Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: Role of p38 MAPK

Abstract

Oxidative stress is characterized as the imbalance between the cellular production of oxidants and cellular antioxidant defenses and contributes to the development of numerous cardiovascular and metabolic disorders, including hypertension and insulin resistance. The effects of prolonged oxidant stress in vitro on the insulin-dependent glucose transport system in mammalian skeletal muscle are not well understood. The current study examined the in vitro effects of low-level oxidant stress (60-90 μM, H2O2) for 4 hr on insulin-stimulated (5 mU/ml) glucose transport activity (2-deoxyglucose uptake) and on protein expression of critical insulin signaling factors (insulin receptor (IR), IR substrates IRS-1 and IRS-2, phosphatidylinositol-3-kinase (PI3-kinase), Akt, and glycogen synthase kinase-3 (GSK-3)) in isolated soleus muscle of lean Zucker rats. This oxidant stress exposure caused significant (50%, p<0.05) decreases in insulin-stimulated glucose transport activity that was associated with selective loss of IRS-1 (59%) and IRS-2 (33%) proteins, increased (64%) relative IRS-1 Ser307 phosphorylation, and decreased phosphorylation of Akt Ser473 (50%) and GSK-3ß Ser9 (43%). Moreover, enhanced (37%) phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was observed. Selective inhibition of p38 MAPK (10 μM A304000) prevented a significant portion (29%) of the oxidant stress-induced loss of IRS-1 (but not IRS-2) protein and allowed partial recovery of the impaired insulin-stimulated glucose transport activity. These results indicate that in vitro oxidative stress in mammalian skeletal muscle leads to substantial insulin resistance of distal insulin signaling and glucose transport activity, associated with a selective loss of IRS-1 protein, in part due to a p38 MAPK-dependent mechanism.

Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes

“…However, in rat testis, decreased levels of IRS2 were observed following exposed to oxidative stress induced by bisphenol A (44). Another study demonstrated IRS2 degradation in muscle cells treated with hydrogen peroxide (45). Our data show that IRS2 levels were not affected by APAP in human and mouse hepatocytes, indicating that IRS2 may be more resistant to degradation compared with IRS1 as reported in primary mouse hepatocytes (30).…”

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

“…Different levels of IRS1 phosphorylation and activation are key processes that modulate insulin signaling in skeletal muscle (29). The molecules involved in the regulation of oxidative stress have been previously associated with differences in IRS1 activation and expression (30,31). Furthermore, JNK phosphorylation is increased in the skeletal muscle of PRDX6 2/2 mice, and augmented JNK activation can lead to the deregulation of IRS1, as has already been reported in insulin-resistant nonobese subjects (32).…”

Oxidative stress programming in a rat model of postnatal early overnutrition — role of insulin resistance

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