Insulin resistance inflammatory hypothesis

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Which aspect of the inflammatory state results in insulin resistance? The first of these potential mechanisms was described by Hotamisligil et al., who demonstrated that TNFa induced serine phosphorylation of IRS-1 which in turn caused the serine phosphorylation of the insulin receptor. This prevented the normal tyrosine phosphorylation of the insulin receptor and thus interfered with insulin signal transduction.55 IL-6 and TNFa have recently been shown to induce suppressor of cytokine signaling-3 (SOCS-3).5657 This protein was hitherto thought to interfere with cytokine signal transduction but is now also known to interfere with tyrosine phosphorylation of the insulin receptor and insulin receptor sub-strate-1 (IRS-1) and cause ubiquitination and proteosomal degradation of IRS-1.58 This in turn reduces the activation of Akt (protein kinase B) which normally causes the translocation of the Glut-4 insulin-responsive glucose transporter to the plasma membrane. It also induces the phosphorylation of the nitric oxide synthase (NOS) enzyme and its activation to generate NO.59

A newly described protein known as TRB3 has also been shown to interfere with the activation of Akt and thus to interfere with insulin action.60 However, the association of TRB3 with inflammatory mechanisms has not been demonstrated.

Recent data indicate that Akt2, a key protein involved in insulin signal transduction that mediates the phosphorylation and activation of e-NOS and NO secretion, also prevents the mobilization of Rac-1 to cell membranes, thus preventing superoxide generation. Superoxide generation is dependent upon the translocation of essential elements of NADPH oxidase (e.g., p47phox) from the cytosol to the membrane. This is mediated by Rac.61 In the absence of Akt2, there will be an increase in the translocation of Rac-1 to the membrane, greater formation of NADPH oxidase complex, increased superoxide generation, and oxi-dative stress. It has been shown that Akt2 null mice develop insulin resistance and mild hyperglycemia in association with hyperinsulinemia.62

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