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- Title
Endoplasmic Reticulum (ER) Stress Induces Insulin Resistance by Down-regulating IRβ.
- Authors
Zhou, Lijun; Dong, Lily Q.; Liu, Feng
- Abstract
Endoplasmic reticulum (ER) stress plays an important role in causing insulin resistance and type 2 diabetes. However, the underlying molecular mechanisms remain largely unknown. Here we show that treatment of mouse hypatocytes with thapsigargin, which induces ER stress by inhibiting the ER calcium-ATPase, significantly reduced the protein levels of the insulin receptor β subunit (IRβ), leading to impaired insulin signaling to both the PI 3-kinase and the ERK1/2 signaling pathways. The inhibition was specific and thapsigargin treatment had no effect on the expression levels of other insulin signaling molecules such as IRS-1, PDK1, Akt and ERK1/2. Pretreatment of cells with the JNK selective inhibitor SP600125 did not protect ER stress-induced inhibition of insulin signaling, suggesting that activation of JNK, which has been shown to cause insulin resistance by serine phosphorylating IRS-1/2, plays a minimal role in ER stress-induced insulin resistance. Inhibition of proteasome, caspases and lysosome by specific inhibitors did not prevent ER stress-induced down-regulation of IRβ, suggesting a novel mechanism may be involved in ER-stress-induced IRβ reduction. Taken together, our results reveal a molecular mechanism by which ER stress induces insulin resistance and provide a potential strategy for the treatment of insulin resistance and type 2 diabetes.
- Subjects
ENDOPLASMIC reticulum; INSULIN resistance; TYPE 2 diabetes; INSULIN receptors; LYSOSOMES; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA347
- ISSN
0012-1797
- Publication type
Article