Insulin mitogenic effects

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

In view of the life long exposure and large patient populations, insulins with increased mitogenic effect in relation to the unmodified human insulin in current use were thus considered to constitute a major public health concern. Therefore a thorough assessment of carcinogenic potential was recommended for all new modified insulins in 2001 [64],... 

Tranque, P.A., Calle, R., Naftolin, F. and Robbins, R. (1992) Involvement of protein kinase C in the mitogenic effect of insulin-like growth factor I on rat astrocytes. Endocrinology 131 1948-1954. 

In vitro studies have shown a correlation of metabolic effects to insulin receptor affinity and mitogenic effects with IGF-1 receptor affinity [10], Both short-acting insulin analogues and insulin detemir have a comparable affinity with these receptors as human insulin [10],... 

EGF has been shown to be secreted by platelets, and to stimulate proliferation of VSMC in culture (262). The mitogenic effects of EGF are calcium dependent and are similar to other mitogens such as IGF-I (262). The VSMC proliferative effects of EGF are potentiated by insulin, suggesting that factors such as hypertension and h3rperinsulinemia may be synergistic in promoting the atherogenic process. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

The effects of insulin on transcription are shown on the left of the illustration. Adaptor proteins Crb-2 and SOS ( son of sevenless ) bind to the phosphorylated IRS (insulin-receptor substrate) and activate the G protein Ras (named after its gene, the oncogene ras see p.398). Ras activates the protein kinase Raf (another oncogene product). Raf sets in motion a phosphorylation cascade that leads via the kinases MEK and ERK (also known as MARK, mitogen-activated protein kinase ) to the phosphorylation of transcription factors in the nucleus. 

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