5.1: Gluconeogenesis and glycogenolysis (2023)

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    Gluconeogenesis and glycogenolysis are the two major pathways for glucose homeostasis. Figure 5.1 illustrates the timing and overlap of glycogenolysis and gluconeogenesis. These signaling pathways are activated almost simultaneously when the ratio of insulin to glucagon is sufficiently reduced. The dependency of the paths changes over time.

    5.1: Gluconeogenesis and glycogenolysis (2)

    Gluconeogenesis (GNG) is an anabolic pathway that produces glucose from lactate, glycerol, or glucogenic amino acids. This pathway is activated primarily in the liver during fasting and is coordinated with the catabolic pathways of \(\beta\)-oxidation and protein degradation. The pathway follows the reverse of glycolysis, with the exception of four unique enzymes that bypass the irreversible steps of glycolysis (Figure 5.2).

    Substrates for GNG

    amino acids

    The primary GNG substrates are derived from glucogenic amino acids released by cortisol-mediated protein catabolism. In the fasting state, cortisol is elevated and supports the fasting pathways by activating protein catabolism (in skeletal muscle) and increasing the transcription of enzymes necessary for gluconeogenesis (specifically phosphoenolcarboxykinase (PEPCK)). As skeletal muscle releases amino acids, primarily glutamine and alanine, they are absorbed by the liver. For use in glucose synthesis, they are transaminated to generate a useful intermediate of the TCA cycle, primarily \(\alpha\)-ketoglutaramate and pyruvate (see Figures 5.3 and 5.10). In the case of alanine, it can be transaminated to generate pyruvate. Glutamine is first deaminated by glutaminase, and the remaining glutamate is transaminated to form \(\alpha\)-ketoglutaramate (see Figure 5.11). Both pyruvate and \(\alpha\)-ketoglutaramate increase substrates in the TCA cycle, which ultimately increases the amount of malate available for transport out of mitochondria. Through this process of protein catabolism and transamination, glucogenic amino acids contribute to the synthesis of oxaloacetate (OAA), which is necessary for gluconeogenesis.

    5.1: Gluconeogenesis and glycogenolysis (4)


    Lactate is mainly produced by the Cori cycle, or the anaerobic oxidation of glucose. (Note: The Cori cycle, or lactic acid cycle, refers to the metabolic pathway in which lactate, produced by anaerobic glycolysis in muscle or red blood cells, travels to the liver and is converted to glucose. Glucose returns to peripheral tissues and is converted to lactate and metabolized there). In the liver, lactate can be oxidized back to pyruvate via the reverse reaction catalyzed by lactate dehydrogenase (Figure 5.3).


    When epinephrine or glucagon stimulates lipolysis, activation of hormone-sensitive lipase in adipose tissue allows hydrolysis of triacylglycerol into free three-chain fatty acids and glycerol. Glycerol released into the circulation is absorbed by the liver. Once in the liver, it can be converted to dihydroxyacetone phosphate (DHAP), a glycolytic intermediate. In this way, additional carbon can be obtained for the synthesis of glucose (fig. 5.4).

    5.1: Gluconeogenesis and glycogenolysis (5)

    (Video) Metabolism | Gluconeogenesis

    Linkage of GNG and other metabolic pathways

    Gluconeogenesis is highly dependent on the support of other signaling pathways. It requires amino acids for carbon substrates of cortisol-mediated protein catabolism. The deamination capacity of these amino acids depends on the ability of the urea cycle to remove ammonia in the form of non-toxic urea and, perhaps most importantly, gluconeogenesis depends on the \(\beta\)-oxidation process.

    5.1: Gluconeogenesis and glycogenolysis (6)


    The \(\beta\) oxidation process supports gluconeogenesis in two ways:

    1. IT WASN'T LONG2resulting from \(\beta\)-oxidation is oxidized to ATP in the electron transport chain. This ATP provides the energy necessary for the synthesis of glucose. It also supplies energy to the urea cycle for nitrogen removal.
    2. \(\beta\)-oxidation also generates acetyl-CoA. This compound is required to allosterically activate pyruvate carboxylase (Figure 5.5).

    The acetyl-CoA produced by \(\beta\)-oxidation is not itself a substrate for gluconeogenesis, but is required for allosteric activation of pyruvate carboxylase, which is the first step of GNG. Again, acetyl-CoA is not a substrate for this process; it is completely oxidized in the TCA cycle and does not provide additional carbons to be exported from the TCA cycle as malate. Therefore, the cell depends on carbon backbones of amino acids, glycerol, and lactate as substrates for glucose production.Section 5.2).

    Regulation of gluconeogenesis

    Pyruvate-carboxylase and phosphoenol-carboxykinase (PEPCK)

    Gluconeogenesis is essentially the opposite of glycolysis, with four major regulatory steps that allow the three irreversible steps of glycolysis to be bypassed (Figure 5.2). This first step of GNG starts in the mitochondria using pyruvate carboxylase (Figure 5.5). This enzyme converts pyruvate to oxaloacetate in mitochondria and requires biotin as a cofactor. This enzyme is allosterically activated by acetyl-CoA. The OAA produced is reduced to malate, which is transported out of the mitochondria by malate-aspartate transport. In the cytosol, malate is oxidized back to OAA and decarboxylated by the enzyme phosphoenolcarboxykinase (PEPCK) to generate phosphoenolpyruvate (Figure 5.3). The combination of these two enzymes, pyruvate carboxylase and PEPCK, allows the cell to bypass the irreversible step catalyzed by pyruvate kinase.

    Once phosphoenolpyruvate (PEP) is synthesized, it continues through the reverse process using glycolytic enzymes until it reaches its next irreversible transformation.

    (Video) Glycogenesis, Glycogenolysis, and Gluconeogenesis

    Fructose-1,6-bisphosphatase (FBP1)

    As PEP continues through the reversal of glycolysis, fructose-1,6-bisphosphate is produced. To bypass the irreversible step of glycolysis catalyzed by phosphofructokinase 1 (PFK1), the enzyme fructose-1,6-bisphosphatase (FBP1) is present and dephosphorylates fructose-1,6-bisphosphate to produce fructose-6-phosphate. This enzyme, FBP1, is inhibited by AMP and fructose-2,6-bisphosphate (Figure 5.2).

    As with glycolysis, there is additional regulation by the bifunctional enzyme phosphofructokinase 2 (PFK2)/fructose-2,6-bisphosphatase (Figure 4.1). When fed, this bifunctional enzyme acts as a kinase (PFK2) and produces fructose-2,6-bisphosphate, which allosterically activates PFK1. In the fasting state, the enzyme is phosphorylated by glucagon-activated protein kinase A, which activates the phosphatase activity of the enzyme. The enzyme dephosphorylates fructose-2,6-bisphosphate and thus decreases the allosteric activation of PFK1 by facilitating the reverse reaction of fructose-1,6-bisphosphatase (Figure 5.2).


    Finally, glucose-6-phosphatase is required to dephosphorylate glucose-6-phosphate so that it can be released from the liver. This is an important step in both glycogenolysis and gluconeogenesis, and a deficiency of this enzyme can lead to severe episodes of fasting hypoglycemia.


    Unlike glycogen synthesis, glycogenolysis is the release of glucose-6-phosphate from glycogen stores. It can occur in both liver and skeletal muscle, but under two different conditions (Figures 5.6 and 5.7). As mentioned above, this is an active sober trail.

    • NOLiverGlycogenolysis is the initial source of glucose used to maintain blood sugar levels when glucagon levels begin to rise. Glucose-6-phosphate, generated by hepatic glycogenolysis, is dephosphorylated and released into the bloodstream.
    • emskeletal muscles, glycogenolysis delivers glucose only to skeletal muscle, and this fuel is not released into the bloodstream because skeletal muscle lacks glucose-6-phosphatase, the enzyme needed to dephosphorylate glucose. Therefore, skeletal muscle glycogen is primarily used under anaerobic exercise conditions when fatty acid oxidation is not rapid enough to produce ATP for stressed tissues.

    Regulation of glycogenolysis

    hepatic glycogenolysis

    In the liver, glucagon initiates glycogenolysis through a GPCR-mediated signaling cascade. This leads to activation of adenylyl cyclase and an increase in cAMP. cAMP activates protein kinase A, which phosphorylates and activates glycogen phosphorylase. Glycogen phosphorylase initiates the breakdown of glycogen. Even under these conditions, glycogen synthase is phosphorylated and inactivated by the same mechanism, ensuring that glycogen synthesis does not occur simultaneously (Figure 5.6).

    Epinephrine can also increase hepatic glycogenolysis by binding to a \(\alpha\) receptor agonist. This stops the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) in inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) by phospholipase C. IP3stimulates the release of \(\ce{Ca}^{2+}\) from the endoplasmic reticulum and causes:

    1. phosphorylation and activation of glycogen phosphorylase and
    2. Phosphorylation and inactivation of glycogen synthase.

    In all cases, glucose-6-phosphate released from glycogen stores is dephosphorylated by glucose-6-phosphatase and released from the liver.

    Skeletal muscle glycogenolysis

    Skeletal muscle glycogen is not affected by glucagon, but responds to AMP, \(\ce{Ca}^{2+}\), and epinephrine (Figure 5.7).

    • The main regulator of this process is AMP. Elevated AMP will allosterically activate glycogen phosphorylase independent of phosphorylation.
    • Then glycogen phosphorylase can be activated by \(\ce{Ca}^{2+}\). Similar to the previous cascade, calcium activates the \(\ce{Ca}^{2+}\) calmodulin complex, which in turn activates phosphorylase kinase, resulting in the phosphorylation and activation of glycogen phosphorylase.
    • Finally, epinephrine can also stimulate skeletal muscle glycogenolysis through an increase in cAMP (the cascade of events is the same as in glucagon-stimulated hepatic glycogenolysis).
    (Video) Gluconeogenesis

    Summary of the track regulations

    metabolic pathway Main regulatory enzymes allosteric effectors hormonal effects
    Glukoneogenese Fructose-1,6-bisphosphatase (FBP1) Citrate (+) Frutose 2,6-BP, AMP (-) Glucagon \(\uparrow\) decreases F 2,6-BP by decreasing PFK1 activation


    Phosphoenolpyruvate carboxycinasa

    Acetyl-CoA (+)

    Cortisol-mediated increased transcription



    AMP-Muskel (+)

    \(\ce{Ca}^{2+}\) (+) without muscle

    Glucagon \(\uparrow\) (Leber)

    Epi \(\up arrow\) (Muskel)

    Table 5.1: Summary of the rules of the road.

    References and resources


    (Video) Gluconeogenesis

    Ferrier, D. R., Hrsg.Lippincott's Illustrated Reviews: Biochemistry, 7th Edition Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 10: Gluconeogenesis: Section II, III, IV, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Bodies and TAG metabolism: Section III, IV, V, Chapter 19: Nitrogen removal from amino acids: Section V, VI, Chapter 23: Metabolic action of insulin and glucagon, Chapter 25: Diabetes mellitus.

    Le, T. y V. Bhushan.First Aid for USMLE Step 1, 29. Aufl. New York: McGraw Hill Education, 2018, 78, 82, 86, 89–90.

    Lieberman, M. y A. Peet, eds.Marks' Basic Medical Biochemistry: A Clinical Approach, 5th Edition Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 3: The Fasting State, Chapter 19: Regulatory Basics, Chapter 24: Oxidative Phosphorylation and ETC, Chapter 26: Glycogen Formation, Chapter 28: Gluconeogenesis, Chapter 30: Fatty Acid Oxidation, Chapter 34: Integration of Carbohydrate and Lipid Metabolism, Chapter 36: Fate of Amino Acids Nitrogen: Urea Cycle.


    Ferrier D. Figure 5.1 Glucose production by glycogenolysis and gluconeogenesis. Adapted under fair use from Lippincott Illustrated Reviews Biochemistry. 7th ed., page 329. Figure 24.11 Blood glucose sources after ingestion of 100 g of glucose. 2017

    Gray, Kindred, Figure 5.2 Comparison of glycolysis and gluconeogenesis. 2021https://archive.org/details/5.2-new. CC POR 4.0.

    Gray, Kindred, Figure 5.3 Amino acid and lactate sites that enter gluconeogenesis as substrates for the signaling pathway. 2021https://archive.org/details/5.3_20210924. CC POR 4.0.

    Grey, Kindred, Figure 5.4 Glycerol as a substrate for gluconeogenesis can, after phosphorylation to glycerol-3-phosphate, be converted to DHAP, which can directly enter glycolysis. 2021https://archive.org/details/5.4_20210924. CC POR 4.0.

    Grey, Stem, Figure 5.5. The reaction catalyzed by pyruvate carboxylase makes it possible to bypass the irreversible step catalyzed by pyruvate kinase. 2021https://archive.org/details/5.5_20210924. CC POR 4.0.

    Grey, Kindred, Figure 5.7 Glycogenolysis of skeletal muscle. 2021https://archive.org/details/5.7_20210924. CC POR 4.0. Muscle Added by Pascal Hesscontent project.

    (Video) Gluconeogenesis | Metabolism

    Lieberman M, Peet A. Figure 5.6 Hepatic glycogenolysis by epinephrine. Adapted under Fair Use from Marks Basic Medical Biochemistry. 5th ed., page 534. Fig. 26.7 Regulation of glycogen synthesis and breakdown in the liver. 2017. Ion channel added by Léa Lortal docontent project.


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