Mild Electrical Stimulation with Heat Shock Reduces Visceral Adiposity and Improves Metabolic Abnormalities in Subjects with Metabolic Syndrome or Type 2 Diabetes: Randomized Crossover Trials

Abstract

BackgroundThe induction of heat shock protein (HSP) 72 by mild electrical stimulation with heat shock (MES + HS), which improves visceral adiposity and insulin resistance in mice, may be beneficial in treating metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM).MethodsUsing open-label crossover trials, 40 subjects with MS or T2DM were randomly assigned using computer-generated random numbers to 12 weeks of therapeutic MES + HS followed by 12 weeks of no treatment, or vice versa. During the intervention period, physical and biochemical markers were measured.FindingsCompared to no treatment, MES + HS treatment was associated with a significant decrease in visceral adiposity (− 7.54 cm2 (− 8.61%), 95% CI − 8.55 to − 6.53 (p = 0.037) in MS, − 19.73 cm2 (− 10.89%), 95% CI − 20.97 to − 18.49 (p = 0.003) in T2DM). Fasting plasma glucose levels were decreased by 3.74 mg/dL (− 5.28%: 95% CI − 4.37 to − 3.09 mg/dL, p = 0.029) in MS and by 14.97 mg/dL (10.40%: 95% CI − 15.79 to 14.15 mg/dL, p < 0.001) in T2DM, and insulin levels were also reduced by 10.39% and 25.93%, respectively. HbA1c levels showed a trend toward reduction (− 0.06%) in MS, and was significantly declined by − 0.43% (95% CI − 0.55 to − 0.31%, p = 0.009) in T2DM. HbA1c level of less than 7.0% was achieved in 52.5% of the MES + HS-treated T2DM patients in contrast to 15% of the non-treated period. Several insulin resistance indices, inflammatory cytokines or adipokines, including C-reactive protein, adiponectin, and tumor necrosis factor-α, were all improved in both groups. In isolated monocytes, HSP72 expression was increased and cytokine expression was reduced following MES + HS treatment. Glucose excursions on meal tolerance test were lower after using MES + HS in T2DM.InterpretationThis combination therapy has beneficial impacts on body composition, metabolic abnormalities, and inflammation in subjects with MS or T2DM. Activation of the heat shock response by MES + HS may provide a novel approach for the treatment of lifestyle-related diseases.FundingFunding for this research was provided by (Grants-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology, Japan).

Cellular stress response pathways and diabetes mellitus

“…Moreover, in 40 Japanese male subjects with type 2 diabetes, the same treatment with HS ? MES significantly reduced HbA1c levels by -0.43 % in addition to the improvements of various metabolic parameters as observed in the subjects with metabolic syndrome [18]. Although we could not investigate the impact of HS ?…”

“…In 40 Japanese male subjects with metabolic syndrome, treatment with HS ? MES [42°C pads and 1.4 ± 0.1 V/cm direct current (55 pulses/s with 0.1 ms duration) for 60 min, four times per week for 12 weeks] significantly reduced fasting blood glucose and insulin levels, visceral fat, circulating inflammatory markers and blood pressure [18]. Moreover, in 40 Japanese male subjects with type 2 diabetes, the same treatment with HS ?…”

Mild electrical stimulation with heat shock reduces inflammatory symptoms in the imiquimod‐induced psoriasis mouse model

“…In clinical studies, we have investigated the optimal condition of MES+HS treatment. The combination treatment of MES+HS and DPP‐4 inhibitor has synergistic effect on metabolic abnormality …”

“…In addition, we showed that MES+HS exerts biological effects via activation of intracellular signaling pathways such as p53 and LKB1‐AMPK axis . In clinical studies for subjects with type 2 diabetes mellitus and metabolic syndrome, MES+HS treatment significantly ameliorated the insulin resistance and inflammatory parameters without any adverse effects . However, it is unclear whether MES+HS treatment has a positive effect on pathological skin condition.…”

Skeletal muscle‐specific overexpression of heat shock protein 72 improves skeletal muscle insulin‐stimulated glucose uptake but does not alter whole body metabolism

“…Hsp72 is downregulated at both the gene and protein level in the skeletal muscle of individuals with T2D, as compared to healthy, non‐diabetic individuals, while Hsp72 mRNA expression levels correlate with glucose infusion rates during euglycaemic hyperinsulinaemic clamp in humans . Furthermore, studies in humans, primates and rodents that have increased endogenous Hsp72 levels via heat treatment, pharmacological activation or genetic manipulation have all led to improvements in metabolic function while, conversely, the loss of Hsp72 (null for Hspa1a and HspA1b ) in mice leads to insulin resistance and mitochondrial dysfunction …”