Infection, traumatic stress, obesity, inactivity, and aging are common physiologic causes of insulin resistance that contribute to various metabolic disorders, including diabetes. Experiments with transgenic mice and clinical investigation reveal that insulin resistance associated with diabetes is usually accompanied by downregulation of IRS-protein expression and function . A common mechanism explaining the occurrence of acute or chronic insulin resistance in people is difficult to identify. Mutations in the insulin receptor are an obvious source of life-long insulin resistance, but these are rare and not necessarily accompanied by P-cell failure [69-72]. Recent experiments with transgenic mice teach us that dysregulation at many steps in the signaling cascade (especially regulatory interactions) might lead to insulin resistance. Elevated activity of protein or lipid phos-phatases, including PTP1B, SHIP2, or PTEN, might be a clinically relevant cause of insulin resistance. Inhibition of these phosphatases by gene knockout or by chemical inhibitors increases glucose tolerance, suggesting that specific phosphatase inhibitors might be useful treatments for diabetes [73-75]; however, modulation of the activity of shared signaling proteins might result in undesirable pheno-types, including activation of signals that promote cancer.
Various cytokines or metabolites promote serine phos-phorylation of the IRS-proteins which inhibits signal trans-duction and causes insulin resistance. Adipose-derived cytokines, especially tumor necrosis factor alpha (TNFa), inhibit signaling by serine phosphorylation of IRS1/IRS2 [76-78]. The signaling cascades regulated by TNFa are complex and involve many branch points, including the activation of various serine kinases and transcription factors that promote apoptosis or proliferation . Inhibition of IkB kinase (IKKP) with high doses of salicylates reverses hyperglycemia, hyperinsu-linemia, and dyslipidemia in obese rodents by sensitizing the insulin signaling pathway [80,81]. Although no physical interaction occurs between IRS-proteins and IKKP, salicy-lates increase insulin-stimulated tyrosine phosphorylation of the IRS-proteins in the liver, suggesting that IKKP might indirectly inhibit insulin receptor function or its coupling to the substrates .
A more direct mechanism to inhibit IRS-protein function might involve activation of the c-Jun N-terminal kinase (JNK) [83-85]. JNK is a prototype stress-induced kinase that is stimulated by many agonists during acute or chronic inflammation. JNK phosphorylates numerous cellular proteins, including IRS1 and IRS2, Shc and Gab1 . A role for JNK during insulin action is compelling, as both IRS1 and IRS2 contain JNK-binding motifs, originally identified
Figure 5 TNFa-induced inhibition of Irs-protein signaling. TNFa binding to TNFR1 results in recruitment of TRAF2/5, RIP1, and FADD through the adapter protein TRADD. TRAF2/5 and RIP1 appear to lead to activation of the protein kinases JNK and IKK. Activated JNK associates with IRS-1 and the JNK-binding LXL motif and promotes phosphorylation of Ser307. Phosphorylation of Ser307 inhibits PTB domain function and inhibits insulin/IGF-stimulated tyrosine phosphorylation and signal transduction. Abbreviations: FADD, Fas-associated death domain protein; IKK, IkB kinase; JNK, c-Jun N-terminal kinase; RIP1, receptor-interacting protein 1; TNFa, tumor necrosis factor a; TNFR1, TNF receptor type 1; TRAF2, TNF-receptor-associated factor 2.
in the JNK-interacting proteins JIP1 and JIP2. This motif mediates the specific association of JNK with IRS1, which promotes serine phosphorylation on the COOH-terminal side of the PTB domain, which inhibits recruitment to the insulin receptor (Fig. 5). Insulin also promotes the binding of active JNK to IRS-proteins, suggesting that it might mediate negative feedback control (Fig. 5).
Degradation of IRS-proteins is also regulated and might contribute to inhibition of insulin signaling. Prolonged insulin stimulation substantially reduces IRS1 and IRS2 protein levels in multiple cell lines, which is blocked by specific inhibitors of the 26S proteasome . These results suggest that proteasome-mediated degradation of IRS2, rather than inhibition of transcription and/or translation of IRS2, determines protein levels and activity of IRS2-mediated signaling pathways . Consistent with this idea, insulin stimulates the ubiquitination of IRS2 . Reduction of IRS2 by ubiquitin/ proteasome-mediated proteolysis in mouse embryo fibrob-lasts lacking IRS1 dramatically inhibits the activation of AKT and ERK1/2 in response to insulin/IGF1; strikingly, proteasome inhibitors completely reverse this inhibition. The activity of the ubiquitin/proteasome system is elevated in diabetes, which might promote degradation of the IRS-proteins and exacerbate insulin resistance [89,90].
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