Hyperthermia With Mild Electrical Stimulation Protects Pancreatic β-Cells From Cell Stresses and Apoptosis

Abstract

Induction of heat shock protein (HSP) 72 improves metabolic profiles in diabetic model mice. However, its effect on pancreatic β-cells is not known. The current study investigated whether HSP72 induction can reduce β-cell stress signaling and apoptosis and preserve β-cell mass. MIN6 cells and db/db mice were sham-treated or treated with heat shock (HS) and mild electrical stimulation (MES) (HS+MES) to induce HSP72. Several cellular markers, metabolic parameters, and β-cell mass were evaluated. HS+MES treatment or HSP72 overexpression increased HSP72 protein levels and decreased tumor necrosis factor (TNF)-α–induced Jun NH2-terminal kinase (JNK) phosphorylation, endoplasmic reticulum (ER) stress, and proapoptotic signal in MIN6 cells. In db/db mice, HS+MES treatment for 12 weeks significantly improved insulin sensitivity and glucose homeostasis. Upon glucose challenge, a significant increase in insulin secretion was observed in vivo. Compared with sham treatment, levels of HSP72, insulin, pancreatic duodenal homeobox-1, GLUT2, and insulin receptor substrate-2 were upregulated in the pancreatic islets of HS+MES-treated mice, whereas JNK phosphorylation, nuclear translocation of forkhead box class O-1, and nuclear factor-κB p65 were reduced. Apoptotic signals, ER stress, and oxidative stress markers were attenuated. Thus, HSP72 induction by HS+MES treatment protects β-cells from apoptosis by attenuating JNK activation and cell stresses. HS+MES combination therapy may preserve pancreatic β-cell volume to ameliorate glucose homeostasis in diabetes.

Effects of heated hydrotherapy on muscle HSP70 and glucose metabolism in old and young vervet monkeys

“…4 Levels of HSP70 in muscle of monkeys were significantly associated with fasting glucose concentrations and were similarly associated with the change in fasting glucose from prestudy (r = −0.65, p = 0.02) such that the higher HSP70 was coupled with lower blood glucose and larger reductions in blood glucose over time the initial hyperglycemic excursion. Heat-treated rodents actually increase beta cell mass over the course of months and have improved insulin sensitivity (Kondo et al 2012). Rodents have a greater beta cell regeneration rate than that seen in humans or vervet monkeys sourced from the same familial colony as the ones studied in this report (Saisho et al 2011).…”

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

“…Lastly, heat shock has been shown to protect from loss of organ function (liver, kidney, pancreatic beta cell, and (Kondo et al 2012) Heat and mild electric stimulation: 42°C electrodes and 12 V direct current (55 pps of 0.1 ms duration), 2 times/week for 12-15 weeks Reduced beta cell apoptosis and ER stress, increased insulin response to glucose challenge, reduced cytokine activation Low-dose streptozotocin rat (Bathaie et al 2010) Hot water immersion: rectal temperature 41.0°C for 20 min, 3 times/week, 5 months Lowered fasting glucose, Hb A1c AGE, triglycerides, low-density lipoprotein cholesterol, increased high-density lipoprotein cholesterol, and insulin secretion peripheral nerves). The uniform amelioration of so many of the pathological features associated with t2DM with Hsp induction through nonpharmacologic methods reflects the fundamental role in the initiation and progression of the disease.…”

“…Apoptotic signals, ER stress, and oxidative stress markers were attenuated. Thus, the therapy preserved beta cell function in addition to improving insulin signaling and body composition (Kondo et al 2012). Finally, the same research group directed their attention to insulin-resistant liver cells, HepG2 cells in high glucose medium, by applying heat at 42°C and MES for 10 min.…”

Cellular stress response pathways and diabetes mellitus

“…In addition to the amelioration of glucose tolerance, we reported an improved b-cell function, assessed by endoplasmic reticular (ER) stress markers, apoptosis signals and insulin content, in db/db mice treated with HS ? MES [14]. These reports suggest the possibility of activation of the heat shock response pathway and/or HSP72 induction for the treatment of type 2 diabetes in humans.…”