1. Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus
- Author
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Mei Yang, Fei Gao, Yuqin Chen, Chunyu Wang, Tingjie Li, Xueting He, Hui Liu, Maoqi Wang, Jiaojiao Hou, Zhuoyuan Yu, Jiang Tan, and Xiaoyan Liu
- Subjects
Male ,endocrine system diseases ,medicine.medical_treatment ,Pharmacology ,Biochemistry ,AQP7, aquaporin 7 ,AMP-activated protein kinase ,Insulin-Secreting Cells ,Insulin ,pancreas ,Cells, Cultured ,ERK1/2, extracellular signal-regulated kinases 1/2 ,CD36, cluster determinant 36 ,diabetes ,TG, triglyceride ,biology ,Chemistry ,HE, hematoxylin and eosin ,VDAC1, voltage-dependent anion channel-1 ,Metformin ,medicine.anatomical_structure ,Mitogen-activated protein kinase ,JNK, c-Jun N-terminal kinase ,KSIS, KCl-stimulated insulin secretion ,Pancreas ,Research Article ,medicine.drug ,FBG, fasting blood glucose ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,aquaporin 7 (AQP7) ,Aquaporins ,Diabetes Mellitus, Experimental ,GSIS, glucose-stimulated insulin secretion ,Downregulation and upregulation ,medicine ,Animals ,Hypoglycemic Agents ,Molecular Biology ,KD, knockdown ,Pancreatic islets ,nutritional and metabolic diseases ,T2DM, type 2 diabetes mellitus ,Cell Biology ,Glu, glucose ,PGC-1α, peroxisome proliferator-activated receptor gamma coactivators-1α ,MAPK ,Rats ,TC, total cholesterol ,AMPK, AMP-activated protein kinase ,Disease Models, Animal ,Diabetes Mellitus, Type 2 ,biology.protein ,MAPK, mitogen-activated protein kinase ,OE, overexpression - Abstract
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 β-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 β-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 β-cells and subsequent insulin secretion in T2DM.
- Published
- 2021