Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis

Abstract

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 phos-phorylation 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 vas-cular 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. What are HSPs? T he unabated global increase in the prevalence of metabolic syndrome and type 2 diabetes mellitus adds urgency and challenge to researchers and health care providers. New insights are needed in order to treat these progressive , indolent, multi-organ diseases. In this review we propose a previously undescribed progressive cycle that promotes insulin resistance , inflammation, and cell-organ-host vulnerability. Novel elements of the cycle are HSPs, HSF-1, and GSK-3. Heat shock proteins (HSPs) are proteins that

Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

“…Activation of GSK3 is found in a number of degenerative diseases, including AD, Parkinson's disease, Huntington's disease, schizophrenia, and diabetes (10,13). Factors such as excessive caloric diet, hypertension, and aging, which have been associated with deficiency in insulin signaling and higher GSK3 activity, could affect the accumulation of aggregated proteins that are involved in neurodegenerative disorders, such as AD (17).…”

“…Factors such as excessive caloric diet, hypertension, and aging, which have been associated with deficiency in insulin signaling and higher GSK3 activity, could affect the accumulation of aggregated proteins that are involved in neurodegenerative disorders, such as AD (17). Therefore, GSK3 has become an interesting target, since it links aging, metabolic disease, inflammation, protein aggregation, and cell death (13). Because brain GSK3 activity is increased in AD brains, this could have consequences for protein aggregation, A␤ generation, tau phosphorylation, and synaptic loss.…”

“…This is based on evidence that GSK3 phosphorylates protein tau and also amyloid precursor protein (APP), thereby promoting A␤ production (3). GSK3␤ transgenic mice have impaired long-term potentiation (LTP) in CA1, while the induction of LTP appears to decrease kinase activity as indicated by phosphorylation of Ser9 (13,14). In addition, tyrosine phosphorylation of GSK3 is increased in AD transgenic mice early in life by soluble amyloid species (38).…”

GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

“…Although several of the previously studied stressors relevant for GSK-3β activation, such as changes in glucose concentrations and high GDP content, are also known to be major factors of PDF toxicity (Aroeira et al 2007) (Hooper 2007), to our knowledge, there are no data yet on GSK-3β in PD. As a first step, we therefore investigated the activation and expression of GSK-3β in mesothelial cells in an in vitro PD model, established recently by our group in order to study the cellular stress responses upon exposure to PDF (Kratochwill et al 2012).…”

Loss of stress response as a consequence of viral infection: implications for disease and therapy

“…They suggest that PKR activation plays a key role in initiating both type 1 and 2 diabetes, and note that PKR activation in hepatitis C may contribute to the high prevalence of diabetes associated with this infection (Nakamura et al 2010). Relevantly, both types of diabetes are associated with impaired cellular stress response, and are ameliorated by restoration of the stress response (Hooper 2007;van Eden et al 2005;Wieten et al 2010). Therefore we ask: "Is a viral impairment of the cellular stress response a major contributor to the pathogenesis of numerous diverse diseases?…”