title: Urotensin II inhibits skeletal muscle glucose transport signaling pathways via the NADPH oxidase pathway.
abstract: Our previous studies have demonstrated that the urotensin (UII) and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM), but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK) mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.forename: Xin-Rui
authors.initials: XR
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Yin
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Shi
authors.forename: Xue-Jiang
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014579:Urotensins / Q000494:pharmacology*
chemical_list: D051275:Glucose Transporter Type 4; D010446:Peptide Fragments; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C495693:Slc2a4 protein, mouse; D014579:Urotensins; C085072:neutrophil cytosol factor 40K; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C029677:urotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose