Cell Stress and Chaperones

, Volume 19, Issue 4, pp 447–464 | Cite as

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

  • Philip L. HooperEmail author
  • Gabor Balogh
  • Eric Rivas
  • Kylie Kavanagh
  • Laszlo Vigh
Perspective and Reflection Article


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.



Protein kinase B


5′ AMP-activated protein kinase

apo A1

Apo-lipoprotein A1


Endoplasmic reticulum


Glucose transporter type 4




Heat shock factor 1


Heat shock protein


Intracellular heat shock proteins


Insulin receptor substrate


Mammalian target of rapamycin


Inhibitor of nuclear factor kappa-B kinase subunit beta


Phosphorylated c-Jun N-terminal kinase


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


Pulses per second


Type 2 diabetes mellitus





The authors thank Paul Hooper, Annie Hooper, and Chassidy Glaze for proof reading; Alistair Nunn and Michael Tytell for sharing ideas; and Paige Geiger, Anisha Gupte, Dan Kemp, Hirofumi Kai, and Tatsuya Kondo for research efforts.


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Copyright information

© Cell Stress Society International 2014

Authors and Affiliations

  • Philip L. Hooper
    • 1
    Email author
  • Gabor Balogh
    • 2
  • Eric Rivas
    • 3
    • 4
  • Kylie Kavanagh
    • 5
  • Laszlo Vigh
    • 2
  1. 1.Division of Endocrinology, Metabolism and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Institute of Biochemistry, Biological Research CenterHungarian Academy of SciencesSzegedHungary
  3. 3.Institute for Exercise and Environmental MedicineTexas Health Presbyterian Hospital of Dallas and University of Texas Southwestern Medical CenterDallasUSA
  4. 4.Department of KinesiologyTexas Woman’s UniversityDentonUSA
  5. 5.Department of PathologyWake Forest School of MedicineWinston–SalemUSA

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