PMID- 36463128
OWN - NLM
STAT- MEDLINE
DCOM- 20221206
LR  - 20221230
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Print)
IS  - 1076-1551 (Linking)
VI  - 28
IP  - 1
DP  - 2022 Dec 3
TI  - Exenatide regulates Th17/Treg balance via PI3K/Akt/FoxO1 pathway in db/db mice.
PG  - 144
LID - 10.1186/s10020-022-00574-6 [doi]
LID - 144
AB  - BACKGROUND: The T helper 17 (Th17)/T regulatory (Treg) cell imbalance is involved 
      in the course of obesity and type 2 diabetes mellitus (T2DM). In the current 
      study, the exact role of glucagon-like peptide-1 receptor agonist (GLP-1RA) 
      exenatide on regulating the Th17/Treg balance and the underlying molecular 
      mechanisms are investigated in obese diabetic mice model. METHODS: Metabolic 
      parameters were monitored in db/db mice treated with/without exenatide during 
      8-week study period. The frequencies of Th17 and Treg cells from peripheral blood 
      and pancreas in db/db mice were assessed. The phosphoinositide 3-kinase 
      (PI3K)/protein kinase B (Akt)/Forkhead box O1 (FoxO1) pathway in Th17 and Treg 
      cells from the spleens of male C57BL/6J mice was detected by western blotting. In 
      addition, the expression of glucagon-like peptide-1 receptor (GLP-1R) in 
      peripheral blood mononuclear cells (PBMCs) of male C57BL/6J mice was analyzed. 
      RESULTS: Exenatide treatment improved beta-cell function and insulitis in addition 
      to glucose, insulin sensitivity and weight. Increased Th17 and decreased Treg 
      cells in peripheral blood were present as diabetes progressed while exenatide 
      corrected this imbalance. Progressive IL-17 + T cell infiltration of pancreatic 
      islets was alleviated by exenatide intervention. In vitro study showed no 
      significant difference in the level of GLP-1R expression in PBMCs between control 
      and palmitate (PA) groups. In addition, PA could promote Th17 but suppress Treg 
      differentiation along with down-regulating the phosphorylation of PI3K/Akt/FoxO1, 
      which was reversed by exenatide intervention. FoxO1 inhibitor AS1842856 could 
      abrogate all these effects of exenatide against lipid stress. CONCLUSIONS: 
      Exenatide could restore systemic Th17/Treg balance via regulating FoxO1 pathway 
      with the progression of diabetes in db/db mice. The protection of pancreatic 
      beta-cell function may be partially mediated by inhibiting Th17 cell infiltration 
      into pancreatic islets, and the resultant alleviation of islet inflammation.
CI  - (c) 2022. The Author(s).
FAU - Xu, Qinqin
AU  - Xu Q
AD  - Division of Endocrinology, Tongji Hospital, Huazhong University of Science and 
      Technology, Jiefang Road 1095, Wuhan, 430030, Hubei Province, People's Republic 
      of China.
AD  - Branch of National Clinical Research Center for Metabolic Diseases, Hubei, 
      People's Republic of China.
FAU - Zhang, Xiaoling
AU  - Zhang X
AD  - Division of Endocrinology, Tongji Hospital, Huazhong University of Science and 
      Technology, Jiefang Road 1095, Wuhan, 430030, Hubei Province, People's Republic 
      of China.
AD  - Branch of National Clinical Research Center for Metabolic Diseases, Hubei, 
      People's Republic of China.
FAU - Li, Tao
AU  - Li T
AD  - Division of Ophthalmology, Tongji Hospital, Huazhong University of Science and 
      Technology, Jiefang Road 1095, Wuhan, 430030, Hubei Province, People's Republic 
      of China. dr_litao@163.com.
FAU - Shao, Shiying
AU  - Shao S
AUID- ORCID: 0000-0001-7077-5184
AD  - Division of Endocrinology, Tongji Hospital, Huazhong University of Science and 
      Technology, Jiefang Road 1095, Wuhan, 430030, Hubei Province, People's Republic 
      of China. shaoshiying@hotmail.com.
AD  - Branch of National Clinical Research Center for Metabolic Diseases, Hubei, 
      People's Republic of China. shaoshiying@hotmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221203
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - 9P1872D4OL (Exenatide)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Forkhead Box Protein O1)
SB  - IM
MH  - Male
MH  - Mice
MH  - Animals
MH  - Phosphatidylinositol 3-Kinase
MH  - Exenatide/pharmacology
MH  - Proto-Oncogene Proteins c-akt
MH  - Phosphatidylinositol 3-Kinases
MH  - T-Lymphocytes, Regulatory
MH  - Glucagon-Like Peptide-1 Receptor
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Leukocytes, Mononuclear
MH  - *Diabetes Mellitus, Experimental
MH  - Mice, Inbred C57BL
MH  - Forkhead Box Protein O1
PMC - PMC9719171
OTO - NOTNLM
OT  - Exenatide
OT  - Forkhead box O1
OT  - T helper 17 cell
OT  - T regulatory cell
OT  - Type 2 diabetes mellitus
COIS- The authors have declared that no conflict of interest exists.
EDAT- 2022/12/04 06:00
MHDA- 2022/12/07 06:00
PMCR- 2022/12/03
CRDT- 2022/12/03 23:15
PHST- 2022/07/04 00:00 [received]
PHST- 2022/11/11 00:00 [accepted]
PHST- 2022/12/03 23:15 [entrez]
PHST- 2022/12/04 06:00 [pubmed]
PHST- 2022/12/07 06:00 [medline]
PHST- 2022/12/03 00:00 [pmc-release]
AID - 10.1186/s10020-022-00574-6 [pii]
AID - 574 [pii]
AID - 10.1186/s10020-022-00574-6 [doi]
PST - epublish
SO  - Mol Med. 2022 Dec 3;28(1):144. doi: 10.1186/s10020-022-00574-6.