Receptor insulin

2 THE INSULIN RECEPTOR GENE AND INSULIN RECEPTOR PROCESSING 

The insulin receptor is synthesized as a preproreceptor of 1370 amino acids. The proreceptor (molecular mass 190 kDa on SDS-PAGE) is glycosylated (Kahn, 1985) in the Golgi region, proteolytically cleaved into mature a- and /3-subunits, and inserted in the plasma membrane (Fehlmann et al., 1982) or degraded. The half-life of the insulin receptor was determined to be 7-12 hours (Kahn, 1985). 

4 HOMOLOGY OF INSULIN- AND INSULIN-LIKE GROWTH FACTOR I (IGF-I) 

The insulin and IGF-I receptors are similar in their structure, both being heterotetrameric glycoproteins (a-/3j8-a) (Massague and Czech, 1982). They show high sequence homology particularly in the domain that encodes the tyrosine kinase of the /3-subunit (approx. 80%) (Ullrich et al., 1986). Their 

Insulin binds with high affinity to the a-subunit of its receptor. The exact binding site has, however, not been defined. Syndromes of extreme insulin resistance have revealed several important domains for ligand binding (Fig. 8). 

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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). 

Insulin is composed of two peptide chains covalently linked by disulfide bonds (Figures 5.17 and 6.35). This monomer of insulin is the active form that binds to receptors in target cells. However, in solution, insulin spontaneously forms dimers, which themselves aggregate to form hexamers. The surface of the insulin molecule that self-associates to form hexamers is also the surface that binds to insulin receptors in target cells. Thus, hexamers of insulin are inactive. 

Akt is activated by binding of plasma membrane phospholipids downstream of insulin receptors, growth and survival factor receptors in a phosphoinositide 3-kinases dependent manner. In humans, there are three genes in the Akt family Aktl, Akt2 and Akt3. Their respective fimctions are still under investigation. 

Phospholipid Insulin Receptor Tyrosin Kinases Growth Factors... 

The increase in insulin concentrations produced by sulphonylureas lowers blood glucose concentrations through decreased hepatic glucose output and increased glucose utilisation, mostly by muscle ( insulin, insulin receptor). 

Diabetes Mellitus Insulin Receptor Glucose Transporters ATP-dependent K+Channel PPARs... 

The first hormonal signal found to comply with the characteristics of both a satiety and an adiposity signal was insulin [1]. Insulin levels reflect substrate (carbohydrate) intake and stores, as they rise with blood glucose levels and fall with starvation. In addition, they may reflect the size of adipose stores, because a fatter person secretes more insulin than a lean individual in response to a given increase of blood glucose. This increased insulin secretion in obesity can be explained by the reduced insulin sensitivity of liver, muscle, and adipose tissue. Insulin is known to enter the brain, and direct administration of insulin to the brain reduces food intake. The adipostatic role of insulin is supported by the observation that mutant mice lacking the neuronal insulin receptor (NDRKO mice) develop obesity. 

Incretin Hormones Appetite Control Insulin Receptor... 

Insulin Receptor ATP-dependent K+ Channels Diabetes Mellitus... 

Loss of the cell s responsiveness to the hormone insulin caused by pathological alterations in the insulin receptor signal transduction pathway, and often leading... 

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. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

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

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