Insulin receptor effects

Metabolic Functions. Chromium (ITT) potentiates the action of insulin and may be considered a cofactor for insulin (137,138). In in vitro tests of epididymal fat tissue of chromium-deficient rats, Cr(III) increases the uptake of glucose only in the presence of insulin (137). The interaction of Cr(III) and insulin also is demonstrated by experimental results indicating an effect of Cr(III) in translocation of sugars into ceUs at the first step of sugar metaboHsm. Chromium is thought to form a complex with insulin and insulin receptors (136). 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

Insulin Receptor. Table 1 The effect of insulin on energy and glucose homeostasis... 

Vanadate (sodium orthovanadate or peroxovanadate) exhibits insulin-like effects in vitro (activation of insulin receptor tyrosine kinase, PI 3-kinase, Akt) and in vivo (diabetic rats, humans). These effects can be explained at least in part by the inhibition of phosphotyrosine phosphatases which deactivate the INSR tyrosine kinase. 

Weiland M, Brandenburg C, Brandenburg D et al (1990) Antagonistic effects of a covalently dimerized insulin derivative on insulin receptors in 3T3-L1 adipocytes. Proc Natl Acad Sci USA 87 1154-1158... 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

Bryant The work published on the mammalian insulin receptor shows that glycosylation is required for function. There is a mutagenesis study showing that there is a particular Asp residue, without which the receptor is expressed on the membrane but doesn t function (Leconte et al 1994). In other studies the biosynthesis of the oligosaccharides has been inhibited, and this has the same kind of effect (Podskalny et al 1984). 

Although many cells in the body express the insulin receptor, its most important targets are skeletal muscle fibres, hepatocytes and adipocytes, where it often antagonizes the effects of... 

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)...

Design concepts are now being applied more effectively to mineral supplements. For example, by controlling the redox potential of iron, toxic effects associated with excess Fe(II) during parental supplementation can be avoided. Peroxovanadate complexes can inhibit insulin-receptor-associated phosphotyrosine phosphatase and activate insulin receptor kinase, and both V(IV) and V(V) offer promise as potential insulin mimics. 

An important question arises about the effects of phospholipid composition and the function of membrane-bound enzymes. The phospholipid composition and cholesterol content in cell membranes of cultured cells can be modified, either by supplementing the medium with specific lipids or by incubation with different types of liposomes. Direct effects of phospholipid structure have been observed on the activity of the Ca2+-ATPase (due to changes in the phosphorylation and nucleotide binding domains) [37]. Evidence of a relationship between lipid structure and membrane functions also comes from studies with the insulin receptor [38]. Lipid alteration had no influence on insulin binding, but modified the kinetics of receptor autophosphorylation. 

A challenge posed to researchers was therefore to account for diverse physiological effects emanating from the same receptor/hormone interaction. Structurally, the insulin receptor (IR) is a tetrameric protein, composed of two smaller extracellular a units and two larger transmembrane [3 units (see Figure 4.20a). 

Another form of diabetes is non-insulin-dependent diabetes mellitus (NIDDM, or adult diabetes, or type II diabetes). In this case, insulin is produced and a normal insulin level is detected in blood. But for various reasons its effect is reduced. This may be caused by a reduced number of insulin receptors on cells, or reduced effectiveness in binding to these receptors. The cause is complex and may involve genetic make-up, changes in lifestyle, nutritional habits, and environmental factors. 

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. 

IGFs induce their characteristic effects by binding to specific receptors present on the surface of sensitive cells. At least three receptor types have been identified the IGF-1 receptor, the IGF-2 receptor and the insulin receptor. As is evident from Table 7.4 (with one important exception), IGF-1, IGF-2 and insulin can bind the three receptor types, but with varying affinities. This renders delineation of which factor is inducing any one characteristic effect quite difficult. 

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