Abstract
Human survival has relied upon the ability to withstand starvation through energy
storage, the capacity to fight off infection by a proinflammatory immune response,
and the ability to cope with physical stressors by an adaptive stress response. Energy
storage, mainly as glycogen in liver and triglycerides in adipose tissue, is regulated
by the anabolic actions of insulin. On the other hand, mobilization of stored energy
during infection, trauma or stress is served by the temporary inhibition of insulin
action (insulin resistance) in target tissues by proinflammatory cytokines and stress
hormones. In the current environment, high energy intake, low physical activity, and
chronic stress favor the storage of surplus fat in adipose tissue depots that far
exceeds their storage capacity and liporegulation. Lipid overload in central fat depots
initiates an inflammatory response and adipocyte dysfunction with resultant low-grade
systemic inflammation and lipid overflow to peripheral tissues. In turn, proinflammatory
cytokines and non-oxidized lipid metabolites, accumulated in liver and muscle cells,
activate the mechanism of insulin resistance as would occur in the case of infection
or stress. The same factors together with the ensuing insulin resistance further contribute
to pancreatic β-cell dysfunction and ultimately to type 2 diabetes and cardiovascular
disease. The present review supports the hypothesis that insulin resistance evolved
as a physiological adaptive mechanism in human survival and that the same mechanism
is inappropriately activated on a chronic basis in the current environment, leading
to the manifestations of the metabolic syndrome.
Abbreviations:
MS (metabolic syndrome), DM2 (type 2 diabetes mellitus), CVD (cardiovascular disease), TGs (triglycerides), IRS (insulin receptor substrates), PI3K (phosphatidylinositol 3-kinase), Akt/PKB (Protein kinase B), MAPK (mitogen activated protein kinase), JNK (c-Jun amino- terminal kinase, IKK, IκB kinase), nPKC (novel protein kinase C), FFAs (free fatty acids), AMPK (AMP -activated protein kinase), CPT-1 (carnitine palmitoyl transferase-1), TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), PAI-1 (plasminogen activator inhibitor −1), ANG (angiotensinogen), MCP-1 (monocyte chemoattractant protein-1), MIF (macrophage inhibitory factor), LPA (lysophosphatidic acid), PA (phosphatidic acid), DAG (diacylglycerol), DGAT-1 (diacylglycerol acyltransferase-1), ER (endoplasmic reticulum), LTB4 (leukotrienes B4), ATMs (adipose tissue macrophages), TLR4 (toll-like receptor-4), HDL-C (high density lipoprotein-C), HPA (hypothalamic- pituitary adrenal), SNS (sympathetic nervous system), GH (growth hormone), TCF7L2 (transcription factor 7-like 2 (T-cell specific, HMG-box)), PPAR-γ (peroxisome proliferator-activated receptor-γ), VEGF-B (vascular endothelial growth factor-B)Keywords
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Article info
Publication history
Published online: December 20, 2012
Accepted:
November 14,
2012
Received:
August 2,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
