The role of heat shock protein 72 in endothelial insulin resistance in type 2 diabetes: using passive heat therapy to improve endothelial insulin responsiveness
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Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) and contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of HSP72 was tested. HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, it was further hypothesized that, in T2D individuals, seven days of passive heat treatment via hot water immersion to waist-level (one hour/day) would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. Contrary to the hypotheses, it was found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling (i.e., activation of Akt), respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving postprandial blood flow in subjects with T2D.
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Ph. D.