Lowered extracellular pH is involved in the pathogenesis of skeletal muscle insulin resistance

• Published in: Biochemical and biophysical research communications 2014-02, Vol.445 (1), p.170-174
• Main Authors: Hayata, Hiroki, Miyazaki, Hiroaki, Niisato, Naomi, Yokoyama, Noriko, Marunaka, Yoshinori
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Differentiation - drug effects; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Deoxyglucose - pharmacokinetics; Extracellular Space - chemistry; Hydrogen-Ion Concentration; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Insulin; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Rats; Receptor; Receptor, Insulin - metabolism; Skeletal muscle
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.01.162

•Low pH media diminish activation of insulin receptor in L6 skeletal muscle cells.•Akt phosphorylation is also decreased by low pH media in L6 cells.•Low pH media reduce insulin binding to its receptor in L6 cells.•Insulin-stimulated 2-deoxyglucose uptake in L6 cells is diminished in low pH media.•Low extracellular pH produces insulin resistance in skeletal muscle cells. 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.