PMID- 36581217
OWN - NLM
STAT- MEDLINE
DCOM- 20230311
LR  - 20230322
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 105
DP  - 2023 May
TI  - 1,25D/VDR inhibits pancreatic beta cell ferroptosis by downregulating FOXO1 
      expression in diabetes mellitus.
PG  - 110564
LID - S0898-6568(22)00326-6 [pii]
LID - 10.1016/j.cellsig.2022.110564 [doi]
AB  - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a global health problem that 
      seriously threatens human health. Vitamin D (VD) has antidiabetic effects. 
      However, the protective mechanism of 1,25-dihydroxyvitamin D3 (1,25D) on T2DM is 
      still unclear. METHODS: A rat model of T2DM was constructed using a high-fat diet 
      combined with intraperitoneal injection of streptozotocin (STZ). Glucose 
      tolerance was assessed by an oral glucose tolerance test (OGTT). Insulin 
      secretion in blood and cell supernatant was determined by ELISA. Cell viability 
      was analysed by CCK-8 assay. The level of ROS was detected by the DCFH-DA 
      fluorescent probe method. The iron level in pancreatic tissues and cells was 
      detected by an iron assay kit. Immunofluorescence staining was used to detect the 
      expression of the pancreatic beta cell marker CD49a. Furthermore, the protein 
      expression levels of ferroptosis pathway-related proteins and vitamin D receptor 
      (VDR) were detected by western blot. Downstream VDR targets were screened by 
      proteomic sequencing. RESULTS: The DM group had increased glucose levels and 
      decreased insulin secretion, while 1,25D treatment decreased glucose levels and 
      increased insulin secretion. 1,25D also suppressed DM-induced ferroptosis in 
      pancreatic tissues in vivo. In addition, 1,25D significantly enhanced the 
      viability of pancreatic beta cells and reduced the levels of ROS and iron. 1,25D 
      significantly upregulated the expression of VDR and the ferroptosis-related 
      pathway protein GPX4 and downregulated the expression of ACSL4. Furthermore, 
      knockdown of VDR reversed the effects of 1,25D on cell viability, ROS and iron 
      levels, and ferroptosis-related protein expression in pancreatic beta cells. 
      Proteomic sequencing revealed that FOXO1 was the downstream target gene of VDR. 
      Knockdown of FOXO1 reduced pancreatic beta cell death, decreased ROS, iron and ACSL4 
      levels, and increased GPX4 levels. CONCLUSION: 1,25D/VDR inhibited pancreatic beta 
      cell ferroptosis in T2DM by downregulating the expression of FOXO1. This study 
      provides a new theoretical basis for basic research on T2DM and is expected to 
      establish a new idea for the treatment of T2DM.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Ding, Yao
AU  - Ding Y
AD  - Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and 
      Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, China.
FAU - Wu, Qinan
AU  - Wu Q
AD  - Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and 
      Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, China. 
      Electronic address: wql455@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221226
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Foxo1 protein, rat)
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Calcitriol)
SB  - IM
MH  - Animals
MH  - Rats
MH  - *Diabetes Mellitus, Type 2/metabolism
MH  - *Ferroptosis
MH  - Forkhead Box Protein O1/metabolism
MH  - Glucose/metabolism
MH  - *Insulin-Secreting Cells/metabolism
MH  - Proteomics
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Calcitriol/genetics/metabolism
OTO - NOTNLM
OT  - 1,25D
OT  - FOXO1
OT  - Ferroptosis
OT  - Type 2 diabetes
OT  - VDR
COIS- Declaration of Competing Interest The authors declare that there are no conflicts 
      of interest.
EDAT- 2022/12/30 06:00
MHDA- 2023/03/10 06:00
CRDT- 2022/12/29 19:17
PHST- 2022/05/20 00:00 [received]
PHST- 2022/12/01 00:00 [revised]
PHST- 2022/12/15 00:00 [accepted]
PHST- 2022/12/30 06:00 [pubmed]
PHST- 2023/03/10 06:00 [medline]
PHST- 2022/12/29 19:17 [entrez]
AID - S0898-6568(22)00326-6 [pii]
AID - 10.1016/j.cellsig.2022.110564 [doi]
PST - ppublish
SO  - Cell Signal. 2023 May;105:110564. doi: 10.1016/j.cellsig.2022.110564. Epub 2022 
      Dec 26.