Glucagon and cAMP

Lu, D., Tamemoto, El., Shibata, El., Saito, I. and Takeuchi, T. (1998) Regulatable production of insulin from primary-cultured hepatocytes Insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin. Gene Ther., 5, 888-895. 

The conversion of oxaloacetate to PEP by PEP-carboxykinase (PEPCK, Eq. 14-43 Fig. 17-20) is another control point in gluconeogenesis. Insulin inhibits gluconeogenesis by decreasing transcription of the mRNA for this enzyme. Glucagon and cAMP stimulate its transcription. The activity of PEP carboxykinase " is also enhanced by Mn + and by very low concentrations of Fe +. However, the enzyme is readily inactivated by Fe " and oxygen. Any regulatory significance is uncertain. 

Campbell, R.M. Scanes, CG. (1987). Growth hormorre inhibition of glucagon- and cAMP-induced lipolysis by chicken adipose tissue in vitro. Proc. Soc. Exp. Biol Med., 184, 456-60. 

Gilboe, D. P., and Nuttall, F. Q., 1978, In vivo glucose-, and glucagon-, and cAMP-induced changes in liver glycogen synthase phosphatase activity, J. Biol. Chem. 253 4078. 

Figure 21-6. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation.The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon (and epinephrine), after increasing cAMP, activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase, probably through an "activator" protein and an insulin-stimulated protein kinase.

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

A few hours after eating, the supply of easily available nutrients has been used up and stores must be mobilized to maintain relatively constant supplies of energy and glucose (Fig. 17-7). Insulin levels drop and glucagon levels rise. Because of the increased glucagon levels, cAMP levels rise and regulated proteins become more phosphorylated. 

Glucagon and insulin are only two of the many hormones that regulate vertebrate metabolism, and cAMP is only one of several so-called second messengers that transduce the hormone signal to the inside of the cell. In the remainder of this chapter we take a comprehensive look at the hormone systems that provide the main mechanisms for regulating energy metabolism and other metabolic activities as well. 

The anabolic hormone insulin has the opposite effect to glucagon and epinephrine. It stimulates the formation of triacylglycerols through decreasing the level of cAMP, which promotes the dephosphorylation and inactivation of hormone-sensitive lipase (Fig. 5). Insulin also stimulates the dephosphorylation of acetyl CoA carboxylase, thereby activating fatty acid synthesis (see Topic K3). Thus fatty acid synthesis and degradation are coordinately controlled so as to prevent a futile cycle. 

The interaction of such hormones as glucagon and epinephrine with their specific receptors increases cellular cAMP levels by activating adenylate cyclase,... 

The enzyme that catalyzes the conversion of PEP to pyruvate is pyruvate kinase. Liver pyruvate kinase is stimulated allosterically by fructose-1,6-diphosphate, AMP, ADP, and glyceraldehyde-3-phosphate. It is inhibited by alanine, ATP, NADH, and, more importantly, by cAMP- and Ca2 calmodulin-controlled phosphorylation. High blood glucagon levels thus inhibit the activities of both PFK II and pyruvate kinase in the liver through phosphorylation. Transcription of pyruvate kinase is also decreased by glucagon and increased by insulin. Muscle pyruvate kinase is not subject to cAMP or Ca2+ regulation. The pyruvate kinase reaction is practically irreversible. 

There is abundant evidence that glucagon elevates cAMP levels in isolated liver parenchymal cells, in perfused liver and in the liver in vivo [58,59], As illustrated in Fig. 2, this occurs rapidly and with concentrations of the hormone [59] within the range found in portal venous blood in vivo i.e., 0.2-2 x 10-10 M. When sufficiently sensitive and accurate methods are employed to measure cAMP, an increase in the nucleotide is consistently observed in situations where the hormone induces metabolic responses [58,59]. However, an increase of only 2- to 3-fold is capable of inducing full stimulation of some major hepatic responses, e.g., phos-phorylase activation (Fig. 2) and gluconeogenesis [58,59]. Since higher concentrations of the hormone can elevate cAMP 10-fold or more [59] it appears that there is considerable receptor reserve for these responses. 

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