Insulin signaling pathways

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

We have seen that the protein Grb2 in the insulin signaling pathway (Fig. 12-6) binds through its SH2 domain to other proteins that contain exposed (P)-Tyr residues. The human genome encodes at least 87 SH2-containing proteins, many already known to participate in signaling. The (P)-Tyr residue is bound in a deep... 

Saltlel, A.R. Pessln, J.E. (2002) Insulin signaling pathways in time and space. Trends Biochem Sci. 12, 65-71. 

Goldstein, B.J., K. Mahadev, X. Wu, L. Zhu, and H. Motoshima. 2005. Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antiox. Redox Signal. 7 1021-1031. 

S. Giorgetti-Peraldi, F. Peyrade, V. Baron, and E. Van Obberghen. Involvement of Janus Idnases in the insulin signalling pathway EurJ Biochem, 234, 656-660, 1996. 

PTPIB operates in the insulin-signalling pathway. When insulin binds to its receptor, there is a conformational change of intracellular region of the protein, which results in the 0-phosphorylation of three tyrosine residues as the first step in the cascade of the insulin signalling. PTPIB is reckoned to be responsible for the dephosphorylation of the insulin receptor. Dephosphorylation results in the down regulation of the insulin receptor and therefore selective inhibition of PTPIB may enhance insulin activity. 

Fig. 6.3 Insulin signaling pathways. Possible routes through which insulin can promote its diverse biological actions Cell proliferation, gluconeogenesis, lipolysis and glycogen syn-...

The full network of pathways initiated by insulin includes a large number of proteins and is substantially more elaborate than indicated in Figure 14.24. Furthermore, many additional proteins take part in the termination of insulin signaling. A defect in any of the proteins in the insulin signaling pathways or in the subsequent termination of the insulin response could potentially cause problems. Therefore, it is not surprising that many different gene defects can cause type 2 diabetes. 

Systems biology is an area that academics and pharmaceutical companies are rapidly embracing. Systems biology seeks to understand the complex relationships between signaling cascades, transcriptional control, and disease-relevant phenotypes at the cellular and organism levels. Usually these interrelationships are presented as a computational model. For example, a model might be built of the insulin-signaling pathway as a means to better treat diabetes. 

Lake, S., A. Krook, and J. R. Zierath. 2003. Analysis of insulin signaling pathways through comparative genomics. Mapping mechanisms for insulin resistance in type 2 (non-insulin-dependent) diabetes mellitus. Exp Clin Endocrinol Diabetes 111 191-7. 

Saltiel AR, Pessin JE. Insulin signalling pathways in time and space. Trends Cell Biol. 2002 12 65-71. 

A possible link between the effects of Cr(III) and Cr(VI) on carbohydrate metabolism and enzyme activation has been overlooked in the studies of Cr(III) as a nutrient (5). Treatment of rats with large doses of Cr(VI) (Na2Cr20v 20-40 mg kg subcutaneously) induced a severe, but short term, decrease in blood insulin levels (624). A significant insulin-independent stimulation of 3-0-methylglucose uptake by isolated rat adipocytes was achieved in the presence of Na2Cr207 [50-300 pM Cr(VI)] this effect was strictly ATP dependent, which implies a relationship to phosphorylation reactions (625). A detailed study of this effect by Yurkow and Kim (295, 626) showed that treatment of intact rat hepatoma cells with Cr(VI) (100 pM) induced the insulin-independent activation of certain types of protein kinases, which led to increased phosphorylation levels in various proteins these phosphorylated proteins could then participate in insulin signaling pathways. Treatment with Cr(VI) did not affect the insulin-dependent phosphorylation on p-subunits of insulin receptors. Thus, Cr(VI), similar to V(V) (618) but unlike the biologically active Cr(III) complexes (496, 497, 618), acts as an insulin mimetic rather than potentiator. Unlike V(V), however, the action of Cr(VI) resulted from kinase activation rather than... 

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