Glucagon stimulates glycogenolysis and gluconeogenesis, thus increasing the plasma glucose concentration — so that tissues get enough glucose in the fasting state.

However glucagon also inhibits glycolysis. In this case, what is the point of having high blood glucose if it cannot be catabolized?

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    $\begingroup$ Hint: Are there some organs on which glucagon does NOT act (i.e. which do not have significant numbers of glucagon receptors)? Could these organs benefit from the increased glucose levels? $\endgroup$
    – Adhish
    Aug 13 '20 at 10:26


The apparent paradox is resolved by the fact that not all tissues possess receptors that cause them to respond to glucagon or, more generally, to the same hormone. Where different tissues do respond to the same hormone, the tissue response may differ because of differences between the pathways or particular enzymes within the different tissues. Tissues that use glucose in starvation generally do not have glucagon receptors. In the related situation of response to epinephrine, the glucose utilizing tissue, skeletal muscle, does not contain the particular enzyme isoform that is subject to cyclic AMP-dependent control in liver.

General principles of hormone action in the regulation of metabolism

Metabolism in simple, especially unicellular, organisms is regulated by supply and demand. The mechanisms underlying this are mass action and allosteric activation or inhibition of key enzymes. In more highly developed organisms with differentiated tissues serving specialized functions there are times when this intercellular control must be over-ridden to produce an integrated response to the overall benefit of the organism. This is the rationale for hormonal control.

An integrated response does not mean that each tissue responds in the same way. It means that each tissue responds in a manner that is appropriate for the organism as a whole, given the function of the tissue and its priority (e.g. for rationing of energy sources). A simplified example of how this is achieved is illustrated below.

Principles of hormone action

Tissues 1 and 2 (e.g. liver and skeletal muscle) both contain pathway P1 (e.g. glycogen degradation), but only Tissue 1 responds to hormone H1 (e.g. glucagon) because Tissue 2 does not have the receptor R1, for H1. (SM is the second messenger involved in the signalling, e.g. cyclic AMP.)

Tissue 2 (e.g. adipose tissue) does have the receptor for hormone H1, but responds in a different way because it lacks pathways P1 and P2 of Tissue 1, but contains a tissue-specific pathway P3 (e.g. triglyceride breakdown).

Hormone H2 (e.g. epinephrine/adrenalin) affects Tissue 2 (e.g. skeletal muscle) as well as Tissue 1 (and 3), but the response is only partially similar in that although they share pathway P1, Tissue 2 lacks pathway P2 (e.g. gluconeogenesis).

Differential response to glucagon

Put simply, glucagon is a signal for starvation. Hence the appropriate integrated response is for those tissues (liver and adipose tissue) that can supply energy sources (glucose and fatty acids, respectively), and those tissues with greatest need for the scarcest resource (brain with its requirement for glucose) are supplied it, while those tissues that can manage with the alternative (fatty acid) are made to use it instead.

The brain has no receptors for glucagon (or insulin), so it can utilize the glucose made available by the liver. (Likewise the erythrocytes.) The main factor preventing other tissues using glucose is that they have insulin-sensitive glucose transporters and the blood concentration of insulin drops in starvation. It is only liver where there is need to make sure that the glucose produced by gluconeogenesis is not glycolyzed.

But doesn’t the paradox remain if we consider epinephrine?

The function of epinephrine is to initiate the ‘fight or flight response’, which involves supplying energy metabolites for skeletal muscle contraction. This involves both the liver, which breaks down glycogen to supply glucose to the muscle through the blood, and the skeletal muscle itself, which breaks down its own stored glycogen. As epinephrine also acts through cyclic AMP, which inhibits glycolysis in liver, why is glycolysis not inhibited in skeletal muscle?

The answer to this is that cyclic AMP inhibits glycolysis by phosphorylating and activating the liver enzyme PFK2, which catalyses the formation of fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase. Skeletal muscle has a different form of FPK2 which is not affected by cyclic AMP, lacking the regulatory phosphorylation sites. (It is regulated by other metabolites.) Hence in liver, glycogen, through cyclic AMP, causes the concentration of fructose 2,6-bisphosphate to decline and, thus, the activity of phosphofructokinase (PFK) to be decreased, preventing glycolysis; whereas in muscle the concentration of fructose 2,6-bisphosphate does not change.

hosophofructokinase 2 regulation

This regulation of phosphofructokinase by fructose 2,6-bisphosphate is described in sections 16.2.2 and 16.4 of Berg et al. (although they seem to have forgotten about skeletal muscle). However as the overall mechanism and details are somewhat complex, I have produced a simplified summary diagram of my own, above, in which the green lines indicate activation, and the red lines inhibition.


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