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|Title:||High glucose enhances antigen-independent CTL killing via TRAIL|
Yanamandra, Archana K.
Schwarz, Eva C.
Roma, Leticia Prates
|Year of Publication:||2021|
|Abstract:||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.|
|DOI of the first publication:||10.1101/2021.08.04.455060|
|URL of the first publication:||https://www.biorxiv.org/content/10.1101/2021.08.04.455060v2|
|Link to this record:||hdl:20.500.11880/32120|
|Date of registration:||4-Jan-2022|
|Faculty:||M - Medizinische Fakultät|
NT - Naturwissenschaftlich- Technische Fakultät
|Department:||M - Biophysik|
M - Humangenetik
M - Innere Medizin
NT - Biowissenschaften
|Professorship:||M - Prof. Dr. Markus Hoth|
M - Prof. Dr. Frank Lammert
M - Prof. Dr. Eckhart Meese
NT - Prof. Dr. Volkhard Helms
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