title: Lowered extracellular pH is involved in the pathogenesis of skeletal muscle insulin resistance.
abstract: Insulin resistance in the skeletal muscle is manifested by diminished insulin-stimulated glucose uptake and is a core factor in the pathogenesis of type 2 diabetes mellitus (DM), but the mechanism causing insulin resistance is still unknown. Our recent study has shown that pH of interstitial fluids was lowered in early developmental stage of insulin resistance in OLETF rats, a model of type 2 DM. Therefore, in the present study, we confirmed effects of the extracellular pH on the insulin signaling pathway in a rat skeletal muscle-derived cell line, L6 cell. The phosphorylation level (activation) of the insulin receptor was significantly diminished in low pH media. The phosphorylation level of Akt, which is a downstream target of the insulin signaling pathway, also decreased in low pH media. Moreover, the insulin binding to its receptor was reduced by lowering extracellular pH, while the expression of insulin receptors on the plasma membrane was not affected by the extracellular pH. Finally, insulin-stimulated 2-deoxyglucose uptake in L6 cells was diminished in low pH media. Our present study suggests that lowered extracellular pH conditions may produce the pathogenesis of insulin resistance in skeletal muscle cells.
authors: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Hiroki
authors: H
authors: Hayata
authors: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Japan Institute for Food Education and Health, Heian Jogakuin (St. Agnes') University, Kyoto, Japan. Electronic address: hmiyazak@koto.kpu-m.ac.jp.
authors: Hiroaki
authors: H
authors: Miyazaki
authors: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Japan Institute for Food Education and Health, Heian Jogakuin (St. Agnes') University, Kyoto, Japan.
authors: Naomi
authors: N
authors: Niisato
authors: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Noriko
authors: N
authors: Yokoyama
authors: Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Japan Institute for Food Education and Health, Heian Jogakuin (St. Agnes') University, Kyoto, Japan. Electronic address: marunaka@koto.kpu-m.ac.jp.
authors: Yoshinori
authors: Y
authors: Marunaka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005110:Extracellular Space / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D003847:Deoxyglucose; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: Insulin; Receptor; Skeletal muscle; pH