Insulin activity, possible mechanisms

FIGURE 23-35 A possible mechanism for cross-talk between receptors for insulin and leptin. The insulin receptor has intrinsic Tyr kinase activity (see Fig. 12-6), and the leptin receptor, when occupied by its ligand, is phosphorylated by a soluble Tyr kinase (JAK). One possible explanation for the observed interaction between leptin and insulin is that both may phosphorylate the same substrate—in the case shown here, insulin receptor substrate-2 (IRS-2). When phosphorylated, IRS-2 activates PI-3K, which has downstream consequences that include inhibition of food intake. IRS-2 serves here as an integrator of the input from two receptors. 

Gins may. also contribute to the mechanism whereby insulin activates glucose transport in adipocytes and heart. This has been suggested to be a two-step process where the first step involves the recruitment of inactive glucose carriers from an internal vesicle pool to the plasma membrane and the second step involves the activation of the newly inserted carriers in the plasma membrane (vide supra). It is possible that this second step may be controlled by Gins. The reasons for thinking that this may be so are related to observations that, under certain conditions, glucagon... 

The study [83] investigated whether resveratrol can improve nonalcoholic fatty liver disease (NAFLD) and evaluated the possible mechanism. Rats fed a high-fat diet were treated with resveratrol and the liver histology was observed. Hyperinsulinemic euglycemic clamp was performed to assess insulin sensitivity. Fat accumulation was induced in FIepG2 cells, and the cells were treated with RSV. AMP-activated protein kinase phosphorylation levels were detected both in the animal study and cell study. Rats fed a high-fat diet developed abdominal obesity, NAFLD, and insulin resistance, which were markedly improved by 10 week. 

Autophosphorylation of the insulin receptor leads to phosphorylation of insulin receptor substrate (IRS). IRS comes in four different forms (IRS-1, IRS-2, IRS-3 and IRS-4). In muscle tissue, IRS-1 is the most important form for mediating insulin-signal transduction and lRS-1 impairment has been observed in muscle tissue of humans with DM-2 (Glund and Zierath, 2005). lRS-1 has many tyrosine phosphorylation sites. When these sites are phosphorylated by the insulin receptor, multiple insulin signals are enabled (Sun et al., 1993). IRS-1 also has several serine phosphorylation sites phosphorylation of serine residue 1101 results in inhibition of insulin signalling and provides a possible mechanism for IR (Li et al., 2004). After IRS is phosphorylated, it recruits and activates phosphatidylinositol 3-kinase (PI3-kinase). PI3-kinase phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to... 

Other possible mechanisms for insulin action have been proposed. It has been proposed that membrane phosphorylation regulates transport activity across membranes. Thus, if membrane phosphorylation decreases transport, it would be expected that dephosphorylation would enhance transport (Randle and Smith, 1958). However, insulin does not appear to phosphorylate plasma membrane proteins (Avruch et al., 1976b,c). The insulin activation of glucose transport in fat cells has been postulated to involve the oxidation of certain membrane sulfhydryl groups to the disulfide form (Czech, 1977). A rat liver plasma membrane subfraction has been isolated containing cAMP phosphodiesterase activity that could be stimulated by nanomolar amounts of... 

The first insight into the mechanism by which autophosphorylation controls the activity of the Tyr kinase was possible via the crystal structure of the Tyr kinase domain of the human insulin receptor (Hubbard et al., 1994). 

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. 

Our observation that CMC lacked the ability to increase the systemic activity of desmopressin is consistent with the findings of Morimoto et al. (13), who reported that 1% CMC failed to enhance intranasal absorption of insulin, whereas, another bioadhesive agent, polyacrylic acid gel, effectively promoted insulin absorption. As the mechanism by which bioadhesives such as polyacrylic acid gel and carboxypolymethylene promote intranasal peptide absorption remains unclear, it is not possible to explain the demonstrated lack of similar activity by CMC. 

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