelins and hexosylceramides showed an increase in C16:0 species, but a reduction in C24:1 species. This demonstrates that sphingolipid species with distinct acyl chain length are differentially regulated during the development of T2D in islets. Furthermore, the role of very long chain C22-C24 ceramides and sphingolipids were analyzed in pancreatic beta cells in vivo and in vitro by ablation of CerS2. Beta cell specific deletion of CerS2 and the concomitant reduction in very long chain sphingolipids impaired glucose tolerance and insulin secretion in mice on normal and high fat diet. Consistently, pancreatic beta cells of CerS2 knockout mice contained less mature insulin due to impaired processing of proinsulin into insulin. Mechanistically, ablation of CerS2 specifically reduced the number of mature insulin granules and decreased prohormone convertase 1 (PC1, encoded by Pcsk1), the rate limiting enzyme for proinsulin processing, while PC2 expression was unaffected. Furthermore, CERS2 deficiency did not alter Pcsk1 mRNA expression and PC1 degradation, indicating that CERS2 is required for efficient PC1 protein biosynthesis, maturation and/or trafficking along the secretory pathway. This data demonstrate the importance of CERS2 and very long chain sphingolipids in prohormone processing of pancreatic beta cells and highlight potentially unwanted consequences of global ceramide and sphingolipid inhibition as diabetes treatment. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Sonstige Einrichtungen/Externe » An-Institute » Deutsches Diabetes-Zentrum | |||||||
| Dokument erstellt am: | 19.01.2023 | |||||||
| Dateien geändert am: | 19.01.2023 | |||||||
| Promotionsantrag am: | 10.09.2020 | |||||||
| Datum der Promotion: | 27.11.2020 |
