title: The impairment of glucose-stimulated insulin secretion in pancreatic β-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response.
abstract: Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of β-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic β-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic β-cells.
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Bei
authors.initials: B
authors.lastname: Yang
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital, China Medical University, 155 Nanjingbei Street, Heping District, Shenyang, Liaoning, 110001, PR China.
authors.forename: Difei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, 201 Dowman Drive, Atlanta, GA, 30322, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China. Electronic address: jbpi@cmu.edu.cn.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000009:adverse effects* / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007328:Insulin; D008055:Lipids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013549:Sweetening Agents; D005947:Glucose
keywords: Adaptive antioxidant response; Glucose-stimulated insulin secretion; Glucotoxicity; Lipotoxicity; Pancreatic β-cells