Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

作者全名："He, Xueting; Gao, Fei; Hou, Jiaojiao; Li, Tingjie; Tan, Jiang; Wang, Chunyu; Liu, Xiaoyan; Wang, Maoqi; Liu, Hui; Chen, Yuqin; Yu, Zhuoyuan; Yang, Mei"

作者地址："[He, Xueting; Hou, Jiaojiao; Li, Tingjie; Tan, Jiang; Wang, Chunyu; Liu, Xiaoyan; Wang, Maoqi; Liu, Hui; Yang, Mei] Chongqing Med Univ, Coll Basic Med, Dept Anat, Chongqing, Peoples R China; [Gao, Fei; Yu, Zhuoyuan] Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, Chongqing, Peoples R China; [Chen, Yuqin] Chongqing Med Univ, Coll Basic Med, Inst Neurosci, Chongqing, Peoples R China"

通信作者："Yang, M (corresponding author), Chongqing Med Univ, Coll Basic Med, Dept Anat, Chongqing, Peoples R China."

来源：JOURNAL OF BIOLOGICAL CHEMISTRY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000690868100002

JCR分区：Q2

影响因子：4.8

年份：2021

卷号：297

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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 (INS1 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 Psi-cells and subsequent insulin secretion in T2DM."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81971230, 81671312, 81672893]; Science and technology research project of Chongqing Education Commission [KJQN201800428]; Senior Young-middle-aged Medical Talents Program of Chongqing Health Committee [204216qn]; Chongqing Science and Health Joint Project [2020GDRC007]; Reserve Talents Program for academic Leaders of the First Affiliated Hospital of Chongqing Medical University [XKTS070]"

基金资助正文："Funding from the National Natural Science Foundation of China (81971230 and 81671312), Science and technology research project of Chongqing Education Commission (KJQN201800428) to M. Y.; National Natural Science Foundation of China (81672893), Senior Young-middle-aged Medical Talents Program of Chongqing Health Committee (No.204216qn), Chongqing Science and Health Joint Project (2020GDRC007) and Reserve Talents Program for academic Leaders of the First Affiliated Hospital of Chongqing Medical University (No.XKTS070) to F. G."