Glycogen synthetase insulin activation

This study has revealed that 2-azetidinones are effective as antihyperglycemic agents and might act either through increased utilization of glucose or through increased insulin activity or induction of glycogen synthetase enzyme. 

In muscle and adipose tissue, insulin promotes transport of glucose and other monosaccharides across cell membranes it al.so facilitates tran.sport of amino icids, potassium ion.s. nucleosides, and ionic phosphate. Insulin also activates certain enzymes—kinases and glycogen. synthetase in muscle und adipose tissue. In adipose tissue, insulin decreases the release of fatty acids induced by epinephrine or glucagon. cAMP promotes fatty acid release from adipose ti.ssue therefore. it is pos.sible that insulin decreases fatty acid release by reducing tissue levels of cAMP. Insulin also facilitates the incorporation of intracellular amino acids into protein. 

The less active phosphorylated form of glycogen synthetase is dephos-phorylated, causing the enzyme to become active. Insulin causes activation of the phosphatase that catalyzes this reaction. 

Another hormone, namely, insulin, acts in the opposite direction, and produces a rapid rise in glycogen synthetase activity. It has been suggested that insulin acts by changing the glycogen synthetase kinase into a form having a low affinity for cyclic AMP, so that the conversion of the independent into the dependent form (that is, inactivation of the glycogen synthetase) is retarded. 

Similarly, a complex sequence of steps leads to the synthesis of glycogen (see metabolic regulation, Chapter 16). A protein kinase transforms active glycogen synthetase (I form) into an inactive phosphory-lated form (D form). There are also inactive and active forms of the protein kinase the conversion to the active enzyme is cAMP dependent. It is believed that insulin reduces the level of cAMP and thereby inhibits the protein kinase and the glycogen synthetase [200]. 

Raising intracellular levels of cyclic AMP stimulates lipolysis in fat pads and isolated cells (4) probably by activating the triglyceride lipase. The nucleotide also stimulates the conversion of phosphorylase b to phosphorylase in muscle and the conversion of the I form of glycogen synthetase to the D form (5, 6). It thus seemed possible that the inhibitory action of insulin on these processes might be mediated by a fall in tissue levels of cyclic AMP. Accordingly we have examined the effect of insulin on cyclic AMP levels in epididymal fat pads incubated with epinephrine and caffeine in the absence of glucose. 

Insulin Liver Increased glucokinase increased glucose uptake Increased glycogen synthase activity glycogen deposition Inhibited gluconeogenesis Increased malic enzyme, acetyl-CoA carboxylase, fatty acid synthetase and stearoylCoA desaturase increased lipogenesis Release of VLDL from hepatocytes... 

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