Insulin glutathione

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

Kaji, H., Kurasaki, M., Ito, K., Saito, T., Saito, K., Niioka, T., Kojima, Y., Ohsaki, Y., Ide, H., Tsuji, M., Kondo, T. and Kawakami, Y. (1985). Increased lipoperoxide value and glutathione peroxidase activity in blood plasma of type II (non-insulin-dependent) diabetic women. Klin. Wochenschr. 63, 765-8. 

Morimoto et al. [33] demonstrated that the ocular absorption of hydrophilic compounds over a wide range of molecular weights could be increased by 2 and 10 mM sodium taurocholate and sodium taurodeoxycholate in a dose-dependent manner. The compounds were glutathione (307 Da), 6-carboxyfluorescein (376 Da), FTTC-dextran (4 kDa), and insulin (5.7 kDa). Of the two bile salts, sodium taurodeoxycholate was more effective. At 10 mM, this bile salt increased the permeability of 6-carboxyfluorescein from 0.02% to 11%, glutathione from 0.08% to 6%, FITC-dextran from 0% to 0.07%, and insulin from 0.06% to 3.8%. Sodium taurocholate, on the other hand, increased the permeability to 0.13%, 0.38%, 0.0011%, and 0.14%, respectively. Taurodeoxycholate was more effective than taurocholate in the nasal epithelium as well [202], This difference in activities can possibly be attributed to their micelle-forming capability, which is higher for taurodeoxycholate, a dihydroxy bile salt [190],... 

Immobilized dihydrolipoamide (thioctic acid) (Gorecki and Patchornick, 1973 Gorecki and Patchornick, 1975) and immobilized N-acetyl-homocysteine thiolactone (Eldjarn and Jellum, 1963 Jellum, 1964) are the two most commonly used immobilized disulfide reductants. In addition, immobilized TCEP provides a reducing matrix that is free of thiols (Thermo Fisher). Such immobilized reductants successfully can be used to reduce many types of biological disulfides, including small molecules like oxidized glutathione and bovine insulin. They... 

At present, antioxidants are extensively studied as supplements for the treatment diabetic patients. Several clinical trials have been carried out with vitamin E. In 1991, Ceriello et al. [136] showed that supplementation of vitamin E to insulin-requiring diabetic patients reduced protein glycosylation without changing plasma glucose, probably due to the inhibition of the Maillard reaction. Then, Paolisso et al. [137] found that vitamin E decreased glucose level and improved insulin action in noninsulin-dependent diabetic patients. Recently, Jain et al. [138] showed that vitamin E supplementation increased glutathione level and diminished lipid peroxidation and HbAi level in erythrocytes of type 1 diabetic children. Similarly, Skyrme-Jones et al. [139] demonstrated that vitamin E supplementation improved endothelial vasodilator function in type 1 diabetic children supposedly due to the suppression of LDL oxidation. Devaraj et al. [140] used the urinary F2-isoprostane test for the estimate of LDL oxidation in type 2 diabetics. They also found that LDL oxidation decreased after vitamin E supplementation to patients. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

There is a correlation between the backbone conformations which commonly flank disulfides and the frequency with which disulfides occur in the different types of overall protein structure (see Section III,A for explanation of structure types), although it is unclear which preference is the cause and which the effect. There are very few disulfides in the antiparallel helical bundle proteins and none in proteins based on pure parallel /3 sheet (except for active-site disulfides such as in glutathione reductase). Antiparallel /3 sheet, mixed /8 sheet, and the miscellaneous a proteins have a half-cystine content of 0-5%. Small proteins with low secondary-structure content often have up to 15-20% half-cystine. Figure 52 shows the structure of insulin, one of the small proteins in which disulfides appear to play a major role in the organization and stability of the overall structure. 

This enzyme [EC 1.8.4.2], also known as glutathione insulin transhydrogenase and insulin reductase, catalyzes the reaction of two glutathione with a disulfide bond in a protein to produce glutathione disulfide and a protein with two new thiol groups. The enzyme can reduce insulin and a number of other proteins. 

Insulin is removed from the circulation by the liver and the kidney. The disulfide connections between the A and B chains are hydrolyzed through the action of glutathione insulin trans-hydrogenase. After this cleavage further degradation occurs by proteolysis. In patients treated with subcutaneous insulin injections the clearance by the liver is 40% and by the kidney 60%. The half-life of circulating insulin is 3-5 min. 

The oxidation state of cysteine in peptides such as glutathione may easily be recognized by the downfield shift of the signal of Cp in the cysteine residue upon oxidation from — CH2SH to -CH2-S-S- [89,790], The signal of the CH2 S-S-CH2- moiety at 41.6 ppm is also recognized in the spectra of oxytocin, vasopressin and insulin [790],... 

Glutathione helps to maintain the sulfhydryl groups of proteins in a reduced state. An enzyme, protein-disulfide reductase, catalyzes sulfhydryl disulfide interchanges between glutathione and proteins. The reductase is important in insulin breakdown and may catalyze the reassortment of disulfide bonds during polypeptide chain folding. 

It has been proposed that GTF is related to a dinicotinatotris(amino acid)chromium(III) complex, which forms a ternary complex at the membrane receptor with insulin. Porcine insulin binds a Cr(nic)2(glutathione) complex very tightly. 

Tomizawa HH. Properties of glutathione insulin trans-hydrogenase from beef liver. J Biol Chem 1962 237 3393-6. 

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