title: Methylglyoxal Impairs Insulin Secretion of Pancreatic β-Cells through Increased Production of ROS and Mitochondrial Dysfunction Mediated by Upregulation of UCP2 and MAPKs.
abstract: Methylglyoxal (MG) is a highly reactive glucose metabolic intermediate and a major precursor of advanced glycation end products. MG level is elevated in hyperglycemic disorders such as diabetes mellitus. Substantial evidence has shown that MG is involved in the pathogenesis of diabetes and diabetic complications. We investigated the impact of MG on insulin secretion by MIN6 and INS-1 cells and the potential mechanisms of this effect. Our study demonstrates that MG impaired insulin secretion by MIN6 or ISN-1 cells in a dose-dependent manner. It increased reactive oxygen species (ROS) production and apoptosis rate in MIN6 or ISN-1 cells and inhibited mitochondrial membrane potential (MMP) and ATP production. Furthermore, the expression of UCP2, JNK, and P38 as well as the phosphorylation JNK and P38 was increased by MG. These effects of MG were attenuated by MG scavenger N-acetyl cysteine. Collectively, these data indicate that MG impairs insulin secretion of pancreatic β-cells through increasing ROS production. High levels of ROS can damage β-cells directly via JNK/P38 upregulation and through activation of UCP2 resulting in reduced MMP and ATP production, leading to β-cell dysfunction and impairment of insulin production.
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Jinshuang
authors.initials: J
authors.lastname: Bo
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Shiya
authors.initials: S
authors.lastname: Xie
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang 325035, China; Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou, Zhejiang 325035, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325035, China; Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qing H
authors.identifier: 0000-0002-1433-9860
authors.initials: QH
authors.lastname: Meng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D011765:Pyruvaldehyde