Editors' ChoiceMetabolism

Resisting Insulin Is Futile; It Will Only Cause Stress

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Science Translational Medicine  14 Apr 2010:
Vol. 2, Issue 27, pp. 27ec59
DOI: 10.1126/scitranslmed.3001145

A membranous network of tubules—the endoplasmic reticulum—winds its way around inside the cell. Here, protein synthesis and modification take place. When the cell is stressed, the endoplasmic reticulum fills with unfolded or misfolded proteins, a reaction termed the unfolded protein response (UPR). The UPR attenuates protein translation and activates the production of chaperones involved in protein folding through the nuclear translocation of the transcription factor XBP-1. Cellular stress accompanies diabetes and obesity, and both conditions can be ameliorated by alleviating endoplasmic reticulum stress. Phosphoinositide 3-kinase (PI3K), which is made up of catalytic (p110) and regulatory (p85) subunits, is essential for insulin signaling. Two papers published back to back, from Park et al. and Winnay et al., elucidate the interaction between XBP-1 and p85.

Park et al. started by identifying p85 as a protein that binds the XBP-1 transcription factor and increases its nuclear translocation, a process that is positively regulated by insulin signaling. In a genetic model of insulin resistance—the ob/ob mouse—the ability of p85 to bind to and induce nuclear translocation of XBP-1 is severely impaired. These authors were then able to markedly improve the animals’ glucose homeostasis by increasing p85 expression in their livers, which increased nuclear translocation of XBP-1, opening a therapeutic avenue for diabetes and obesity. Winnay et al. also start by demonstrating the binding of p85 to XBP-1 and the nuclear accumulation of XBP-1, albeit by different methods. This group then took advantage of mice in which p85 had been knocked out, which they had generated years earlier, and showed that these mice fail to resolve endoplasmic reticular stress in the liver, leading to increased inflammation. Thus, these two papers complement and confirm each other and establish a molecular pathway through which insulin resistance is linked to endoplasmic reticulum stress. Interference with this link may point to new strategies to combat obesity and type 2 diabetes.

S. W. Park et al., The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nature Med. 28 March 2010 (10.1038/nm.2099). [Abstract]

J. N. Winnay et al., A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box–binding protein-1 to modulate the unfolded protein response. Nature Med. 28 March 2010 (10.1038/nm.2121). [Abstract]

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