Molecular mechanisms of insulin action

Insulin exerts its effects on target organs (liver, muscle, fat) by binding to a cell surface receptor and activating a number of intracellular signaling cascades.7,8 This is an area of intense scientific scrutiny because it is hoped that understanding the mechanism of action of insulin will reveal new drug targets that may be amenable to manipulation by small, nonpeptide agonists. The intracellular signaling cascades activated are, to some extent, tissue specific — one mechanism whereby insulin can have different effects on different organs. Even though a tissue may not possess many insulin receptors, it must also be remembered that insulin can exert an indirect effect by altering the flux of metabolites (e.g., fatty acids) delivered to or extracted from that tissue.9,10

Insulin binds reversibly to cell surface transmembrane receptors that are found in highest concentrations in insulin-sensitive tissues (Figure 1.2). The intracellular region of the insulin receptor possesses tyrosine kinase activity (enzymatic activity adding phosphate groups to tyrosine residues in proteins). Binding of insulin to its receptor is thought to induce a conformational change in the insulin receptor molecule; this increases its tyrosine kinase activity, which then autophos-phorylates multiple tyrosine residues within its intracellular portion.8 Phosphorylated tyrosine residues on the insulin receptor create binding sites for a number of soluble intracellular proteins that attach to the insulin receptor and are phosphorylated by the insulin receptor tyrosine kinase.11 This initial event precipitates the activation of a number of diverging intracellular signaling cascades

* Glycogenolysis is the breakdown of glycogen into glucose; glycogenesis is the formation of glycogen from glucose precursors; gluconeogenesis is the formation of new glucose molecules from substrates such as lactate and amino acids; and glycolysis is the conversion of glucose into other molecules to release energy.

Images Glucose Glut4 Insulin

FIGURE 1.2 Simplified schematic of molecular effectors of insulin action. (IRS — insulin receptor substrate; PI3K — PI-3 kinase; PKC — protein kinase C; PKB — protein kinase B; GLUT4 — insulin-sensitive glucose transporter; GSK3 — glycogen synthase kinase-3; GSynthase — glycogen synthase; P — phosphate groups)

FIGURE 1.2 Simplified schematic of molecular effectors of insulin action. (IRS — insulin receptor substrate; PI3K — PI-3 kinase; PKC — protein kinase C; PKB — protein kinase B; GLUT4 — insulin-sensitive glucose transporter; GSK3 — glycogen synthase kinase-3; GSynthase — glycogen synthase; P — phosphate groups)

involving other tyrosine kinases, serine kinases, and lipid kinases. The principal molecules involved include the lipid kinase PI 3-kinase, protein kinase B, glycogen synthase kinase-3, and certain isoforms of protein kinase C (Figure 1.2).12

Two major endpoints of insulin action are stimulation of glucose uptake into skeletal muscle and adipose tissue, and stimulation of glycogen storage in the liver. Insulin stimulates the translocation of the glucose transporter GLUT4 from an intracellular location up to the plasma membrane in insulin-sensitive tissues, allowing glucose to enter cells down its concentration gradient.1314 This effect of insulin on cellular glucose uptake depends on the upstream signaling molecules PI 3-kinase and protein kinase C.12 The effect of insulin on glycogen synthesis is partly due to PI 3-kinase-dependent inhibition of glycogen synthase kinase-3 (Figure 1.2).12

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