Loss of PDCD4 results in insulin resistance through ER stress

Disruption of the mTOR nutrient complex, which is a crucial evolutionarily-conserved pathway that regulates cellular metabolism and protein translation, produces a cellular stress condition that disrupts the homeostasis of the ER and leads to the accumulation of unfolded proteins in the ER lumen. This accumulation produces a condition known as ER stress. ER stress, through the UPR, produces a tripartite effect within the cell that includes the inhibitory phosphorylation of IRS-1, a decrease in overall protein translation and an increase in the ER\u27s protein-folding capacity. The mTOR nutrient pathway regulates a variety of translational repressors, among which is PDCD4. We have discovered that the loss of functionality of PDCD4 within the cell leads to its inability to switch off protein translation which in turn causes ER stress. The advent of ER stress induces a biochemical cascade that results in JNK activation, insulin resistance and ultimately, Type-II diabetes. Obesity is known to induce ER stress and play a central role in the onset of insulin resistance and Type-II diabetes by triggering JNK activity and inhibiting insulin receptor signaling. To determine the role of ER stress produced by the deletion of PDCD4 in the development of insulin resistance, cells undergoing ER stress were treated with molecules classified as artificial protein-folding chaperones. These molecules are known to protect the cell from ER stress and to facilitate the folding of proteins. The artificial protein-folding chaperone, 4-phenyl butyric acid (PBA) was administered in the course of our investigation to obese mice that were experiencing insulin resistance. The drug-treated mice recovered their insulin sensitivity. These chaperone-treated mice then presented with undetectable levels of ER stress markers and also displayed no detectable JNK activation. Having elucidated the above biochemical mechanism for the development of insulin insensitivity due to the deletion of PDCD4, we have further discovered that the introduction of artificial protein-folding chaperones into animal models deficient in PDCD4 restores full insulin functioning. Thus, these results indicate that existing pharmacological regimens may prove decisive in ameliorating the symptoms of Type-II diabetes that result from ER stress and the hypertranslation of proteins