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

Cardiac response to pressure overload in the rat: The selective alteration of in vitro directed RNA translation products

As cardiac hypertrophy develops, total cardiac RNA and protein synthesis increase significantly. We have identified specific messenger RNAs that change in predominance with the induction of pressure-overload-stimulated cardiac hypertrophy. Total cardiac RNA was isolated from rats either undergoing cardiac hypertrophy secondary to subdiaphragmatic aortic constriction or subjected to sham surgery. The products translated in vitro were separated by two-dimensional gel electrophoresis and quantitated. The translation of four proteins decreased while the translation of four others increased in preparations from hypertrophied hearts compared with those from sham-treated rats. Two isoforms of creatine kinase M were translated in vitro. Only one of these isoforms decreased with cardiac hypertrophy, suggesting that the transcriptional or translation control for creatine kinase is much more complex than previously believed. Finally, since only eight of over 700 different translation products change in relative predominance with cardiac hypertrophy, we conlude that the accumulation of existing RNA and protein products is the primary adaptive process responsible for cardiac hypertrophy.link_to_subscribed_fulltex