| Autor: |
Gertrud Schäfer, Volkhard Helms, Markus Hoth, Grigorios Christidis, Arne Knörck, Archana K. Yanamandra, Eva C. Schwarz, Caroline Diener, Leticia Soriano-Baguet, Eckart Meese, Leticia Prates Roma, Frank Lammert, Martin Hart, Bin Qu, Wenjuan Yang, Frederic Küppers, Dirk Brenner, Renping Zhao, Andreas Denger |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL-mediated antigen-independent killing remains elusive. Here, we report that TNF-related apoptosis inducing ligand (TRAIL) is substantially up- regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. The PI3K- Akt-NFκB axis and non-mitochondrial reactive oxygen species are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect 1.4E7 cells from TRAIL-mediated apoptosis. Notably, in patients with diabetes, correlation between Vitamin D concentrations in plasma and glucose levels is linked to HG-enhanced TRAIL expression on CTLs. Microarray data reveal that OXCT2, an important enzyme in ketone body catabolism, is a promising target in response to vitamin D. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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