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

Abstract

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.

Fig. 1

Ventral aspect of high fat-fed mice sham-treated (control) or treated with heat shock and mild electrical stimulation [42 °C electrodes and 12 V direct current (55 pps of 0.1 ms duration) 10 min, two times per week] after 15 weeks of treatment with exposed peritoneal cavity, showing decrease in visible adipose tissues in treated mice. The diet induced t2DM phenotype is normalized by therapy [from open access journal, Plos1 (Morino et al. 2008)]. Similarly, but not shown here, heme oxygenase stimulation with cobalt protoporphyrin in the Zucker fat rat alters the t2DM phenotype to a thin, smaller rat (Nicolai et al. 2009)

Fig. 2

Exercise, heat shock, and the multitarget, membrane-interacting HSP inducers (like hydroximic acid derivatives) can activate many of the same metabolic pathways. These activators increase insulin receptor auto-phosphorylation, block JNK’s inhibitory phosphorylation of insulin receptor, increase Akt phosphorylation, activate mTOR, activate ras-related C3 botulinum toxin substrate 1 (RAC1), increase GLUT4 translocation and increase glucose uptake, increase second messenger H₂O₂, remodel membranes, increase AMPK, decrease HSF-1 acetylation, deactivates glycogen synthase kinase (GSK) inhibition of HSF-1, increase activation of HSF-1, inhibit poly ADP ribose polymerase (PARP), increase mitochondrial biogenesis and function, increase HSPs that restores stress resilience and organ survival—beta-cell, heart, liver kidney, retina, skin, etc., increase occludin expression and tight junction barrier function, activate the heat sensor transient receptor potential (TRP) that releases calcium as a second messenger to ultimately activate HSF1 and PGC1-α to increase mitochondrial function and synthesis (Dokladny et al. ; Crul et al. ; Török et al. 2013)

Fig. 3

HSP induction addresses the diverse pathological complications of t2DM