Metabolic pathways figure 60-2 Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation (Y-P) of the receptor's fi subunits and a small number of specific substrates (light blue shapes): the insulin receptor substrate (IRS) proteins, Gab-1 and Shc; within the membrane, a caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosine-phosphorylated proteins interact with signaling cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects of insulin resulting from each pathway. In target tissues such as skeletal muscle and adipocytes, a key event is the translocation of the GLUT4 glucose transporter from intracellular vesicles to the plasma membrane; this translocation is stimulated by both the cave-olar and noncaveolar pathways. In the noncaveolar pathway, the activation of PI3K is crucial, and PKB/Akt (anchored at the membrane by PIP3) and/or an atypical form of PKC is involved. In the caveolar pathway, the caveolar protein flotillin localizes the signaling complex to the caveola; the signaling pathway involves series of SH2 domain interactions that add the adaptor protein CrkII, the guanine nucleotide exchange protein C3G, and small GTP-binding protein, TC10. The pathways are inactivated by specific phosphoprotein phosphatases (e.g., PTB1B) and possibly by actions of Ser/Thr protein kinases. In addition to the actions shown, insulin also stimulates the plasma membrane Na+,K+-ATPase by a mechanism that is still being elucidated; the result is an increase in pump activity and a net accumulation of K+ in the cell.
abbreviations: APS, adaptor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator of kinase II; GLUT4, glucose transporter 4; Gab-1, Grb-2 associated binder; MAP kinase, mitogen-acti-vated protein kinase; PDK, phosphoinositide-dependent kinase; PI3 kinase, phosphatidylinositol-3-kinase; PIP3, phos-phatidylinositol trisphosphate; PKB, protein kinase B (also called Akt); aPKC, atypical isoform of protein kinase C; Y, tyrosine residue; Y-P, phosphorylated tyrosine residue.
Some effects of insulin occur within seconds or minutes, including the activation of glucose and ion transport systems, the covalent modification of enzymes (i.e., phosphorylation or dephospho-rylation), and some effects on gene transcription (i.e., inhibition of the phosphoenolpyruvate carboxykinase gene). Effects on protein synthesis and gene transcription require hours, while those on cell proliferation and differentiation may take days.
regulation of glucose transport Stimulation of glucose transport into muscle and adipose tissue is a key response to insulin. Glucose enters cells by facilitated diffusion through one of a family of five glucose transporters, GLUTs 1-5, that mediate Na+-independent facilitated diffusion of glucose into cells. Insulin stimulates glucose transport by promoting translocation of intracellular vesicles that contain the GLUT4 and GLUT1 glucose transporters to the plasma membrane (Figure 60-2). The transporters return to the intracellular pool on removal of insulin.
regulation of glucose metabolism The facilitated diffusion of glucose into cells down a concentration gradient is ensured by glucose phosphorylation. The conversion of glucose to glucose-6-phosphate (G-6-P) is accomplished by one of a family of hexokinases. Hexokinase IV, or glucokinase, is coexpressed with GLUT2 in liver and pancreatic 3 cells and is regulated by insulin. Hexokinase II is found in association with GLUT4 in skeletal and cardiac muscle and in adipose tissue, and also is regulated transcriptionally by insulin.
G-6-P is a branch-point substrate that can enter several pathways. Following isomerization to G-1-P, G-6-P can be stored as glycogen (insulin enhances the activity of glycogen synthase); G-6-P can enter the glycolytic pathway (leading to ATP production); and G-6-P can also enter the pentose phosphate pathway (providing NADPH). Effects of insulin on cellular metabolic enzymes are myriad and generally are mediated by modulating activities of protein kinases and phosphoprotein phosphatases. Figure 60-2 depicts the signaling events following the binding of insulin to its membrane receptor.
regulation of gene transcription A major action of insulin is the regulation of transcription of more than 100 specific genes. Insulin inhibits the transcription of phosphoenolpyruvate carboxykinase, contributing to insulin's inhibition of gluconeogenesis; this effect of insulin may explain why the liver overproduces glucose in the insulin-resistant state that is characteristic of type 2 DM.
the insulin receptor Insulin initiates its actions by binding to its cell-surface receptor. Insulin receptors are present in virtually all cells, including not only the classic targets for insulin action (i.e., liver, muscle, and fat) but also nonclassic targets such as circulating blood cells, neurons, and gonadal cells.
The insulin receptor is a transmembrane glycoprotein composed of two 135 kDa a subunits and two 95 kDa 3 subunits; the subunits are linked by disulfide bonds to form a fi-a-a-fi heterotetramer (Figure 60—2). Both subunits are derived from a single-chain precursor molecule that contains the entire sequence of the a and 3 subunits separated by a processing site consisting of four basic amino acid residues. The a subunits are entirely extracellular and contain the insulin-binding domain, whereas the 3 subunits are transmembrane proteins that possess tyrosine protein kinase activity. After insulin is bound, receptors aggregate and are internalized rapidly. Since bivalent (but not monovalent) anti-insulin receptor antibodies cross-link adjacent receptors and mimic the actions of insulin, it has been suggested that receptor dimerization is essential for signal trans-duction. After internalization, the receptor may be degraded or recycled back to the cell surface.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...