Analytical Questions on Carbohydrates

Definition, Functions & Classification of Carbohydrates

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Section A: Definition and Basic Understanding

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Q1. Define carbohydrates. Why are they also known as “hydrates of carbon”?

Answer:

Definition:
Carbohydrates are organic compounds composed of carbon (C), hydrogen (H), and oxygen (O), usually in the empirical formula (CH₂O)ₙ.

Why “hydrates of carbon”?
Because their molecular formula resembles carbon chemically bonded with water molecules.

Example:
Glucose → C₆H₁₂O₆ → (CH₂O)₆

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Q2. How do carbohydrates differ structurally from lipids and proteins?

Answer:

• Carbohydrates: Composed of monosaccharide units, rich in hydroxyl groups, and usually polar and water-soluble.

• Lipids: Long non-polar hydrocarbon chains, hydrophobic, and mainly used for energy storage and insulation.

• Proteins: Composed of amino acids with amino and carboxyl groups, used for structure and enzymatic functions.

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Section B: Functions of Carbohydrates

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Q3. Why is glucose called the “universal fuel” of the body?

Answer:

• Most tissues can utilize glucose.

• Brain and RBCs rely exclusively on glucose under normal conditions.

• Glucose is water-soluble, easily transported in blood, and can be metabolized aerobically and anaerobically.

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Q4. How do structural carbohydrates differ from storage carbohydrates? Give examples.

Answer:

Structural carbohydrates are often indigestible in humans (e.g., cellulose), while storage forms are readily mobilized for energy.

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Section C: Classification of Carbohydrates

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Q5. A disaccharide yields glucose and galactose on hydrolysis. Identify it and explain the bond involved.

Answer:

• The disaccharide is lactose.

• Composed of glucose + galactose.

• Linked by a β-1,4 glycosidic bond.

Clinical relevance:
Lactose intolerance results from deficiency of lactase enzyme, leading to bloating, diarrhea, and gas upon milk consumption.

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Q6. Explain why humans can digest starch but not cellulose, even though both are made of glucose.

Answer:

• Both are polymers of glucose.

• Starch has α-1,4 and α-1,6 glycosidic bonds → hydrolyzed by amylase.

• Cellulose has β-1,4 glycosidic bonds → humans lack cellulase enzyme to break them.

Hence, cellulose acts as dietary fiber, not a nutrient.

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Clinical Integration

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Q7. How does carbohydrate classification aid in understanding inborn errors like galactosemia and fructose intolerance?

Answer:

• Both involve monosaccharide metabolism:

  • Galactosemia → defect in galactose-1-phosphate uridyltransferase

  • Fructose intolerance → defect in aldolase B

• Understanding the structure and metabolic fate of monosaccharides helps in diagnosis and dietary management.

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Q8. Why is glucose the preferred energy source during hypoxia or anaerobic conditions?

Answer:

• Glucose can be metabolized via anaerobic glycolysis to lactate, yielding 2 ATP without requiring oxygen.

• Other fuels (fatty acids) require mitochondrial oxidation, which depends on oxygen.

 

Digestion and Absorption of Carbohydrates

Section A: Overview and Basic Concepts

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Q1. What is the end product of carbohydrate digestion, and why must carbohydrates be broken down before absorption?

Answer:

• The end products of carbohydrate digestion are monosaccharides: primarily glucose, galactose, and fructose.
• Carbohydrates must be broken down because only monosaccharides can be absorbed through the intestinal epithelium.
• Disaccharides and polysaccharides are too large to be absorbed intact.

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Section B: Digestion of Carbohydrates

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Q2. Describe the role of salivary amylase in carbohydrate digestion. Where is it active and why does its action stop in the stomach?

Answer:

• Salivary amylase (ptyalin) begins digestion in the oral cavity, hydrolyzing α-1,4 glycosidic bonds in starch to form maltose, maltotriose, and dextrins.
• Its action ceases in the stomach due to the acidic pH (<4), which denatures the enzyme.

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Q3. What enzymes are involved in the final steps of carbohydrate digestion at the brush border?

Answer:
The intestinal brush border enzymes include:

These enzymes are located on the microvilli of intestinal epithelial cells.

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Section C: Absorption of Carbohydrates

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Q4. Explain how glucose and galactose are absorbed in the small intestine.

Answer:

• Absorbed via SGLT-1 (sodium-dependent glucose transporter-1) in the apical membrane of enterocytes.
• This is secondary active transport, using the Na⁺ gradient maintained by Na⁺/K⁺ ATPase on the basolateral side.
• After entry, glucose exits the cell into blood via GLUT-2 transporter.

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Q5. How is fructose absorbed, and why is it absorbed more slowly than glucose?

Answer:

• Fructose is absorbed by facilitated diffusion via the GLUT-5 transporter (apical membrane).
• Since this process is passive and not energy-dependent, it is slower than active absorption of glucose/galactose.

Fructose exits enterocytes via GLUT-2 (basolateral membrane).

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Q6. A patient with diarrhea after consuming milk is diagnosed with lactase deficiency. Explain the pathophysiology.

Answer:

• Lactase deficiency → lactose is not hydrolyzed into glucose + galactose.
• Undigested lactose:
  • Retains water in the lumen → osmotic diarrhea
  • Is fermented by colonic bacteria → gas, bloating, and cramps

Condition: Lactose intolerance (can be primary or secondary)

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Section D: Clinical and Applied Concepts

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Q7. What is the significance of glucose absorption via SGLT-1 in oral rehydration therapy (ORT)?

Answer:

• SGLT-1 co-transports glucose and sodium, which enhances water absorption due to osmotic pull.
• ORT solutions contain glucose + NaCl → stimulates water reabsorption in the intestines → rehydrates effectively, especially in diarrheal illnesses.

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Q8. Differentiate between dietary fiber and digestible carbohydrates in terms of digestion, absorption, and function.

Answer:

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Q9. A patient on total parenteral nutrition (TPN) has elevated blood glucose. Explain the mechanism behind hyperglycemia.

Answer:

• TPN may deliver high concentrations of glucose intravenously.
• Rapid infusion bypasses intestinal regulation → spikes blood glucose.
• In critically ill patients with insulin resistance, glucose uptake is impaired → persistent hyperglycemia.

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Q10. How do artificial sweeteners like sucralose affect carbohydrate digestion or absorption?

Answer:

• Sucralose is a chlorinated derivative of sucrose.
• It is not hydrolyzed by digestive enzymes and is poorly absorbed.
• Hence, it provides no calories and does not affect blood glucose.

 

Glycolysis

1. Question:

How does the regulation of phosphofructokinase-1 (PFK-1) reflect the energy status of the cell, and what is its significance in glycolysis?

Answer:
Phosphofructokinase-1 (PFK-1) is the key rate-limiting enzyme in glycolysis, converting fructose-6-phosphate to fructose-1,6-bisphosphate. It is allosterically regulated by:

• Activated by:

  • AMP and ADP (indicate low energy state)

  • Fructose-2,6-bisphosphate (potent activator)

• Inhibited by:

  • ATP (high energy status)

  • Citrate (indicator of high mitochondrial activity)

This regulation ensures that glycolysis proceeds when energy is needed and slows when the cell has sufficient ATP. It prevents wasteful glucose breakdown and integrates cellular energy demands with substrate availability.

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2. Question:

Why is glycolysis especially important in erythrocytes and how does it adapt in anaerobic conditions?

Answer:
Erythrocytes lack mitochondria, so glycolysis is their sole source of ATP. In anaerobic conditions (like hypoxia), glycolysis becomes the primary ATP-generating pathway for all cells.

In erythrocytes:

• Glucose is metabolized to lactate, regenerating NAD⁺ required for glycolysis.

• ATP produced is critical for maintaining ion gradients (Na⁺/K⁺ pump), preventing hemolysis.

• This adaptation allows survival in low-oxygen environments.

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3. Question:

What would be the metabolic consequence of a deficiency in pyruvate kinase in red blood cells?

Answer:
Pyruvate kinase deficiency in erythrocytes leads to:

• Decreased ATP production

• Impaired Na⁺/K⁺ ATPase function

• Cell membrane instability

• Hemolytic anemia

Since RBCs depend entirely on glycolysis, any block in the pathway (especially the final ATP-generating step) reduces their lifespan.

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4. Question:

How does glycolysis link to other metabolic pathways?

Answer:
Glycolysis intersects with:

• Gluconeogenesis: Reversible steps are used in reverse during glucose synthesis.

• TCA Cycle: Pyruvate enters mitochondria and is converted to acetyl-CoA.

• Pentose Phosphate Pathway (PPP): Glucose-6-phosphate can be shunted into PPP for NADPH and ribose-5-phosphate production.

• Lipid metabolism: Dihydroxyacetone phosphate (DHAP) can form glycerol-3-phosphate for triglyceride synthesis.

This integration ensures metabolic flexibility and coordination among pathways.

 

Rapaport–Leubering Cycle (Shunt)

5. Question:

What is the Rapaport–Leubering cycle and why is it important in red blood cells?

Answer:
The Rapaport–Leubering shunt is a bypass of glycolysis in erythrocytes, where 1,3-bisphosphoglycerate is converted to 2,3-bisphosphoglycerate (2,3-BPG) by bisphosphoglycerate mutase, skipping the ATP-producing step.

Importance:

• 2,3-BPG binds to hemoglobin and reduces its oxygen affinity, facilitating oxygen release to tissues.

• This adaptation is crucial during hypoxia, high altitude, or anemia.

Though ATP yield is reduced, the physiological benefit of oxygen delivery outweighs this in RBCs.

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6. Question:

How does the Rapaport–Leubering cycle affect the net ATP production in glycolysis?

Answer:
In the shunt:

• 1,3-BPG → 2,3-BPG → 3-PG (bypasses phosphoglycerate kinase step)

• No ATP is generated at this point.

Net effect: Reduced ATP yield (from 2 ATP/glucose to 1 ATP/glucose in RBCs when the shunt is active). This is a trade-off for enhanced oxygen delivery to tissues.

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7. Question:

Under what physiological conditions does 2,3-BPG concentration increase, and what is the clinical relevance?

Answer:
2,3-BPG increases in:

• Hypoxia (e.g., COPD, anemia)

• High altitude

• Chronic lung diseases

Clinical relevance:

• Enhances oxygen unloading in tissues

• Compensatory mechanism in anemia or low oxygen tension

• Explains why patients with anemia may not be severely symptomatic initially

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8. Question:

How does the 2,3-BPG concentration affect the oxygen dissociation curve of hemoglobin?

Answer:
Increased 2,3-BPG:

• Shifts the oxygen dissociation curve to the right

• Promotes oxygen release to tissues

• Decreases hemoglobin’s affinity for O₂

Decreased 2,3-BPG:

• Shifts the curve to the left

• Hemoglobin holds onto oxygen more tightly

This modulation is crucial for adapting to varying oxygen needs.

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9. Question:

Why is the Rapaport–Leubering cycle unique to erythrocytes?

Answer:

• The key enzyme bisphosphoglycerate mutase is highly expressed only in RBCs.

• RBCs have a specialized role in oxygen transport, making 2,3-BPG production vital.

• Other cells do not require modulation of hemoglobin function and thus do not express this pathway.

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10. Question:

A patient with chronic anemia shows increased levels of 2,3-BPG in red blood cells. What is the biochemical and physiological rationale behind this?

Answer:

• Chronic anemia → reduced oxygen-carrying capacity

• RBCs compensate by increasing 2,3-BPG → reduces hemoglobin’s oxygen affinity

• Facilitates oxygen unloading to tissues

Biochemically, more glycolytic intermediates are diverted through the Rapaport–Leubering cycle, sacrificing ATP for better tissue oxygenation.

Krebs Cycle: Inhibitors, Regulation, Amphibolic Nature

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Section 1: Inhibitors

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1. Question:

How does fluoroacetate inhibit the Krebs cycle, and what is the biochemical consequence of this inhibition?

Answer:

• Fluoroacetate is converted to fluorocitrate in the body.

• Fluorocitrate inhibits aconitase, the enzyme that converts citrate to isocitrate.

• This causes a block in the cycle, leading to accumulation of citrate and depletion of downstream intermediates.

• Biochemical consequence: Inhibition of ATP production, leading to cellular energy failure, especially in high-energy-demand tissues like the brain and heart.

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2. Question:

Which steps of the Krebs cycle are directly inhibited by NADH accumulation, and what is the physiological relevance of this inhibition?

Answer:

• NADH inhibits:

  • Isocitrate dehydrogenase

  • α-Ketoglutarate dehydrogenase

  • Citrate synthase

Relevance:

• NADH is a product of the cycle; its accumulation signals that the energy demand is low.

• Inhibition prevents unnecessary oxidation of acetyl-CoA, conserving substrates and preventing overproduction of ATP.

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3. Question:

How do arsenic compounds inhibit the Krebs cycle and what are the clinical implications?

Answer:

• Arsenite (As³⁺) inhibits lipoic acid, a cofactor for α-ketoglutarate dehydrogenase.

• This prevents conversion of α-ketoglutarate to succinyl-CoA.

• Clinical implications: Disruption of energy metabolism → neurological symptoms, vomiting, and multi-organ dysfunction. Arsenic poisoning is a medical emergency.

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Section 2: Regulation

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4. Question:

Which enzymes regulate the Krebs cycle and how are they modulated by the energy status of the cell?

Answer:
Key regulatory enzymes:

• High ATP/NADH: Inhibit the cycle (energy abundance).

• High ADP/Ca²⁺: Activate the cycle (energy demand, especially in muscles).

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5. Question:

How does calcium regulate the Krebs cycle during muscle contraction?

Answer:

• During muscle contraction, intracellular Ca²⁺ increases.

• Calcium activates:

  • Isocitrate dehydrogenase

  • α-Ketoglutarate dehydrogenase

This ensures that more ATP is produced to meet energy demands of contracting muscles.

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6. Question:

Explain the feedback inhibition mechanism in the Krebs cycle. Provide one example.

Answer:

• Feedback inhibition occurs when a product of the cycle inhibits an earlier enzyme to control flux.

• Example: Succinyl-CoA inhibits citrate synthase and α-ketoglutarate dehydrogenase.

• This prevents overaccumulation of intermediates and balances energy production with demand.

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Section 3: Amphibolic Nature

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7. Question:

What does it mean that the Krebs cycle is amphibolic, and what are two anabolic and two catabolic roles of the cycle?

Answer:

• Amphibolic = both catabolic and anabolic roles.

Catabolic roles (energy generation):

• Oxidation of acetyl-CoA to CO₂ → Produces NADH, FADH₂, ATP.

Anabolic roles (biosynthesis):

• Citrate → fatty acid and cholesterol synthesis.

• α-Ketoglutarate → amino acid (glutamate) synthesis.

• Succinyl-CoA → heme synthesis.

• Oxaloacetate → gluconeogenesis, aspartate synthesis.

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8. Question:

How does the Krebs cycle supply intermediates for gluconeogenesis and amino acid synthesis?

Answer:

• Oxaloacetate: Converted to phosphoenolpyruvate → gluconeogenesis.

• α-Ketoglutarate: Transaminated to glutamate → other amino acids.

These reactions link energy metabolism with biosynthetic pathways, showing the integrative role of the cycle.

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9. Question:

What is an anaplerotic reaction, and why is it important in the context of the Krebs cycle?

Answer:

• Anaplerotic reactions replenish Krebs cycle intermediates that are withdrawn for biosynthesis.

Key example:

• Pyruvate carboxylase converts pyruvate → oxaloacetate.

Importance:

• Maintains cycle function when intermediates are depleted for anabolic needs.

• Especially crucial in liver for gluconeogenesis.

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10. Question:

Why is the Krebs cycle central to intermediary metabolism?

Answer:

• It is the hub of metabolism, connecting carbohydrate, fat, and protein catabolism.

• Provides:

  • ATP/NADH for energy

  • Intermediates for biosynthesis

• Integrated with glycolysis, β-oxidation, gluconeogenesis, amino acid metabolism.

This central role allows the cell to adapt to varying metabolic states.

Gluconeogenesis

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1. Question:

Why is gluconeogenesis essential during prolonged fasting, and which organs are primarily involved?

Answer:

• During fasting, glycogen stores deplete within ~24 hours.

• Gluconeogenesis becomes the primary source of blood glucose, especially critical for the brain, RBCs, and renal medulla.

• Organs involved:

  • Liver (major site)

  • Kidney cortex (during prolonged fasting)

These organs convert non-carbohydrate precursors (like lactate, glycerol, alanine) into glucose, maintaining normoglycemia and preventing hypoglycemic coma.

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2. Question:

List three key irreversible steps in gluconeogenesis that bypass glycolysis, and name the enzymes involved.

Answer:

These steps are necessary to reverse the irreversible steps of glycolysis, making gluconeogenesis thermodynamically feasible.

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3. Question:

How does the energy requirement of gluconeogenesis differ from glycolysis?

Answer:

• Glycolysis (Glucose → Pyruvate): Net gain of 2 ATP

• Gluconeogenesis (Pyruvate → Glucose): Consumes 6 high-energy phosphate bonds per glucose

  • 4 ATP

  • 2 GTP

This energy investment is necessary to drive the endergonic process of glucose synthesis from non-carbohydrate precursors.

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4. Question:

What role does alanine play in gluconeogenesis, and how is it clinically relevant in starvation?

Answer:

• Alanine transports amino groups from muscle to liver (via glucose-alanine cycle).

• In the liver, alanine is transaminated to pyruvate, which enters gluconeogenesis.

• Clinical relevance: During starvation or catabolic states, muscle proteolysis releases amino acids like alanine to maintain blood glucose levels.

This also helps in nitrogen excretion via urea cycle.

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5. Question:

Why can’t fatty acids (even-chain) serve as substrates for gluconeogenesis?

Answer:

• β-oxidation of even-chain fatty acids produces acetyl-CoA.

• Acetyl-CoA cannot be converted back to pyruvate or oxaloacetate in animals due to the irreversible nature of pyruvate dehydrogenase.

• Hence, acetyl-CoA enters the TCA cycle, but the carbon is lost as CO₂, not contributing to net glucose formation.

Exception: Odd-chain fatty acids → Propionyl-CoA → Succinyl-CoA → Gluconeogenesis

Cori’s Cycle

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6. Question:

Explain the biochemical basis of the Cori Cycle and its significance during anaerobic glycolysis.

Answer:

• In anaerobic conditions (e.g., intense exercise), muscle cells convert glucose → lactate via glycolysis.

• Lactate diffuses into blood → transported to liver.

• In the liver: Lactate → Pyruvate → Glucose (via gluconeogenesis).

• This glucose returns to muscle for energy.

Significance:

• Prevents lactic acidosis

• Regenerates NAD⁺ in muscles

• Maintains blood glucose

This inter-organ lactate-glucose cycle supports energy needs when oxygen is limited.

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7. Question:

Why is the Cori cycle energetically costly, and how is it justified?

Answer:

• In muscle:

  • Glucose → 2 Lactate → 2 ATP produced

• In liver:

  • 2 Lactate → Glucose → 6 ATP consumed

Net energy cost: 4 ATP per cycle

Justification:

• Muscle needs rapid ATP → uses anaerobic glycolysis.

• Liver sacrifices energy to detoxify lactate and maintain glucose supply.

• Essential during hypoxia, sepsis, exercise.

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8. Question:

Compare and contrast the Cori Cycle and the Alanine Cycle.

Answer:

Both cycles conserve blood glucose and connect muscle to liver, but the alanine cycle also assists in nitrogen disposal.

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9. Question:

A patient with liver failure accumulates high levels of blood lactate. Explain the mechanism.

Answer:

• In liver failure, gluconeogenesis is impaired.

• The liver cannot convert lactate → glucose.

• This leads to lactate accumulation → lactic acidosis.

• Muscles continue to produce lactate during exertion, worsening the acidosis.

Clinical implication: Elevated lactate is a marker of poor hepatic function and metabolic stress.

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10. Question:

How does NAD⁺ regeneration differ in aerobic vs anaerobic conditions, and how is it relevant to the Cori cycle?

Answer:

• Aerobic conditions: NAD⁺ regenerated in the electron transport chain.

• Anaerobic conditions: NAD⁺ regenerated by converting pyruvate to lactate via lactate dehydrogenase.

Relevance to Cori Cycle:

• In muscle, this allows glycolysis to continue by maintaining NAD⁺.

• Lactate is then shuttled to liver for gluconeogenesis, closing the loop.

Glycogen Metabolism

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1. Question:

Explain the roles of glycogen synthase and glycogen phosphorylase in glycogen metabolism. How are they regulated?

Answer:

• Hormonal regulation:

  • Insulin: Promotes glycogen synthesis (activates synthase, inhibits phosphorylase).

  • Glucagon/Epinephrine: Promote glycogen breakdown (via cAMP → PKA pathway).

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2. Question:

Why is branching important in glycogen structure and metabolism?

Answer:

• Branching (α-1,6 bonds):

  • Increases solubility of glycogen.

  • Creates multiple non-reducing ends for rapid synthesis and degradation.

  • Provides compact storage form.

Branching enzyme creates these α-1,6 linkages; its deficiency causes GSD type IV (Andersen disease).

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3. Question:

How does glycogen metabolism differ in the liver vs muscle?

Answer:

• Muscle glycogen is not shared with other tissues due to lack of glucose-6-phosphatase.

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4. Question:

Why is UDP-glucose used in glycogen synthesis instead of glucose-1-phosphate directly?

Answer:

• UDP-glucose is an activated form of glucose.

• Its formation from glucose-1-phosphate and UTP (via UDP-glucose pyrophosphorylase) drives the reaction forward by removing PPi (which is rapidly hydrolyzed).

• Makes glycogen synthesis thermodynamically favorable.

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5. Question:

Explain the biochemical basis of the “fight or flight” response related to glycogen metabolism in muscle.

Answer:

• Epinephrine binds to β-adrenergic receptors → activates adenylyl cyclase → increases cAMP.

• cAMP activates protein kinase A (PKA) → phosphorylates and activates phosphorylase kinase → activates glycogen phosphorylase.

• Result: Rapid glycogen breakdown → glucose-1-P → energy production via glycolysis.

This enables muscle to respond quickly to energy demands.

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Glycogen Storage Diseases (GSDs)

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6. Question:

Why do patients with Von Gierke disease (GSD type I) present with severe fasting hypoglycemia?

Answer:

• Defect: Glucose-6-phosphatase deficiency (liver and kidney).

• Impaired final step of gluconeogenesis and glycogenolysis → inability to release free glucose into blood.

• Accumulation of glucose-6-phosphate leads to:

  • Lactic acidosis

  • Hyperuricemia

  • Hyperlipidemia

Clinical features: Protuberant abdomen (hepatomegaly), hypoglycemic seizures, doll-like face.

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7. Question:

Compare and contrast GSD type I (Von Gierke) and GSD type V (McArdle) in terms of enzyme defect and clinical presentation.

Answer:

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8. Question:

Why do patients with McArdle disease experience muscle cramps during exercise but normal blood glucose levels?

Answer:

• Deficiency in muscle glycogen phosphorylase → muscle can’t access its own glycogen stores.

• ATP deficiency during exertion → muscle cramps, fatigue.

• No effect on liver glucose output → normal blood glucose.

• Myoglobinuria may occur due to muscle breakdown.

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9. Question:

What is the biochemical defect in Pompe disease (GSD type II), and how does it differ from other GSDs?

Answer:

• Deficiency: Lysosomal acid α-glucosidase (acid maltase).

• Glycogen accumulates in lysosomes, especially in cardiac and skeletal muscle.

• Unique feature: It’s a lysosomal storage disorder, not a defect in cytosolic glycogen metabolism.

Clinical types:

• Infantile form: Cardiomegaly, hypotonia, early death.

• Late-onset: Progressive muscle weakness, no hypoglycemia.

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10. Question:

A child presents with hepatomegaly and mild hypoglycemia but no lactic acidosis. What is the likely GSD and the enzyme defect?

Answer:

• Likely Cori disease (GSD type III).

• Defect: Debranching enzyme deficiency.

• Features:

  • Hepatomegaly

  • Mild hypoglycemia

  • Normal lactate (since gluconeogenesis is intact)

• Accumulation of limit dextrin-like structures in liver and muscle.