Metabolic syndrome and
type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of
heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In
insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in
insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased
insulin action leading to less phosphorylation of PI3K, PKB, and
glycogen synthase kinase-3 (GSK-3). Importantly, less
GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic
inflammation, raise
islet amyloid polypeptide, and increase
insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption,
hypertension, inactivity, aging, and
genetic predisposition- all of which are a associated with high
GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that
GSK-3 inhibition and Hsp stimulation result in increased
insulin sensitivity, reduced accumulation of degenerative
proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular
ischemia. Recognizing
GSK-3 and Hsps in the pathogenesis of
insulin resistance, the central common feature of the
metabolic syndrome, and
type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.