Hormonal Regulation of Fuel Metabolism:- Glucagon Counters Low Blood Glucose
Several hours after the intake of dietary carbohydrate, blood glucose levels fall slightly because of the ongoing oxidation of glucose by the brain and other tissues. Lowered blood glucose triggers secretion of glucagon and decreases insulin release (Fig. 1). Glucagon causes an increase in blood glucose con centration in several ways (Table 23–4). Like epinephrine, it stimulates the net breakdown of liver glycogen by activating glycogen phosphorylase and inactivating glycogen synthase; both effects are the result of phos phorylation of the regulated enzymes, triggered by cAMP. Glucagon inhibits glucose breakdown by glycolysis in the liver and stimulates glucose synthesis by gluconeogenesis. Both effects result from lowering the concentration of fructose 2,6-bisphosphate, an allosteric inhibitor of the gluconeogenic enzyme fructose 1,6-bis phosphatase (FBPase-1) and an activator of phospho fructokinase-1. Recall that [fructose 2,6-bisphosphate] is ultimately controlled by a cAMP-dependent protein phosphorylation reaction . Glucagon also inhibits the glycolytic enzyme pyruvate kinase (by promoting its cAMP-dependent phosphorylation), thus blocking the conversion of phosphoenolpyruvate to pyruvate and preventing oxidation of pyruvate via the citric acid cycle. The resulting accumulation of phosphoenolpyruvate favors gluconeogenesis. This effect is augmented by glucagon’s stimulation of the synthesis of the gluconeogenic enzyme PEP carboxykinase. By stimulating glycogen breakdown, preventing glycolysis, and promoting gluconeogenesis in hepatocytes, glucagon enables the liver to export glucose, restoring blood glucose to its normal level. Although its primary target is the liver, glucagon (like epinephrine) also affects adipose tissue, activating TAG breakdown by causing cAMP-dependent phosphorylation of perilipin and triacylglycerol lipase. The activated lipase liberates free fatty acids, which are ex ported to the liver and other tissues as fuel, sparing glucose for the brain. The net effect of glucagon is therefore to stimulate glucose synthesis and release by the liver and to mobilize fatty acids from adipose tissue, to be used instead of glucose as fuel for tissues other than the brain (Table 23–4). All these effects of glucagon are mediated by cAMP-dependent protein phosphorylation.
FIGURE 1 The fasting state: the glucogenic liver. After some hours without a meal, the liver becomes the principal source of glucose for the brain. Liver glycogen is broken down, and the glucose 1-phosphate produced is converted to glucose 6-phosphate, then to free glucose, which is released into the bloodstream. Amino acids from the degradation of proteins and glycerol from the breakdown of TAGs in adipose tissue are used for gluconeogenesis. The liver uses fatty acids as its principal fuel, and excess acetyl-CoA is converted to ketone bodies for export to other tissues for fuel; the brain is especially dependent on this fuel when glucose is in short supply.
