Insulin glycogen synthesis

Earner, J., 1990. Insulin and the stimulation of glycogen synthesis The road from glycogen structure to glycogen synthase to cyclic AMP-dependent protein kinase to insulin mediators. Advances in Enzymology 63 173-231. 

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). 

It was discovered nearly 20 years ago that V(V) as vanadate and V(IV) as vanadyl can mimic some of the effects of insulin (stimulate glucose uptake and oxidation and glycogen synthesis) (512, 513). Vanadate is an effective insulin mimetic in the diabetic rat (514), but has proved to be too toxic for human use. Vanadyl, as VOS04, is also unsuitable because high doses are needed on account of its poor oral absorption. Vanadium complexes with organic ligands have proved to be less toxic and can have improved aqueous solubility and lipophil-icity. 

Glucagon stimulation of liver cells in particular leads to phosphorylation of regulatory enzymes whereas insulin has the opposite effect. So, after a meal, we would expect glycolysis and glycogen synthesis to operate very efficiently so the control enzymes will be dephosphorylated. 

Glycogen synthesis is important in two tissues, muscle and liver. In muscle the major factors regulating the rate of synthesis are insulin and the amount of glycogen already present in the muscle. In liver, the major factor is the intracellular concentration of glucose (see below) (Figure 6.19). 

Figure 6.19 Regulation of the synthesis of glycogen from glucose in liver and muscle. Insulin is the major factor stimulating glycogen synthesis in muscle it increases glucose transport into the muscle and the activity of glycogen synthase, activity which is also activated by glucose 6-phosphate but inhibited by glycogen. The latter represents a feedback mechanism and the former a feedforward. The mechanism by which glycogen inhibits the activity is not known. The mechanism for the insulin effect is discussed in Chapter 12.

Figure 12.18 Sites at which insulin stimulates glycogen synthesis in muscle. An increase in the blood glucose level, after a meal, increases secretion of insulin from the p-cells in the Islets of Langerhans. Insulin increases the transport of glucose into the muscle fibre and the activity of glycogen synthase (Chapter 6). The result is that insulin increases the rate of glycogen synthesis without marked changes in concentrations of glucose 6-phos-phate, glucose 1-phosphate or UDP-glucose in the liver.

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

The decreased insulin/glucagon ratio leads to inhibition of glycogen synthesis and increased glycogenolysis to supply some of the body s glucose needs on an immediate basis. 

Insulin simultaneously stimulates glycogen synthesis and inhibits glycogen breakdown. 

Fig. 7.21. Activation of glycogen-bound protein phosphatase I by insulin. Insulin has a stimulating effect on glycogen synthesis by initiating the dephosphorylation and activation of glycogen synthase and the dephosphorylation and inhibition of glycogen phosphorylase. Both enzymes (substrate S in the figure) are dephosphorylated by protein phosphatase PPIG. Insulin mediates the activation of a protein kinase (insulin-sensitive protein kinase) within an insulin-stimulated signal pathway, which phosphorylates and thus activates protein phosphatase PPIG at the PI site.

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