Fig. 1Heat shock response activation by mild electrical stimulation with hyperthermia (MET) improves insulin resistance. MET using simultaneous heat shock with mild electrical stimulation decreases fasting plasma glucose (A) and improves glucose tolerance (B) and insulin resistance (C) accompanied by reduction of visceral adiposity and hepatic steatosis (D). Circulating adiponectin is increased (E) and hepatic insulin signal is restored with HSP72 induction and c-jun N-terminal kinase (JNK) attenuation by MET (F, G). I.p, intraperitoneal; GTT, glucose tolerance test; ITT, insulin tolerance test; HFD, high fat diet. Adapted from Morino S, et al. Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. PLoS One 2008;3:e4068 [8].
Fig. 2Heat shock response activation by mild electrical stimulation with hyperthermia (MET) protects pancreatic β-cells. Although c-jun N-terminal kinase (JNK), endoplasmic reticulum stress marker BiP and death signal caspase-3 are activated in tumor necrosis factor α (TNF-α) stimulated MIN6 cells, MET treatment attenuates these abnormal activations (A). Akt phosphorylation is partially restored by MET as well (A). MET treatment alleviates glucose dysregulation (B) with insulin insufficiency (C) in aged db/db mice. This therapy protects pancreatic β-cells from apoptotic signals and increases PDX-1 nuclear expression (D-H). I.p, intraperitoneal; GTT, glucose tolerance test. Adapted from Kondo T, et al. Diabetes 2012;61:838-47 [14].
Fig. 3Heat shock response activation by geranylgeranyl acetone (GGA) (A) improves insulin resistance. HSP72 expression is mainly increased in liver (D), and fasting plasma glucose (B), insulin levels (C) and insulin resistance are ameliorated with reductions in hepatic gluconeogenic enzymes (F, G) by the GGA oral administration. GGA treatment decreases visceral adipocyte size (H), c-jun N-terminal kinase (JNK) activation and restores insulin signaling (E). PEPCK, phosphoenolpyruvate carboxykinase; G6P, glucose 6-phosphatase. Adachi H, et al. Am J Physiol Endocrinol Metab 2010;299:E764-71, with permission from the American Physiological Society [3].
Fig. 4The summarized effects of mild electrical stimulation with hyperthermia (MET) on metabolic diseases. MET treatment or geranylgeranyl acetone (GGA) administration decreases the amount of visceral fat, insulin resistance, c-jun N-terminal kinase (JNK) activation, inflammatory cytokines and contributes to protect pancreatic β-cells in mice models of diabetes. In normal human subjects, MET exerts anti-inflammatory effect in normal range. MET exerts antidiabetic, antiobesity, and anti-inflammatory effects in metabolic syndrome or type 2 diabetes mellitus subjects. These observations are quite similar to those in mice models. ND, not determined.