Glucagon fasting state

In the GI tract, different hydrodynamic conditions are present, depending on the fasted or the fed state. Contraction patterns are controlled in terms of electromechanical impulses (myoelectric activity) as well as by various hormones (cholecystokinin, secretin, glucagon, motilin, and insulin, for example). In the fasted state, the motility pattern is regulated by the (interdigestive) migrating myoelectric complex [(I)... 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

Fatty add synthetase is not controlled directly by phosphorylation however, insulin, glucagon, and thyroxine have an effect on its activity by controlling its cellular concentration. Both insulin and thyroxine increase the biosynthesis of the enzyme, whereas glucagon is inhibitory. Thyroxine and glucagon appear to regulate the biosynthesis at the transcription level, whereas insulin affects the enzyme activity at the translation level. It has no effect on cellular fatty add synthetase mRNA concentration. In summary, fatty add synthetase levels are up in the fed state and down in the fasting state. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

The level of insulin in the blood increases in the fed state and promotes fuel storage the level of glucagon increases in the fasting state and promotes the release of stored fuel. 

PFK2 is phosphorylated in the fasting state (when glucagon is elevated) by protein kinase A, which is activated by cAMP. 

D. The low body weight and fat mass observed in the patient are consistent with a metabolically fasted state. During such a condition, circulating insulin levels will be low, whereas counterregulatory hormones (e.g., glucagon, epinephrine, and cortisol) will be elevated. 

Thus, in addition to hormonal effects (see here), the liver senses the fed state and acts to store fuel derived from glucose. The liver also senses the fasted state and increases the synthesis and export of glucose when blood glucose levels are low. (Other organs also sense the fed state, notably the pancreas, which adjusts its glucagon and insulin outputs accordingly.)... 

F. 33.25. Mobilization of adipose triacylglycerol (TG). In the fasted state, when insulin levels are low and glucagon is elevated, intracellular cAMP increases and activates protein kinase A, which phosphorylates hormone-sensitive lipase (HSL). Phosphorylated HSL is active and initiates the breakdown of adipose TG. Recall, however, that re-esterification of fatty acids does occur, along with glyceroneogenesis, in the fasted state. HSL is also called triacylglycerol lipase. FA = fatty acid. 

The liver synthesizes fatty acids in the fed state, and oxidizes them in the fasting state. The direction of metabolic flux (lipogenesis or lipolysis) is controlled both in response to insulin and glucagon and also by intracellular concentrations of substrates. 

Even though AMP, not cAMP, may be the protein kinase activator, glucagon causes its activation and insulin, inactivation. Details on such hormone effects are lacking. Also recall that malonyl-CoA inhibits palmitoyl-CoA-camitine acyltrans ferase, the rate-controlling enzyme in the /3-oxidation process. Thus, lipid oxidation is inhibited in an environment that favors lipid synthesis, as in the fed state, whereas lipid biosynthesis is inhibited in an environment favoring lipid oxidation, as in fasting. 

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