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

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

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

Induction of heat shock protein (HSP) 72 improves metabolic profiles in diabetic model mice.However, its impact on pancreatic β-cells is not known. The present study investigated whetherHSP72 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) + mild electricalstimulation (MES) to induce HSP72. Several cellular markers, metabolic parameters and β-cellmass were evaluated.HS+MES treatment or HSP72 overexpression increased the HSP72 protein levels and decreasedTNF-β-induced JNK phosphorylation, ER stress and pro-apoptotic signal in MIN6 cells. In db/dbmice, HS+MES treatment for 12 weeks significantly improved the insulin sensitivity and glucosehomeostasis. Upon glucose challenge, a significant increase in insulin secretion was observed invivo. Compared with sham treatment, the HSP72, insulin, PDX-1, GLUT2 and IRS-2 levels wereupregulated in the pancreatic islets of HS+MES-treated mice, whereas JNK phosphorylation,nuclear translocation of FOXO1 and NF-βB p65 were reduced. Apoptotic signals, ER stress andoxidative stress markers were attenuated.Thus, HSP72 induction by HS+MES treatment protects β-cells from apoptosis by attenuatingJNK activation and cell stresses. HS+MES combination therapy may preserve pancreatic β-cellvolume to ameliorate glucose homeostasis in diabetes