PMID- 34303707
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20211214
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 297
IP  - 2
DP  - 2021 Aug
TI  - Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression 
      to induce insulin secretion in type 2 diabetes mellitus.
PG  - 101002
LID - S0021-9258(21)00804-8 [pii]
LID - 10.1016/j.jbc.2021.101002 [doi]
LID - 101002
AB  - Metformin is the first-line antidiabetic agent for type 2 diabetes mellitus 
      (T2DM) treatment. Although accumulated evidence has shed light on the 
      consequences of metformin action, the precise mechanisms of its action, 
      especially in the pancreas, are not fully understood. Aquaporin 7 (AQP7) acts as 
      a critical regulator of intraislet glycerol content, which is necessary for 
      insulin production and secretion. The aim of this study was to investigate the 
      effects of different doses of metformin on AQP7 expression and explore the 
      possible mechanism of its protective effects in the pancreatic islets. We used an 
      in vivo model of high-fat diet in streptozocin-induced diabetic rats and an 
      in vitro model of rat pancreatic beta-cells (INS-1 cells) damaged by hyperglycemia 
      and hyperlipidemia. Our data showed that AQP7 expression levels were decreased, 
      whereas p38 and JNK mitogen-activated protein kinases (MAPKs) were activated 
      in vivo and in vitro in response to hyperglycemia and hyperlipidemia. T2DM rats 
      treated with metformin demonstrated a reduction in blood glucose levels and 
      increased regeneration of pancreatic beta-cells. In addition, metformin upregulated 
      AQP7 expression as well as inhibited activation of p38 and JNK MAPKs both in vivo 
      and in vitro. Overexpression of AQP7 increased glycerol influx into INS-1 cells, 
      whereas inhibition of AQP7 reduced glycerol influx, thereby decreasing subsequent 
      insulin secretion. Our findings demonstrate a new mechanism by which metformin 
      suppresses the p38 and JNK pathways, thereby upregulating pancreatic AQP7 
      expression and promoting glycerol influx into pancreatic beta-cells and subsequent 
      insulin secretion in T2DM.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - He, Xueting
AU  - He X
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Gao, Fei
AU  - Gao F
AD  - Department of Urology, The First Affiliated Hospital, Chongqing Medical 
      University, Chongqing, People's Republic of China.
FAU - Hou, Jiaojiao
AU  - Hou J
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Li, Tingjie
AU  - Li T
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Tan, Jiang
AU  - Tan J
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Wang, Chunyu
AU  - Wang C
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Liu, Xiaoyan
AU  - Liu X
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Wang, Maoqi
AU  - Wang M
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Liu, Hui
AU  - Liu H
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China.
FAU - Chen, Yuqin
AU  - Chen Y
AD  - Institute of Neuroscience, College of Basic Medicine, Chongqing Medical 
      University, Chongqing, People's Republic of China.
FAU - Yu, Zhuoyuan
AU  - Yu Z
AD  - Department of Urology, The First Affiliated Hospital, Chongqing Medical 
      University, Chongqing, People's Republic of China.
FAU - Yang, Mei
AU  - Yang M
AD  - Department of Anatomy, College of Basic Medicine, Chongqing Medical University, 
      Chongqing, People's Republic of China. Electronic address: 
      yangmei503@cqmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210722
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Aqp7 protein, rat)
RN  - 0 (Aquaporins)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Aquaporins/genetics/*metabolism
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology
MH  - Diabetes Mellitus, Type 2/*drug therapy/metabolism/pathology
MH  - Disease Models, Animal
MH  - Hypoglycemic Agents/pharmacology
MH  - Insulin/*metabolism
MH  - Insulin-Secreting Cells/drug effects/*metabolism
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Metformin/*pharmacology
MH  - Rats
PMC - PMC8374641
OTO - NOTNLM
OT  - MAPK
OT  - aquaporin 7 (AQP7)
OT  - diabetes
OT  - metformin
OT  - pancreas
COIS- Conflict of interest The authors declare that they have no conflict of interest 
      associated with this study.
EDAT- 2021/07/26 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/07/22
CRDT- 2021/07/25 20:29
PHST- 2021/01/19 00:00 [received]
PHST- 2021/07/15 00:00 [revised]
PHST- 2021/07/21 00:00 [accepted]
PHST- 2021/07/26 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/07/25 20:29 [entrez]
PHST- 2021/07/22 00:00 [pmc-release]
AID - S0021-9258(21)00804-8 [pii]
AID - 101002 [pii]
AID - 10.1016/j.jbc.2021.101002 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Aug;297(2):101002. doi: 10.1016/j.jbc.2021.101002. Epub 2021 
      Jul 22.