Glucagon regulation

Insulin and glucagon regulate gluconeogenesis via changes in cyclic AMP concentration. 

Woodcroft, K.J. and R.F. Novak (1999). The role of phosphatidylinositol 3-kinase, Src kinase, and protein kinase A signaling pathways in insulin and glucagon regulation of CYP2E1 expression. Biochem. Biophys. Res. Commun. 266, 304-307. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Storage and utilization of tissue glycogen, maintenance of blood glucose concentration, and other aspects of carbohydrate metabolism are meticulously regulated by hormones, including insulin, glucagon, epinephrine, and the glucocorticoids. 

Appetite-suppressing. Neuropqrtide modulators and gut hormones with anorexigenic effects are a-melanocortin-stimulating hormone (a-MSH), cocaine- and amphetamine-regulated transcript (CART), glucagon-like peptide-1 (GLP-1), leptin, insulin, oxyntomodulin, pancreatic peptide PP, peptide YY and PYY3 36, and others. 

Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via... 

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.

Lipogenesis is regulated at the acetyl-CoA carboxylase step by allosteric modifiers, phosphorylation/de-phosphorylation, and induction and repression of enzyme synthesis. Citrate activates the enzyme, and long-chain acyl-CoA inhibits its activity. Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. 

Figure 26-4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Asterisk See Figure 18-6.

Discuss functions and factors regulating release of the following hormones thyroid hormones, calcitonin, parathyroid hormone, catecholamines, aldosterone, cortisol, adrenal androgens, insulin, and glucagon... 

When glucagon levels fall, cAMP phosphodiesterase destroys the accumulated cAMP, and specific protein phosphatases remove the phosphate from the phosphoproteins. These phosphatases themselves are often regulated by phosphorylation—yes, there are phosphatase kinases and phosphatase phosphatases. It s really easy to lose it here, but the key factor is that increased glucagon levels lead to increased protein phosphorylation, and decreased glucagon levels lead to decreased protein phosphorylation. 

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. 

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