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

  • Perspective and Reflection Article
  • Published:
Cell Stress and Chaperones Aims and scope

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.

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Abbreviations

Akt:

Protein kinase B

AMPK:

5′ AMP-activated protein kinase

apo A1:

Apo-lipoprotein A1

ER:

Endoplasmic reticulum

GLUT4:

Glucose transporter type 4

GM3:

Monosialodihexosylganglioside

HSF1:

Heat shock factor 1

HSP:

Heat shock protein

iHSP:

Intracellular heat shock proteins

IRS:

Insulin receptor substrate

mTOR:

Mammalian target of rapamycin

pIKK-β:

Inhibitor of nuclear factor kappa-B kinase subunit beta

pJNK:

Phosphorylated c-Jun N-terminal kinase

PGC1-α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

pps:

Pulses per second

t2DM:

Type 2 diabetes mellitus

V:

Volts

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Acknowledgments

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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Authors and Affiliations

  1. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Philip L. Hooper

  2. Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary

    Gabor Balogh & Laszlo Vigh

  3. Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital of Dallas and University of Texas Southwestern Medical Center, Dallas, TX, USA

    Eric Rivas

  4. Department of Kinesiology, Texas Woman’s University, Denton, TX, USA

    Eric Rivas

  5. Department of Pathology, Wake Forest School of Medicine, Winston–Salem, NC, USA

    Kylie Kavanagh

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  1. Philip L. Hooper
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  2. Gabor Balogh
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  3. Eric Rivas
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  4. Kylie Kavanagh
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  5. Laszlo Vigh
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Correspondence to Philip L. Hooper.

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Hooper, P.L., Balogh, G., Rivas, E. et al. The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes. Cell Stress and Chaperones 19, 447–464 (2014). https://doi.org/10.1007/s12192-014-0493-8

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  • DOI: https://doi.org/10.1007/s12192-014-0493-8

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