title: TCF2 attenuates FFA-induced damage in islet β-cells by regulating production of insulin and ROS.
abstract: Free fatty acids (FFAs) are cytotoxic to pancreatic islet β-cells and play a crucial role in the diabetes disease process. A recent study revealed a down-regulation of transcription factor 2 (TCF2) levels during FFA-mediated cytotoxicity in pancreatic β-cells. However, its function during this process and the underlying mechanism remains unclear. In this study, treatment with palmitic acid (PA) at high levels (400 and 800 μM) decreased β-cell viability and TCF2 protein expression, along with the glucose-stimulated insulin secretion (GSIS). Western and RT-PCR analysis confirmed the positive regulatory effect of TCF2 on GSIS through promotion of the key regulators pancreatic duodenal homeobox-1 (PDX1) and glucose transporter 2 (GLUT2) in β-cells. In addition, both PI3K/AKT and MEK/ERK showed decreased expression in PA (800 μM)-treated β-cells. Overexpression of TCF2 could effectively restore the inhibitory effect of PA on the activation of PI3K/AKT and MEK/ERK as well as β-cell viability, simultaneously, inhibited PA-induced reactive oxygen species (ROS) generation. After blocking the PI3K/AKT and MAPK/ERK signals with their specific inhibitor, the effect of overexpressed TCF2 on β-cell viability and ROS production was obviously attenuated. Furthermore, a protective effect of TCF2 on GSIS by positive modulation of JNK-PDX1/GLUT2 signaling was also confirmed. Accordingly, our study has confirmed that TCF2 positively modulates insulin secretion and further inhibits ROS generation via the PI3K/AKT and MEK/ERK signaling pathways. Our work may provide a new therapeutic target to achieve prevention and treatment of diabetes.
authors: Department of Geriatrics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China. yongyun_wu@mail.xjtu.edu.cn.
authors: Xiaojuan
authors: X
authors: Quan
authors: Department of Geriatrics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China. mengjingcn@mail.xjtu.edu.cn.
authors: Lin
authors: L
authors: Zhang
authors: Department of Geriatrics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China. wxd.wxd@mail.xjtu.edu.cn.
authors: Yingna
authors: Y
authors: Li
authors: Department of Geriatrics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China. zlyang54@mail.xjtu.edu.cn.
authors: Chunlian
authors: C
authors: Liang
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000633:toxicity*; D005947:Glucose / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D005227:Fatty Acids; D005947:Glucose; D051273:Glucose Transporter Type 2; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D019308:Palmitic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D017382:Reactive Oxygen Species; D015534:Trans-Activators; C068755:Hnf1b protein, rat; C495683:Slc2a2 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein