Hooper Philip L, Balogh Gabor, Rivas Eric, Kavanagh Kylie, Vigh Laszlo
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,
Cell Stress Chaperones. 2014 Jul;19(4):447-64. doi: 10.1007/s12192-014-0493-8. Epub 2014 Feb 13.
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.
生物体已经进化到能够在恶劣环境中生存，但并不适应在热量过剩和久坐不动的世界中茁壮成长。认识到体育锻炼（或缺乏锻炼）在2型糖尿病（T2DM）的发病机制和治疗中都起着关键作用，引发了治疗性运动模拟物这一引人深思的概念。十年前，我们试图通过让T2DM患者每天浸泡在热水浴缸中诱导3周的高热来模拟运动的有益效果。这种短期干预取得了显著成功，糖化血红蛋白（HbA1）下降了1%，有体重减轻的趋势，并且糖尿病神经病变症状有所改善。运动和高热有益效果的一种解释集中在它们诱导细胞应激反应（热休克反应）和恢复细胞内稳态的能力上。应激反应受损先于与T2DM相关的主要代谢缺陷，并且可能是该疾病发病机制中的一个近乎关键的事件，使健康与疾病之间的平衡发生倾斜。热休克蛋白诱导剂与运动共享与AMPK、PGC1-α和沉默调节蛋白激活相关的代谢途径。无论是通过热、生物活性化合物还是基因操作来诱导应激反应的糖尿病治疗方法，都能改善或预防与该疾病相关的所有发病率和合并症。这些药物可降低胰岛素抵抗、炎症细胞因子、内脏脂肪和体重，同时增加线粒体活性，使膜结构和脂质组成正常化，并保护器官功能。恢复应激反应的治疗方法可以使平衡从疾病状态重新恢复到健康状态，并解决与该疾病相关的多方面缺陷。
