Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance.
Arnold N OnyangoPublished in: Oxidative medicine and cellular longevity (2018)
Insulin resistance (IR), a key component of the metabolic syndrome, precedes the development of diabetes, cardiovascular disease, and Alzheimer's disease. Its etiological pathways are not well defined, although many contributory mechanisms have been established. This article summarizes such mechanisms into the hypothesis that factors like nutrient overload, physical inactivity, hypoxia, psychological stress, and environmental pollutants induce a network of cellular stresses, stress responses, and stress response dysregulations that jointly inhibit insulin signaling in insulin target cells including endothelial cells, hepatocytes, myocytes, hypothalamic neurons, and adipocytes. The insulin resistance-inducing cellular stresses include oxidative, nitrosative, carbonyl/electrophilic, genotoxic, and endoplasmic reticulum stresses; the stress responses include the ubiquitin-proteasome pathway, the DNA damage response, the unfolded protein response, apoptosis, inflammasome activation, and pyroptosis, while the dysregulated responses include the heat shock response, autophagy, and nuclear factor erythroid-2-related factor 2 signaling. Insulin target cells also produce metabolites that exacerbate cellular stress generation both locally and systemically, partly through recruitment and activation of myeloid cells which sustain a state of chronic inflammation. Thus, insulin resistance may be prevented or attenuated by multiple approaches targeting the different cellular stresses and stress responses.
Keyphrases
- insulin resistance
- type diabetes
- metabolic syndrome
- induced apoptosis
- cell cycle arrest
- endoplasmic reticulum stress
- glycemic control
- adipose tissue
- cardiovascular disease
- oxidative stress
- nuclear factor
- cell death
- endothelial cells
- high fat diet
- endoplasmic reticulum
- dna damage response
- high fat diet induced
- heat shock
- skeletal muscle
- polycystic ovary syndrome
- toll like receptor
- depressive symptoms
- signaling pathway
- spinal cord
- dna repair
- mental health
- risk assessment
- small molecule
- coronary artery disease
- heat shock protein
- cognitive decline
- dendritic cells
- acute myeloid leukemia
- inflammatory response
- uric acid
- cancer therapy
- protein protein
- sleep quality
- mild cognitive impairment