Insulin receptor, activation

Yenush L, Fernandez R, Myers MG Jr et al 1996 The Drosophila insulin receptor activates multiple signaling pathways but requires insulin receptor substrate proteins for DNA... 

IRS-l, phosphorylated by the insulin receptor, activates PI-3K by binding to its SH2 domain. PI-3K converts PIP2 to PIP3. 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

Insulin could also promote glycogen synthesis by activating glycogen synthase phosphatase, rather than inactivating glycogen synthase kinase. However, a pathway linking insulin receptor activation to the activation of serine/threonine phosphatases of the PPl type has not yet been identified. 

Vainio S, Bykov I, Hermansson M, et al. (2005) Defective insulin receptor activation and altered lipid rafts in Niemann-Pick type C disease hepatocytes. Biochem J 391(Pt 3) 465 72... 

FIGURE 3.1 Early biochemical steps following insulin receptor activation. Following insulin binding and insulin receptor autophosphorylation and activation, insulin receptor substrates-1 and -2 (IRS-1 and -2) are phosphorylated allowing binding of p85 and pi 10 phosphatidylinositol kinases and the generation of inositol triphosphate (IP3). Source Redrawn from Thirone et al ... 

After insulin binds to insulin receptor on cell surface, insulin receptor and its substrates are phosphorylated, which leads to activation of various insulin signaling pathways [202]. Reynoso et al. [203] evaluated several aspects of the insulin resistance induced by palmitic acid in rats and found that after treatment with 0.09 g/kg of palmitic acid there is a delay in the curve of tolerance to glucose. The authors concluded that occur an increase in the phosphorylations in serine of the insulin receptor after the treatment with palmitate, suggesting that PKC has a role as negative regulator of the insulin receptors activation in the insulin resistance induced by palmitic acid. 

Blondel O, Simon J, Chevalier B, Portha B. 1990. Impaired insulin action but normal insulin receptor activity in diabetic rat Uver effect of vanadate. Am J Physiol 258 E459-E467. 

The studies on the insulin receptor of human lymphocytes led to the development of a sensitive radioreceptor assay which complements the radioimmunoassay in measuring minute quantities of substances in plasma with insulin bioactivity. Using this technique clinically, a patient with a primary defect in insulin receptor deficiency was reported . In the same study, acquired and reversible receptor deficiency was also observed in obese patients . In the obese-hyperglycemic mutant mouse, insulin-resistance appears to correlate directly with an irreversible deficiency in insulin receptor activity on the adipocyte and hepatocyte plasma membranes. Cuatrecasas and his co-workers, on the other hand, reported the same number of insulin-binding sites in adipocytes from obese and insulin-resistant rats as were present in those from normal animals They proposed that the metabolic defect in these animals resides in the coupling of the signals of the insulin-receptor complex to glucose transport. 

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