ABSTRACT
Low-intensity electrical current (or mild electrical stimulation; MES) influences signal transduction and activates phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Because insulin resistance is characterized by a marked reduction in insulin-stimulated PI3K-mediated activation of Akt, we asked whether MES could increase Akt phosphorylation and ameliorate insulin resistance. In addition, it was also previously reported that heat shock protein 72 (Hsp72) alleviates hyperglycemia. Thus, we applied MES in combination with heat shock (HS) to in vitro and in vivo models of insulin resistance. Here we show that 10-min treatment with MES at 5 V (0.1 ms pulse duration) together with HS at 42 degrees C increased the phosphorylation of insulin signaling molecules such as insulin receptor substrate (IRS) and Akt in HepG2 cells maintained in high-glucose medium. MES (12 V)+mild HS treatment of high fat-fed mice also increased the phosphorylation of insulin receptor beta subunit (IRbeta) and Akt in mice liver. In high fat-fed mice and db/db mice, MES+HS treatment for 10 min applied twice a week for 12-15 weeks significantly decreased fasting blood glucose and insulin levels and improved insulin sensitivity. The treated mice showed significantly lower weight of visceral and subcutaneous fat, a markedly improved fatty liver and decreased size of adipocytes. Our findings indicated that the combination of MES and HS alleviated insulin resistance and improved fat metabolism in diabetes mouse models, in part, by enhancing the insulin signaling pathway.
Subject(s)
Heat-Shock Response/physiology , Insulin Resistance/physiology , Insulin/metabolism , Signal Transduction , Animals , Blood Glucose/metabolism , Electric Stimulation , HSP72 Heat-Shock Proteins/metabolism , Hepatocytes/metabolism , Humans , Hyperglycemia/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
To explore the cellular effects of mild electrical stimulation (MES), we treated A549 cells with low-intensity direct current at 5 V applied for 10 min. MES did not induce cell cytotoxicity or the unfolded protein response (UPR). Interestingly, the expression of ubiquitinated proteins and heat shock protein (Hsp) 72 was increased but not that of other Hsps. MES attenuated the degradation of Hsp72, which is a substrate of the proteasome-ubiquitin system. These results, along with the observed increase in expression of ubiquitinated proteins, imply that MES may affect the proteasome system, which regulates the fate of many proteins.
