Reaction with insulin, mechanism

Insulin is capable of producing allergic reactions through a variety of immunologic mechanisms. A protein molecule, insulin is a complete antigen. Allergic reactions have been reported with beef, pork, and recombinant human insulin, although the frequency of reactions with human insulin appears low. Reactions to insulin may involve the insulin molecule itself or other substances that have been added to insulin (e.g., protamine). Most patients have anti-insulin IgG antibodies after a few months of therapy. 

The aquation of [IrCl6]2- to [Er( E120)C1S] and Ir(H20)2Cl4 has been found to activate the complex toward the oxidation of insulin in acidic solutions, with measured rate constant of 25,900 and 8,400 Lmol-1 s 1, respectively.50 The oxidation reaction proceeds via an outer-sphere mechanism. 

It is interesting to note that serine peptidases can, under special conditions in vitro, catalyze the reverse reaction, namely the formation of a peptide bond (Fig. 3.4). The overall mechanism of peptide-bond synthesis by peptidases is represented by the reverse sequence f-a in Fig. 3.3. The nucleophilic amino group of an amino acid residue competes with H20 and reacts with the acyl-enzyme intermediate to form a new peptide bond (Steps d-c in Fig. 3.3). This mechanism is not relevant to the in vivo biosynthesis of proteins but has proved useful for preparative peptide synthesis in vitro [17]. An interesting application of the peptidase-catalyzed peptide synthesis is the enzymatic conversion of porcine insulin to human insulin [18][19]. 

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. 

As work with vanadium compounds and diabetes in cell system has continued, it has become clear that there are also insulin-independent mechanisms at work. One insulin-independent signal transduction pathway appears to be involved in glycogen metabolism reactions in rat adipocytes [137] that also involve PI-3K. A major difference was that only vanadate promoted glycogenesis through the activation of a cytosolic protein tyrosine kinase, which was mediated in an insulin receptor-independent manner. 

Metformin is a biguanide derivative that can normalize an elevated blood glucose level, provided that insulin is present. The mechanism underlying this effect is not completely understood. Decreased glucose release from the liver appears to play an essential part. Metformin does not increase release of insulin and therefore does not promote hyperinsulinemia. The risk of hypoglycemia is relatively less common. Triglyceride concentrations can decrease. Metformin has proved itself as a monotherapeutic in obese type II diabetics. It can be combined with other oral antidiabetics as well as insulin. Frequent adverse effects include anorexia, nausea, and diarrhea. Overproduction of lactic acid (lactate acidosis) is a rare, potentially fatal reaction. It is contraindicated in renal insuf ciency and therefore should be avoided in elderly patients. 

A process by which a substrate protein, usually a receptor, catalyzes selfphosphorylation, usually at a tyrosine residue. The mechanism can be either intramolecular (cis) or intermolecular (trans) although at least one system has been described with both cis and trans processes. See Cobb, M.H., Sang, B.-C., Gonzalez, R., Goldsmith, E., and Ellis, L., Autophosphorylation activates the soluble cytoplasmic domain of the insulin receptor in an intermolecular reaction, J. Biol. Chem. 264, 18701-18706, 1989 Frattali, A.L., Treadway, J.L., and Pessin, J.E., Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular subunit trans- and c A-autophosphorylation and substrate kinase activation, J. Biol. Chem. 267, 19521-19528, 1992 Rim, J., Faurobert, E., Hurley,... 

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