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11: Glycogenesis and Gluconeogenesis

Last updated

Apr 19, 2025
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- 10: Metabolism and Glycolysis
- 12: TCA cycle

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Learning Objectives

Define glycogenesis, glycogenolysis, and gluconeogenesis.
Identify the tissues involved in glycogen storage and glucose production.
Describe the purpose and physiological role of glycogen and gluconeogenesis in energy balance.
Recognize key regulatory enzymes in glycogen metabolism and gluconeogenesis.
Understand how hormones like insulin, glucagon, and epinephrine regulate glycogen and glucose metabolism.
Predict metabolic changes in fasting versus fed states related to glycogen use and glucose synthesis.

Definition: Term

Glycogen: A branched polymer of glucose used as a storage form of energy in animals, primarily in liver and muscle.
Glycogenesis: The metabolic process of synthesizing glycogen from glucose.
Glycogenolysis: The breakdown of glycogen to release glucose-1-phosphate.
Gluconeogenesis: The generation of glucose from non-carbohydrate precursors such as lactate, amino acids, and glycerol.
Glycogen Synthase: The key enzyme responsible for forming α-1,4-glycosidic bonds in glycogen.
Glycogen Phosphorylase: The enzyme that cleaves glucose units from glycogen during glycogenolysis.
Debranching Enzyme: A dual-function enzyme that removes branches in glycogen to allow continued degradation.
Glucose-6-Phosphatase: Enzyme that converts glucose-6-phosphate into free glucose; active only in liver and kidney.
Pyruvate Carboxylase: Biotin-dependent enzyme initiating gluconeogenesis by converting pyruvate to oxaloacetate.
Phosphoenolpyruvate Carboxykinase (PEPCK): Converts oxaloacetate to phosphoenolpyruvate in gluconeogenesis.
Fructose-1,6-bisphosphatase: Removes a phosphate group from fructose-1,6-bisphosphate in gluconeogenesis.
Insulin: A hormone that promotes glycogen synthesis and inhibits gluconeogenesis.
Glucagon: A hormone that stimulates glycogen breakdown and gluconeogenesis during fasting.
Epinephrine: A stress hormone that mobilizes glycogen stores in muscle and liver.
Reciprocal Regulation: Coordinated regulation where activation of one pathway (e.g., gluconeogenesis) inhibits the opposing one (e.g., glycolysis).

Glycogen Catabolism: Breaking Down Stored Glucose (Glycogenolysis)

Glycogen catabolism, also known as glycogenolysis, is the biochemical pathway by which stored glycogen is broken down to release glucose when energy is needed. Glycogen itself is a dense, highly branched polymer of glucose molecules, mainly stored in the liver and skeletal muscles. The liver acts as a glucose reservoir for the whole body, especially critical during fasting, while muscle glycogen is reserved locally for muscle contraction during physical activity. During times of fasting, intense exercise, or sudden energy demand (e.g., stress, trauma), hormones like glucagon and epinephrine stimulate glycogenolysis to ensure adequate glucose supply. In the liver, this glucose can be exported into the bloodstream to maintain normal blood sugar levels. In muscles, the glucose remains intracellular and fuels ATP production through glycolysis.

While glycogenolysis refers to the breakdown of stored glycogen inside cells, it’s important to clarify a related process—the digestion of dietary starch, which begins in the digestive tract. When you chew starchy foods like bread or rice, salivary amylase, an enzyme secreted in the mouth, begins breaking down starch (a plant-based polysaccharide similar to glycogen but less branched). This is why starchy foods often taste sweet after prolonged chewing—some glucose and maltose are being released. In the small intestine, pancreatic amylase (secreted by the pancreas) continues this digestion, cleaving α(1→4) glycosidic bonds in starch to form smaller sugars like maltose, maltotriose, and dextrins. While these enzymes do not break down animal glycogen stored in our cells, they illustrate the general concept of enzymatic carbohydrate degradation. Both starch and glycogen are polymers of glucose, but glycogen is more highly branched due to frequent α(1→6) linkages.

In cells, glycogen phosphorylase is the primary enzyme initiating glycogen breakdown. It catalyzes a reaction known as phosphorolysis, in which a molecule of inorganic phosphate (Pi), not water, is used to cleave glucose residues from the non-reducing ends of glycogen. This produces glucose-1-phosphate (G1P). A major advantage of this reaction is that no ATP is consumed; instead, the glucose is immediately phosphorylated and ready to enter metabolic pathways. However, glycogen has a branched structure, and glycogen phosphorylase cannot remove glucose near branch points. That’s where the debranching enzyme complex comes into play to ensure complete degradation of glycogen, even at its branch points. This includes two activities:

A transferase activity that shifts a block of three glucose residues to a nearby chain.
A glucosidase activity that hydrolyzes the remaining α(1→6)-linked glucose at the branch point, releasing free glucose (unphosphorylated).

The glucose-1-phosphate generated by glycogen phosphorylase is not directly used in energy metabolism. Instead, it's converted into glucose-6-phosphate (G6P) by the enzyme phosphoglucomutase. This is a simple rearrangement of the phosphate group from carbon 1 to carbon 6.

In muscle cells, G6P enters glycolysis to generate ATP on-site, especially during exercise.
In the liver, G6P can be converted into free glucose by the enzyme glucose-6-phosphatase, which is present only in the liver and kidneys. This free glucose is then transported into the bloodstream to maintain blood glucose homeostasis—a critical function during fasting.
Example: Imagine someone is running a marathon. Their muscles rely on glycogen breakdown to fuel glycolysis and generate rapid ATP. Meanwhile, their liver simultaneously breaks down glycogen to release glucose into the blood, ensuring that the brain and red blood cells continue to function properly.

Glycogen Anabolism: Storing Glucose (Glycogenesis)

Glycogenesis is the anabolic process of converting glucose into glycogen for storage. This occurs when there is excess glucose, such as after a carbohydrate-rich meal. The liver stores glycogen to regulate blood glucose, while muscles store it for use during activity. This process is essential to prevent hyperglycemia (high blood sugar) and to store energy efficiently. The process is hormonally regulated, with insulin playing a major role. Insulin is secreted in response to elevated blood glucose and promotes glucose uptake and storage in the liver and muscles.

The first step of glycogenesis involves the phosphorylation of glucose to form glucose-6-phosphate (G6P), catalyzed by either hexokinase (in muscles) or glucokinase (in the liver). Then, phosphoglucomutase converts G6P into glucose-1-phosphate (G1P). Next, G1P is activated by reacting with UTP (uridine triphosphate), catalyzed by the enzyme UDP-glucose pyrophosphorylase. This reaction yields UDP-glucose and pyrophosphate (PPi), which is rapidly hydrolyzed to drive the reaction forward. The formation of UDP-glucose is crucial because it acts as an "activated" glucose donor—it has a high-energy bond that facilitates the transfer of glucose. The enzyme glycogen synthase then catalyzes the addition of glucose from UDP-glucose to a pre-existing glycogen primer (usually started by a protein called glycogenin). The glucose is added via α(1→4) linkages. After a certain length, a branching enzyme introduces α(1→6) branches every 8–12 glucose residues, making glycogen more soluble and allowing for rapid glucose release when needed.

Example: After eating a large meal—say a plate of pasta and a banana—your blood glucose rises sharply. In response, the pancreas releases insulin, which signals liver and muscle cells to absorb glucose. Inside these cells, the glucose is converted to glycogen via the steps described. This prevents hyperglycemia and stores the glucose for future use. Later, during an overnight fast or the next workout, this stored glycogen will be mobilized back into glucose through glycogenolysis, providing energy without needing immediate food intake

Gluconeogenesis: Making Glucose from Non-Carbs

Gluconeogenesis is a critical metabolic pathway that allows the body to synthesize glucose from non-carbohydrate precursors. This pathway becomes essential during periods when dietary glucose is unavailable, such as fasting, prolonged exercise, low-carbohydrate diets, or starvation. Unlike glycogenolysis (which breaks down glycogen), gluconeogenesis generates new glucose molecules from substrates that are not carbohydrates—primarily lactate, glycerol, and certain amino acids. This process is not merely the reverse of glycolysis; it requires several bypass reactions due to the irreversibility of key glycolytic steps.

Gluconeogenesis is a tissue-specific process, mainly occurring in:

Liver (~90%): The primary site under normal physiological conditions. The liver maintains systemic glucose homeostasis, especially during the early stages of fasting.
Kidneys (~10%): The kidneys contribute more significantly during prolonged fasting, starvation, or metabolic acidosis. In acidosis, renal gluconeogenesis helps buffer blood pH by consuming protons (H⁺) during amino acid metabolism.
It’s important to note that muscle cells do not perform gluconeogenesis because they lack the enzyme glucose-6-phosphatase, which is required to release free glucose into the blood. Instead, muscles send substrates like lactate and alanine to the liver for gluconeogenesis.

Some tissues in the body have an absolute requirement for glucose. The brain relies heavily on glucose, especially under normal, non-fasting conditions. Although the brain can adapt to using ketone bodies during prolonged starvation, glucose remains vital for certain neuronal functions. Red blood cells (RBCs) lack mitochondria, so they depend entirely on anaerobic glycolysis, which requires a constant glucose supply. The renal medulla and the lens and cornea of the eye also depend largely on glucose for energy. Gluconeogenesis ensures a continuous supply of glucose, especially when dietary intake is insufficient and glycogen stores are depleted. This is crucial to prevent hypoglycemia, which can impair brain function and, in severe cases, lead to coma or death.

Example: During fasting or overnight sleep, glycogen stores in the liver begin to deplete. By the time you wake up, gluconeogenesis is already activated to maintain blood glucose levels. The liver converts lactate (from muscle), glycerol (from fat breakdown), and alanine (from muscle proteins) into glucose.
In prolonged exercise, like marathon running or heavy endurance workouts, muscles produce lactate through anaerobic glycolysis. This lactate enters the Cori cycle, traveling to the liver where it's converted back into glucose and returned to the muscles—this cycle reduces muscle fatigue and supports ongoing activity.
In low-carb diets or ketogenic states, the body restricts incoming carbohydrates, forcing the liver to ramp up gluconeogenesis. Glycerol, released from adipose tissue during fat breakdown, becomes a key substrate. Meanwhile, glucogenic amino acids (like alanine and glutamine) from muscle protein catabolism provide additional carbon skeletons for glucose production.

The Reverse of Glycolysis: Gluconeogenesis

Although glycolysis and gluconeogenesis seem like mirror-image pathways at first glance, they are not simply reversible processes. This is due to the presence of three strongly exergonic steps in glycolysis that have a large negative ΔG (free energy change), making them thermodynamically irreversible under normal physiological conditions. In gluconeogenesis, these steps are bypassed using special enzymes to allow the synthesis of glucose from pyruvate without violating energy principles.

Glucose-6-Phosphatase (Gluconeogenesis)

In glycolysis, the enzyme hexokinase catalyzes the first committed step: converting glucose to glucose-6-phosphate (G6P) by adding a phosphate from ATP. This reaction is highly favorable (ΔG ≪ 0), which helps trap glucose inside the cell and commit it to metabolism. However, this strong directionality means that the reverse reaction is not possible under normal conditions. To bypass this in gluconeogenesis, cells use glucose-6-phosphatase, an enzyme found primarily in liver and kidney cells. It removes the phosphate group from G6P, releasing free glucose into the bloodstream. This step is essential for maintaining blood glucose levels, especially during fasting. Muscles lack glucose-6-phosphatase, which is why they retain glucose for their own use and don’t contribute to blood sugar regulation. For example, a person who’s fasting overnight depends on liver glucose-6-phosphatase to generate free glucose from G6P for the brain and red blood cells.

Fructose-1,6-Bisphosphatase

PFK-1 is the rate-limiting enzyme of glycolysis, converting fructose-6-phosphate (F6P) into fructose-1,6-bisphosphate (F1,6BP) using ATP. This step commits glucose to full breakdown and is highly regulated—AMP and fructose-2,6-bisphosphate activate it, while ATP and citrate inhibit it. In gluconeogenesis, this irreversible step is bypassed by fructose-1,6-bisphosphatase, which hydrolyzes the phosphate group from F1,6BP to produce F6P. This step is also regulated but in the opposite way: it’s inhibited by AMP and activated by ATP and citrate, reflecting the cell’s energy status. For example, during prolonged exercise or fasting, high ATP levels (from fat oxidation) promote gluconeogenesis by activating fructose-1,6-bisphosphatase, helping the liver send glucose to tissues like the brain.

Pyruvate Carboxylase and PEP Carboxykinase (PEPCK)

The final irreversible glycolytic step involves pyruvate kinase, which converts phosphoenolpyruvate (PEP) into pyruvate, generating ATP in the process. This reaction is highly exergonic and is strongly regulated—inhibited by ATP and alanine, and in the liver, it is inactivated by phosphorylation during fasting (via glucagon signaling). To bypass this in gluconeogenesis, two enzymes are required: (1) Pyruvate Carboxylase converts pyruvate into oxaloacetate (OAA) inside the mitochondria. This reaction requires biotin as a coenzyme and ATP as an energy source. (2) Phosphoenolpyruvate carboxykinase (PEPCK) then converts oxaloacetate into PEP, using GTP. This step occurs either in the cytoplasm or mitochondria, depending on the tissue. Together, these two enzymes bypass the irreversible pyruvate kinase step and restore the carbon skeleton to the PEP level, allowing gluconeogenesis to continue upward toward glucose synthesis. For example, a biotin deficiency (e.g., due to excessive raw egg white consumption, which contains avidin) can impair pyruvate carboxylase activity, leading to poor gluconeogenesis and symptoms like hypoglycemia and lethargy.

Overall, these bypass reactions are not only necessary but also thermodynamically favorable in the direction of glucose synthesis. Each step is coupled to the hydrolysis of high-energy phosphate bonds (e.g., from ATP, GTP) to drive the reactions forward. Importantly, by using different enzymes and regulatory mechanisms, the cell can avoid a futile cycle (simultaneous glycolysis and gluconeogenesis), ensuring that these two pathways are mutually exclusive depending on energy needs.

Summary:

Glycolysis = fast energy release
Gluconeogenesis = glucose conservation and redistribution
Regulation = based on energy status, hormones (insulin/glucagon), and tissue specificity

Hormonal Regulation: Balancing Blood Sugar

Maintaining stable blood glucose levels is essential for survival, as glucose is the primary energy source for the brain and red blood cells. This delicate balance is achieved by a finely tuned system of hormonal regulation, primarily involving insulin, glucagon, and epinephrine. These hormones act in opposition to either promote the storage or release of glucose depending on the body’s energy state—fed, fasting, or under stress.

Insulin

Insulin is an anabolic hormone secreted by the β-cells of the pancreas in response to high blood glucose levels, such as after a carbohydrate-rich meal. Its primary role is to reduce blood glucose levels by promoting glucose uptake into tissues like muscle and fat and enhancing storage processes in the liver. One way insulin achieves this is by increasing the expression and activity of glucokinase in the liver. Glucokinase is the isoform of hexokinase that phosphorylates glucose to form glucose-6-phosphate (G6P). This is a crucial first step for glucose to be retained in the cell and directed into metabolic pathways such as glycolysis, glycogenesis, or lipogenesis. Importantly, glucokinase has a high Km of ~8 mM, meaning it is only active when glucose levels are high—making it perfectly suited to operate after meals, preventing blood sugar spikes. By increasing glucose uptake and phosphorylation, insulin facilitates the conversion of excess glucose into glycogen (via glycogenesis) and fat (via lipogenesis). It also inhibits gluconeogenesis and glycogenolysis, ensuring that glucose is not being produced or released when it’s already abundant. For example, after eating a bowl of rice, insulin is released, prompting the liver and muscles to store glucose as glycogen and adipose tissue to convert glucose into fat. This prevents hyperglycemia and sets aside energy for later use.

Glucagon

Glucagon is the major catabolic hormone, secreted by the α-cells of the pancreas in response to low blood glucose levels, such as during overnight fasting or between meals. Its main target is the liver, where it stimulates processes that increase blood glucose, namely glycogenolysis (glycogen breakdown) and gluconeogenesis (glucose synthesis from non-carbohydrate sources). One of the key mechanisms by which glucagon works is through the cAMP signaling cascade. When glucagon binds to its G-protein-coupled receptor on hepatocytes (Liver cells), it activates adenylate cyclase, which increases levels of cyclic AMP (cAMP). This activates protein kinase A (PKA), a key regulatory kinase that phosphorylates and modulates several metabolic enzymes.

One important target of PKA is pyruvate kinase, the enzyme that catalyzes the final step of glycolysis (conversion of phosphoenolpyruvate to pyruvate). PKA phosphorylates and inhibits pyruvate kinase, effectively slowing down glycolysis. This is crucial because, in a fasting state, the liver must preserve pyruvate and its precursors for gluconeogenesis, not burn them for energy. For example, during fasting or low-carb dieting, glucagon ensures that blood sugar remains stable by stimulating hepatic glucose production and limiting its breakdown within the liver.

Epinephrine (Adrenaline)

Epinephrine, also known as adrenaline, is released by the adrenal medulla during acute stress, exercise, or in response to fear—the classic "fight or flight" situations. Its effects are rapid and powerful, mobilizing energy stores to prepare the body for action. Epinephrine enhances glycogenolysis dramatically—up to 2000-fold, especially in skeletal muscle. It binds to adrenergic receptors, activating a signaling cascade similar to glucagon’s, leading to cAMP production and PKA activation. In muscle, this increases glycogen breakdown and glucose availability for immediate ATP production via glycolysis. Since muscle cells lack glucose-6-phosphatase, they do not export glucose but use it locally.

Epinephrine also increases heart rate, constricts blood vessels (vasoconstriction) to raise blood pressure, and promotes water retention, all of which prepare the body to respond quickly to stress. Unlike glucagon, epinephrine acts on both liver and muscle, and its effects are not just about maintaining blood glucose, but also about rapid energy mobilization for physical activity. For example, during a sprint or emergency situation, epinephrine floods the bloodstream, causing the heart to beat faster, sharpening focus, and driving the rapid breakdown of muscle glycogen to generate quick ATP for muscular action.

Summary:

Insulin acts during the feeding to store glucose and suppress production.
Glucagon acts during fasting to produce and release glucose.
Epinephrine overrides both in acute stress, mobilizing energy rapidly.

Clinical Relavence

What happens if pyruvate kinase can't be phosphorylated?

Pyruvate kinase (PK) is a key glycolytic enzyme that catalyzes the final, irreversible step in glycolysis—converting phosphoenolpyruvate (PEP) to pyruvate, while producing ATP. In the liver, PK is hormonally regulated: during fasting, glucagon activates protein kinase A (PKA) via the cAMP pathway, which phosphorylates and inactivates pyruvate kinase. This shuts down glycolysis to favor gluconeogenesis, preserving glucose for the brain and red blood cells.

Now imagine a mutation in PK that prevents phosphorylation (e.g., mutation at the serine phosphorylation site). The enzyme remains constitutively active, even when fasting. This forces the liver to keep burning glucose via glycolysis, rather than preserving or producing it. The result? A paradoxical drop in blood sugar—hypoglycemia, especially during prolonged fasting or exertion. Clinically, such a scenario could mimic or exacerbate fasting hypoglycemia syndromes. Though rare, this situation parallels some metabolic disorders where glycolysis is inappropriately active. It also demonstrates the importance of post-translational regulation—here, phosphorylation of an enzyme—to adapt metabolism to hormonal cues.

What happens if glucokinase K_m is too low (e.g., 0.1 mM like hexokinase)?

Glucokinase is a specialized isoform of hexokinase found primarily in the liver and pancreatic β-cells. It has a high K_m (~8 mM) and low affinity for glucose, which makes it act like a glucose sensor—it only becomes active when glucose levels are high (after meals). This helps the liver store excess glucose and β-cells regulate insulin release appropriately.

Now consider a hypothetical or pathological mutation that reduces the K_m of glucokinase to 0.1 mM, making it behave like hexokinase, which is always active. The liver would begin phosphorylating glucose even at very low concentrations, aggressively converting it into G6P and storing or using it. This can lead to dangerous hypoglycemia, especially post-exercise, when glucose is already low. A real-world parallel is seen in glucokinase-activating mutations (GKAM), which are associated with congenital hyperinsulinism. These patients over-secrete insulin and aggressively clear glucose from the blood, resulting in persistent hypoglycemia. On the other hand, glucokinase loss-of-function mutations cause MODY type 2 (Maturity-Onset Diabetes of the Young), characterized by mild fasting hyperglycemia.

When should you use a glucagon inhibitor?

In type 2 diabetes mellitus (T2DM), especially in the early stages, patients often show inappropriately elevated glucagon levels, even in the feeding state. This leads to increased hepatic gluconeogenesis and glycogenolysis, contributing to fasting and postprandial hyperglycemia. Inhibiting glucagon signaling can help reduce hepatic glucose output. Glucagon receptor antagonists or drugs that interfere with cAMP production (like phosphodiesterase inhibitors) are being explored to blunt glucagon’s effect on the liver. Another experimental target is GCGR (glucagon receptor) antagonists. For example, volagidemab is a monoclonal antibody targeting the glucagon receptor currently in clinical trials. Glucagon inhibitors are not yet widely approved, but they hold promise in patients with poor glucose control despite high insulin and those with excessive hepatic glucose production.

When should you use an insulin inhibitor?

While insulin is vital for glucose homeostasis, excessive insulin secretion can cause life-threatening hypoglycemia, particularly in rare tumors like insulinomas (insulin-secreting pancreatic neuroendocrine tumors). In such cases, pharmacological insulin inhibitors are used. A key example is diazoxide, which opens K⁺ channels in β-cells, inhibiting depolarization and calcium influx, thereby reducing insulin release. Diazoxide is used both in insulinomas and in congenital hyperinsulinism to manage dangerously low glucose levels. Other scenarios where insulin action might be temporarily dampened include counter-regulatory support in hypoglycemia, or experimental studies in insulin-sensitizing therapies. However, in clinical practice, inhibiting insulin is done cautiously and typically in very specific settings, as the risk of hyperglycemia and metabolic acidosis is high.

Reflective Questions

How do glycogen metabolism and gluconeogenesis complement each other in maintaining blood glucose?
What enzymes distinguish gluconeogenesis from glycolysis, and why are they important?
How does hormonal regulation change in the fed vs. fasting state?
Why can't muscle export glucose into the bloodstream?
What would happen in the case of enzyme deficiencies affecting these pathways?

Post-Lecture Objectives

Trace the steps of glycogen synthesis and degradation, including the enzymes involved.
Describe how gluconeogenesis bypasses irreversible steps in glycolysis.
Explain the hormonal signals that direct metabolic pathways during fasting and feeding.
Apply knowledge of enzyme functions to predict symptoms of metabolic disorders like Von Gierke's or McArdle's disease.
Contrast the roles of liver and muscle in glucose homeostasis.