Insulin resistance is a key metabolic abnormality of type 2 diabetes and is characterized by diminished insulin action in skeletal muscle, liver, and adipose tissue. While the precise mechanisms involved in the etiology of insulin resistance are not fully understood, many agree that inflammation and stress kinase activation are central mediators of impaired insulin signal transduction. A primary cellular defense against inflammatory insult includes the rapid synthesis of a family of chaperone proteins known as heat shock proteins (HSPs) through the induction of heat shock transcritpion factor (HSF)-1. Impaired heat shock protein induction in response to cellular stress may contribute to the development of insulin resistance as induction of HSF-1 and the inducible HSP (HSP72) are significantly diminished in patients with impaired glucose tolerance and type 2 diabetes compared with lean healthy subjects. To advance these clinical observations we propose to establish a causal relationship between HSP72 protein expression, inflammation and insulin action. We will achieve this in two specific aims employing experimental manipulations of HSP72 expression by genetic and pharmacologic means.
In Aim 1 we hypothesize that pharmacologic or genetic overexpression of HSP72 will protect against inflammation, insulin resistance, and obesity induced by high fat diet (HFD) or leptin deficiency.
In Aim 2 we hypothesize that genetic ablation of HSP72 or its transcription factor HSF-1 is causal for heightened inflammation, insulin resistance, and susceptibility to the deleterious effects of a HFD. Our preliminary findings show that muscle specific transgenic overexpression of HSP72 suppresses phosphorylation of a key inflammatory marker, c-Jun N-terminal kinase (JNK), and preserves insulin action in the face of HFD. These findings were recapitulated in genetically obese mice administered an HSF-1 co-inducer, BGP-15, which caused a marked increase in skeletal muscle HSP72 levels, blunted JNK activity, and improved insulin sensitivity (as measured by the glucose clamp technique). Furthermore we now provide evidence in this revised application that ablation of HSP72 causes JNK activation, glucose intolerance, insulin resistance and increased adiposity. Based upon these compelling preliminary data we anticipate that the studies outlined in these two aims will show that: (1) HSP72 expression is critical for normal insulin action, (2) HSP72 induction protects against metabolic insults known to cause insulin resistance, and (3) HSP72 is a promising therapeutic target that can be exploited to combat obesity and type 2 diabetes.
Type 2 diabetes afflicts over 24 million Americans and this poses a large healthcare and financial burden on the United States. We intend for our work to provide the foundation for a better understanding of the molecular underpinnings responsible for insulin resistance or "pre-diabetes." We find that an impaired stress protein induction in response to cellular stress is causal for insulin resistance and that pharmacologic strategies to restore stress protein levels can be used clinically to combat insulin resistance and type 2 diabetes.
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