title: Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: possible mitochondrial mechanism.
abstract: We examined the effects of anti-six-transmembrane epithelial antigen of the prostate-4 (STEAP4) antibodies on glucose transport in mature adipocytes and determined the mechanism of insulin resistance in obesity. Western blotting was performed to determine STEAP4 expression, to assess translocation of insulin-sensitive glucose transporter 4 (GLUT4), and to measure phosphorylation and total protein content of insulin-signaling proteins. Confocal laser microscopy and flow cytometry were used to detect intracellular reactive oxygen species (ROS) and fluctuations in mitochondrial membrane potential (ΔΨ). ATP production was measured by using a luciferase-based luminescence assay kit. After the application of anti-STEAP4 antibodies at 0.002 mg/mL, adipocytes exhibited reduced insulin-stimulated glucose transport by attenuating the phosphorylation of IRS-1, PI3K (p85), and Akt. The antibodies also potentially increase the level of ROS and decrease cellular ATP production and ΔΨ. In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin-induced GLUT4 translocation and glucose uptake; (ii) ROS-related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance. These observations highlight the potential role of STEAP4 in glucose homeostasis and possibly in the pathophysiology of type 2 diabetes related to obesity and may provide new insights into the mechanisms of insulin resistance in obesity.
authors.affiliation: Department of Pediatrics, Nanjing Maternal and Child Health Hospital of Nanjing Medical University, No.123 Tianfei Road, Nanjing, 210004, China.
authors.forename: Da-ni
authors.initials: DN
authors.lastname: Qin
authors.forename: Jin-Gai
authors.initials: JG
authors.lastname: Zhu
authors.forename: Chen-bo
authors.initials: CB
authors.lastname: Ji
authors.lastname: Chunmei-Shi
authors.forename: Chun-zhao
authors.initials: CZ
authors.lastname: Kou
authors.forename: Guan-zhong
authors.initials: GZ
authors.lastname: Zhu
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Zhang
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Yu-hui
authors.initials: YH
authors.lastname: Ni
authors.forename: Xi-rong
authors.initials: XR
authors.lastname: Guo
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017667:Adipocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000276:immunology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C495692:SLC2A4 protein, human; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; C503310:STEAP4 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose