Lxr

membrane tyrosine — kinase domain

COOH COOH

FIGURE 18 Model of the insulin receptor.

the p-subunit from the inhibitory effects of the a-subunit allowing it to phosphorylate itself and other proteins on tyrosine residues. Autophosphorylation of the kinase domain is required for full activation. Tyrosine phos-phorylation of the receptor also provides docking sites for other proteins that participate in transducing the hormonal signal. Docking on the phosphorylated receptor may position proteins optimally for phosphorylation by the receptor kinase.

Among the proteins that are phosphorylated on tyrosine residues by the insulin receptor kinase are four cytosolic proteins called insulin receptor substrates (IRS-1, IRS-2, IRS-3, and IRS-4). These relatively large proteins contain multiple tyrosine phosphorylation sites and act as scaffolds on which other proteins are assembled to form large signaling complexes. IRS-1 and IRS-2 appear to be present in all insulin target cells, whereas IRS-3 and IRS- 4 have more limited distribution. Despite their names, the IRS proteins are not functionally limited to transduction of the insulin signal, but are also important for expression of effects of other hormones and growth factors. Moreover, they are not the only substrates for the insulin receptor kinase. A variety of other proteins that are tyrosine phosphorylated by the insulin receptor kinase have also been identified. Proteins recruited to the insulin receptor and IRS proteins may have enzymatic activity or they may in turn recruit other proteins by providing sites for protein-protein interactions. The assemblage of proteins initiates signaling cascades that ultimately express the various actions of insulin described earlier. One of the most important of the proteins that is activated is phosphatidylinositol-3 (PI3) kinase. PI3 kinase plays a critical role in activating many downstream effector

41. The Pancreatic Islets molecules including protein kinase B, which is thought to mediate the effects of insulin on glycogen synthesis and GLUT 4 translocation. PI3 kinase, however, is also activated by a variety of other hormones, cytokines, and growth factors whose actions do not necessarily mimic those of insulin. The uniqueness of the response to insulin probably reflects the unique combination of biochemical consequences produced by the simultaneous activity of multiple signaling pathways and the particular set of effector molecules expressed in insulin target cells. Although insulin is known to regulate expression of more than 150 genes, few of the nuclear regulatory proteins that are activated by insulin are known, and precisely how the insulin receptor communicates with these regulatory proteins is unknown. A more detailed discussion of the complex molecular events that govern insulin action can be found in articles listed at the end of this chapter.

Regulation of Insulin Secretion

As might be expected of a hormone whose physiologic role is promotion of fuel storage, insulin secretion is greatest immediately after eating and decreases during between-meal periods (Fig. 19). Coordination of insulin secretion with nutritional state as well as with fluctuating demands for energy production is achieved through stimulation of beta cells by metabolites, hormones, and neural signals. Because insulin plays the primary role in regulating storage and mobilization of metabolic fuels, the beta cells must be constantly apprised of bodily needs, not only with regard to feeding and fasting, but also to the changing demands of the environment. Energy needs differ widely when an individual is at peace with the surroundings and when struggling for survival. Maintaining constancy of the internal environment is achieved through direct monitoring of circulating metabolites by beta cells themselves. This input can be overridden or enhanced by hormonal or neural signals that prepare the individual for rapid storage of an influx of food or for massive mobilization of fuel reserves to permit a suitable response to environmental demands.

Glucose

Glucose is the most important regulator of insulin secretion. In normal individuals its concentration in blood is maintained within the narrow range of about 70 or 80 mg/dL after an overnight fast to about 150 mg/dL immediately after a glucose-rich meal. When blood glucose increases above a threshold value of about 100 mg/dL, insulin secretion increases proportionately. At lower concentrations adjustments in insulin secretion meal meal meal

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