Cell Stress and Chaperones

, Volume 19, Issue 4, pp 447–464

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

Authors

    • Division of Endocrinology, Metabolism and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Gabor Balogh
    • Institute of Biochemistry, Biological Research CenterHungarian Academy of Sciences
  • Eric Rivas
    • Institute for Exercise and Environmental MedicineTexas Health Presbyterian Hospital of Dallas and University of Texas Southwestern Medical Center
    • Department of KinesiologyTexas Woman’s University
  • Kylie Kavanagh
    • Department of PathologyWake Forest School of Medicine
  • Laszlo Vigh
    • Institute of Biochemistry, Biological Research CenterHungarian Academy of Sciences
Perspective and Reflection Article

DOI: 10.1007/s12192-014-0493-8

Cite this article as:
Hooper, P.L., Balogh, G., Rivas, E. et al. Cell Stress and Chaperones (2014) 19: 447. doi:10.1007/s12192-014-0493-8

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.

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

Copyright information

© Cell Stress Society International 2014