Insuhn receptors

M. Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insuhn receptor substrate-2. Mol. Endocrinol., 16, 1612-1628 (2002)... 

Rondinone, C.M. Carvalho, E. Rahn, T. Manganiello, V.C. Degerman, E. Smith, U.P. Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insuhn receptor. J. Biol. Chem., 275, 10093-10098 (2000)... 

Figure 1 Proposed mechanism for the activation of uisulm receptor kinase activity by chromodulin. The inactive form of insuhn receptor (IR) is converted to the active form by binding insulin (I). This triggers a movement of Cr (in the form of Cr-transferrin, Cr-Tf) from the blood into cells, which in turn results in the binding of Cr to apochromodulin (triangle). Finally, holochromoduhn (square) binds to insuhn receptor, further activating the receptor s kinase activity. When the insulin concentration drops, holochromodulin is released from the cell to relieve its effects. (Ref 1. Reproduced by permission of Elsevier)...

Vuori K, Ruoslahti E. Association of insuhn receptor substrate-1 with integrins. Science 1994 266 1576-1578. 

Bruneau C, Staedel-Haig C, Cremel G, Leray C, Beck JP, Hubert P. Influence of lipid environment on insulin binding in cultured hepatoma cells. Biochim. Biophys. Acta 1987 928 287-296. Bruneau C, Hubert P, Waksman A, Beck JP, Staedel-Haig C. Modifications of cellular hpids induce insulin resistance in cultured hepatoma cells. Biochim. Biophys. Acta 1987 928 297-304. Ginsberg BH, Jabour J, Spector AA. Effect of alterations in membrane hpid unsaturation on the properties of the insuhn receptor of Ehrhch ascites cells. Biochim. Biophys. Acta 1982 690 157-164. 

Yamamoto T, Sato T, Mori T, Yamakita T, Hasegawa T, Miyamoto M, Hosoi M, Ishii T, Yoshioka K, Tanaka S, Fujii S. Clinical efficacy of insulin-like growth factor-1 in a patient with autoantibodies to insuhn receptors a case report. Diabetes Res Chn Pract 2000 49(l) 65-9. 

The design and use of insuUn-like molecules acting downstream insuhn receptor might be useful in treating insuhn-resistance states in this context, IPG is a good candidate molecule as an alternative to insuhn treatment The abihty of IPG to mimic insuhn actions is certainly striking. Tab. 6.2 summarises insuhn-hke effects of IPG on both intact ceUs and cellular extracts [2-5, 8, 10, 32, 34, 72-74]. 

In detail, adipocytes from visceral adipose tissue are more resistant to insuhn-induced anti-lipolysis and re-esterification of NEFA than those from leg and non-visceral body fat both in vitro [503, 504] and in vivo [505]. Various functional differences in these ceUs have been identified at the level of the insuhn receptor and the post-receptor insulin signahng cascade [503, 504]. PDE3B involved in hpolysis regulation by insuhn (see above. Fig. 11.7) and protein tyrosine phosphatases de-phosphorylating fhe insuhn receptor, such as PTPlb, could be affected in differen-... 

Several genetic mutations have been described in the insuhn receptor and are associated with insulin resistance. Type A insuhn resistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia. Leprechaunism is a pediatric syndrome with specific facial features and severe insulin resistance due to a defect in the insuhn receptor gene. Lipoatrophic diabetes probably results from postreceptor defects in insulin signaling. 

Insuhn analogs are modified human insuhn molecules, and safety is paramount for FDA approval. Key factors that should be considered in the approval process include local injection reactions, antigeiucity, efficacy compared to human insuhn, insuhn receptor binding affiiuty, and insulin-like growth factor 1-receptor affinity (which is compared to that of human insuhn to determine mitogeiuc potential). 

Hooper NM, Turner AJ (2002) The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease. Curr Med Chem 9 1107-1119 Hoyer S (2004) Glucose metabohsm and insuhn receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490 115-125... 

Heffetz, D. and Zick, Y. (1986). Receptor aggregation is necessary for activation of the soluble insuHn receptor kinase. J. Biol. Chem. 261, 889-894. 

Richardson AE, Hamilton N, Davis W, Brito C, De Leon D. Insuhn-like growth factor-2 (IGF-2) activates estrogen receptor-a and -p via the IGF-1 and the insuhn receptors in breast cancer cells. Growth Factors. 2011 29 82-93. 

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