Insulin response element

Several insulin-responsive ds-acting gene elements have been identified, referred to as insulin response elements (IREs). The problem is, that the IREs include so many common targets, such as the serum response element (SRE) and immediate early genes, controlled by many growth factors. Thus, activation of these genes is not specific for insulin. 

Figure 16.31. The Promoter of the Phosphoenolpyruvate Carhoxykinase Gene. This promoter is approximately 500 bp in length and contains regulatory sequences (response elements) that mediate the action of several hormones. IRE, insulin response element GRE, glucocorticoid response element TRE, thyroid hormone response element CREI and CREII, cAMP response elements. [After M. M. McGrane, J. S Jun, Y. M. Patel, and R. W. Hanson. Trends Biochem. Sci. 17(1992) 40.]...

This promoter is approximately 500 bp in length and contains regulatory sequences (response elements) that mediate the action of several hormones. Abbreviations IRE, insulin response element GRE, glucocorticoid response element TRE, thyroid hormone response element CREI and CREII, cAMP response elements. 

Moustaid, N., Beyer, R. S. and Sul, H. S., Identification of an insulin response element in the fatty acid synthase promoter, J Biol Chem 269 (1994) 5629-5634. 

H.F. Zhao, J.A. Gustafsson et al. (1998). IRE-ABP (insulin response element-A binding protein), an SRY-like protein, inhibits C/EBPalpha (CCAAT/ enhancer-binding protein alpha)-stimulated expression of the sex-specific cytochrome P450 2C12 gene. Mol. Endocrinol. 12, 1294-1309. 

If beta cells are incubated in media containing 2 mM glucose and then treated with forskolin and/or tolbutamide, there is a small transient increase in insulin secretion. The subsequent addition of CCK8S leads to a very marked first phase of insulin secretion, but causes no sustained increase or second phase of insulin secretion. These results mean that an increase in cAMP alters the Ca2+ sensitivity of the response elements underlying the first phase of secretion. These elements, presumed to be Ca2+-calmodulin-dependent processes including CaM-dependent protein kinases, become more sensitive to activation by Ca2+ either because cAMP acts to enhance the sensitivity of CaM-dependent kinases to Ca2+, or because cAMP inhibits, by an unknown mechanism, the activity of phosphoprotein phosphatases. 

For extended operation, insulin release systems will need to require many times the lethal dose of insulin. Therefore, in addition to failure of the responsive element, there is a signihcant risk associated with accidental release resulting from a mechanical failure. This requires careful consideration of the mechanical design of a unit intended to operate as an implant. 

Halofenic acid is a SPPARM that functions primarily as a partial agonist characterized by the differential recruitment of PPAR cofactors, i.e. displacement of corepressors [NCoR and silencing mediator for retinoid and thyroid receptors (SMRT)] and inefficient recruitment of coactivators [cAMP response element binding protein (CREB) binding protein (CBP) and TRAP220] [73]. When dosed orally to diabetic mice and rats as the acetamidoethyl ester, halofenic acid produces insulin sensitization comparable to rosiglitazone without increases in body weight. 

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