Carbohydrate Metabolism Biochemistry MBBS 1st Year by Dr. Rajesh Jambhulkar

Carbohydrate metabolism maintains energy homeostasis through interconnected pathways. Glycolysis converts glucose to pyruvate for ATP, while Gluconeogenesis and Glycogenolysis (stimulated by glucagon) replenish blood glucose during fasting. Conversely, Glycogenesis (stimulated by insulin) stores excess glucose as glycogen. The TCA Cycle serves as the final oxidative hub, and the HMP Shunt provides NADPH for antioxidant defense and ribose for biosynthesis.

Clinical relevance is centered on enzymatic defects. G6PD deficiency impairs NADPH production, leading to hemolysis, while GSDs like Von Gierke’s cause severe hypoglycemia. In Diabetes Mellitus, hyperglycemia drives the Polyol pathway, causing osmotic damage (cataracts/neuropathy). Understanding these biochemical regulators, such as PFK-1 and 2,3-BPG, is foundational for managing metabolic and endocrine disorders.

Carbohydrate Metabolism Biochemistry MBBS 1st Year- Video Explanation

This video breakdown simplifies complex biochemical cycles into high-yield concepts for your professional exams. We visualize the intricate regulation of glycolysis, gluconeogenesis, and the TCA cycle, while correlating enzymatic defects to clinical presentations like G6PD deficiency and Diabetes Mellitus.

What is Carbohydrate Metabolism?

Carbohydrate metabolism is fundamental for energy production and maintaining cellular homeostasis. This comprehensive overview details the crucial biochemical pathways involved in processing carbohydrates, from digestion and absorption to complex metabolic cycles and their regulation. 

Understanding these processes is vital for medical students to grasp various physiological states and common clinical disorders impacting human health.

Carbohydrate Digestion and Absorption

Digestion converts complex carbohydrates into simpler, absorbable monosaccharides. This process begins in the mouth, continues in the stomach, and is completed in the small intestine.

1. Dietary Carbohydrates

Main dietary carbohydrates include:

• Polysaccharides: Starch, Glycogen

• Disaccharides: Lactose, Sucrose

• Monosaccharides: Glucose, Fructose

• Dietary Fiber: Cellulose (indigestible)

2. Process of Digestion by Location

• Mouth: Salivary amylase begins breaking down starch by cleaving α-1,4 glycosidic linkages. Its action is limited by short transit time.

• Stomach: Acidic pH inactivates salivary amylase. HCl causes some acid hydrolysis of sucrose.

• Small Intestine:

• Pancreatic amylase (released in response to Secretin and Cholecystokinin - CCK) is the major enzyme, cleaving α-1,4 glycosidic linkages to produce dextrins, maltose, and isomaltose.

• Brush Border Enzymes (Disaccharidases):

• Lactase: Lactose → Glucose + Galactose

• Sucrase: Sucrose → Glucose + Fructose

• Maltase: Maltose → Glucose + Glucose

• Isomaltase: Cleaves α-1,6 glycosidic linkages (branch points) → Glucose + Glucose

3. Absorption of Monosaccharides

Final products (glucose, galactose, fructose) are absorbed into intestinal cells.

• Glucose and Galactose: Absorbed via secondary active transport by SGLT1 (Sodium-Glucose Transporter 1), powered by the Sodium-Potassium ATPase pump (Memory Tip: Remember 'Nokia' for Na⁺ out, K⁺ in, active transport).

• Fructose: Absorbed via facilitated diffusion by GLUT5.

• Exit from Intestinal Cell: All three monosaccharides exit into the bloodstream via facilitated diffusion through GLUT2 on the basolateral membrane.

Glucose Transporters (GLUTs)

GLUTs are crucial proteins facilitating glucose transport across cell membranes via facilitated diffusion.

Comparative Structure: Types of GLUT Transporters

Glycolysis (Embden-Meyerhof-Parnas Pathway)

Glycolysis is the metabolic pathway that converts one glucose molecule into two pyruvate (aerobic) or lactate (anaerobic) molecules.

Clinical Application: Sodium fluoride in blood sample tubes inhibits glycolytic enzyme enolase, preventing RBCs from consuming glucose, thus ensuring accurate blood glucose measurement.

Key Features of Glycolysis:

• Location: Cytoplasm of all cells.

• Oxygen Requirement: Can be aerobic or anaerobic.

• Phases: Energy Investment (consumes ATP) and Energy Generation (produces ATP and NADH).

• Irreversible Steps: Three key regulatory points.

• Substrate-Level Phosphorylation: Two steps produce ATP directly.

Steps of Glycolysis (Key Regulatory and Energy-Generating Steps):

1. Glucose → Glucose-6-Phosphate (G6P): Catalyzed by Hexokinase (most tissues) or Glucokinase (liver, pancreas). First irreversible step, traps glucose. Consumes ATP.

2. Fructose-6-Phosphate (F6P) → Fructose-1,6-bisphosphate (F1,6BP): Catalyzed by Phosphofructokinase-1 (PFK-1). Second irreversible step, major rate-limiting step. Consumes ATP.

3. Glyceraldehyde-3-Phosphate (G3P) → 1,3-Bisphosphoglycerate (1,3-BPG): Catalyzed by Glyceraldehyde-3-Phosphate Dehydrogenase. Produces NADH.

4. 1,3-BPG → 3-Phosphoglycerate (3-PG): Catalyzed by Phosphoglycerate Kinase. Produces ATP (Substrate-Level Phosphorylation).

5. Phosphoenolpyruvate (PEP) → Pyruvate: Catalyzed by Pyruvate Kinase. Produces ATP (Substrate-Level Phosphorylation). Third irreversible step. Inhibited by fluoride.

Fate of Pyruvate:

• Aerobic: Converted to Acetyl-CoA for TCA cycle in mitochondria.

• Anaerobic: Converted to Lactate by Lactate Dehydrogenase, regenerating NAD⁺ for glycolysis to continue.

Energetics of Glycolysis (Net Yield per Glucose Molecule)

Regulation of Glycolysis

Regulation primarily occurs at the three irreversible steps, with PFK-1 being critical.

• Hormonal: Insulin promotes, Glucagon inhibits.

• Allosteric:

• PFK-1: Activated by AMP, Fructose 2,6-bisphosphate. Inhibited by ATP, Citrate.

Regulation of Glycolysis & Clinical Significance

Regulation:

1. Hormonal Regulation: Insulin (anabolic, promotes synthesis) and Glucagon.

2. Covalent Modification: Phosphorylation/dephosphorylation of enzymes.

3. Allosteric Regulation: Activation/inhibition by metabolic intermediates.

Clinical Significance:

• Muscle Phosphofructokinase (PFK) Deficiency: Known as Tarui's disease (GSD Type VII), leading to exercise intolerance and mild hemolysis.

• Inhibition by Fluoride: Fluoride ions specifically inhibit enolase in glycolysis, hence their use in blood sample collection to preserve glucose levels.

Rapoport-Luebering Cycle

This metabolic shunt occurs specifically in Red Blood Cells (RBCs), primarily generating 2,3-Bisphosphoglycerate (2,3-BPG). RBCs depend solely on glucose for energy.

The Pathway:

1. 1,3-Bisphosphoglycerate (1,3-BPG) (from glycolysis) is converted to 2,3-BPG by bisphosphoglycerate mutase.

2. 2,3-BPG is then converted back to 3-Phosphoglycerate by 2,3-bisphosphoglycerate phosphatase, rejoining glycolysis.
   Crucially, this shunt bypasses the ATP-generating step of glycolysis.

Function and Mechanism of 2,3-BPG:

2,3-BPG is a critical modulator of hemoglobin's oxygen affinity. It binds to deoxyhemoglobin, stabilizing its T-state (tense), which decreases hemoglobin's affinity for oxygen and promotes oxygen unloading to tissues.

The Oxygen-Hemoglobin Dissociation Curve:

The curve is sigmoidal due to cooperative binding. A right shift indicates decreased oxygen affinity and enhanced oxygen delivery.

Factors Causing a Right Shift (Important for MCQs):

1. Increased 2,3-BPG

2. Increased H+ concentration (decreased pH, acidity)

3. Increased pCO2

4. Increased Temperature

Clinical and Physiological Significance:

• Increased 2,3-BPG: Compensatory in anemia, hypoxia (e.g., high altitude), COPD.

• Fetal Hemoglobin (HbF): Has low affinity for 2,3-BPG, ensuring higher oxygen affinity for efficient oxygen transfer from mother to fetus.

• Stored Blood: 2,3-BPG levels decrease during storage, reducing oxygen-carrying capacity.

Gluconeogenesis

Gluconeogenesis is the synthesis of new glucose molecules from non-carbohydrate precursors. It is predominant during prolonged fasting. Glucagon strongly stimulates this pathway.

Substrates for Gluconeogenesis:

1. Lactate (from anaerobic glycolysis)

2. Glycerol (from triglyceride breakdown)

3. Glucogenic Amino Acids (e.g., Alanine from muscle protein breakdown)

• Cannot be converted to glucose: Even-chain fatty acids and their breakdown product, Acetyl-CoA, because the pyruvate to acetyl-CoA conversion is irreversible.

Bypassing the Irreversible Steps of Glycolysis:

Gluconeogenesis uses four unique enzymes to bypass the three irreversible glycolytic steps:

Reciprocal Regulation of Glycolysis and Gluconeogenesis:

Pyruvate Dehydrogenase (PDH) Complex

The PDH Complex catalyzes the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA, linking glycolysis to the TCA cycle.

Components of the PDH Complex

Regulation: The PDH complex is active in its dephosphorylated state. Insulin promotes its dephosphorylation and activation.

The Tricarboxylic Acid (TCA) Cycle (Krebs Cycle)

The TCA cycle is the final common oxidative pathway for carbohydrates, proteins, and lipids, which are all converted to Acetyl-CoA. It generates reducing equivalents (NADH, FADH₂) for ATP production.

The Cycle Steps (Key Intermediates and Products):

(Memory Tip: "Citrate Is A Krebs' Starting Substrate For Making Oxaloacetate")

1. Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate (6C) (Citrate Synthase).

2. Citrate → Isocitrate.

3. Isocitrate → α-Ketoglutarate (5C): Produces 1 NADH, 1 CO₂.

4. α-Ketoglutarate → Succinyl-CoA (4C): Produces 1 NADH, 1 CO₂.

5. Succinyl-CoA → Succinate: Produces 1 GTP (ATP equivalent).

6. Succinate → Fumarate: Produces 1 FADH₂.

7. Fumarate → Malate.

8. Malate → Oxaloacetate: Produces 1 NADH.

Energetics of the TCA Cycle (per Acetyl-CoA):

• 3 NADH → 7.5 ATP

• 1 FADH₂ → 1.5 ATP

• 1 GTP → 1.0 ATP

• Total = 10 ATP per turn

• Total from one Glucose: (2 Acetyl-CoA) = 20 ATP.

• Total ATP from complete aerobic respiration (1 Glucose): Glycolysis (7 ATP) + PDH (5 ATP) + TCA Cycle (20 ATP) = 32 ATP.

Amphibolic Role: The TCA cycle is both catabolic (oxidizes Acetyl-CoA to CO₂) and anabolic (intermediates are precursors for fatty acids, amino acids, heme synthesis).

Anaplerotic Reactions: Replenish TCA cycle intermediates. The most important is Pyruvate → Oxaloacetate (catalyzed by pyruvate carboxylase).

Glycogen Metabolism

Glycogen is a branched homopolysaccharide of glucose, serving as glucose storage in animals, primarily in the liver and muscle.

Comparative Structure: Glycogenesis vs. Glycogenolysis

Glycogenesis (Synthesis of Glycogen):

1. Activation of Glucose: Glucose is converted to UDP-glucose (activated form).

2. Elongation: Glycogen Synthase transfers glucose from UDP-glucose to form α-1,4 glycosidic linkages.

3. Branching: Branching enzyme creates α-1,6 glycosidic linkages.

Glycogenolysis (Breakdown of Glycogen):

1. Phosphorolysis: Glycogen Phosphorylase (requires pyridoxal phosphate - PLP) cleaves α-1,4 glycosidic bonds, releasing glucose-1-phosphate. It stops at 4 glucose units from a branch point, forming a limit dextrin.

2. Debranching: Debranching Enzyme (bifunctional) moves 3 glucose residues (transferase activity) and hydrolyzes the α-1,6 glycosidic bond (glucosidase activity), releasing free glucose.

Fate of Glucose-6-Phosphate:

• Liver: Contains Glucose-6-Phosphatase, releasing free glucose to maintain blood sugar.

• Muscle: Lacks Glucose-6-Phosphatase, uses G6P directly for its own energy via glycolysis.

Regulation of Glycogen Metabolism:

• Hormonal Regulation (Cascade Mechanism):

• Glucagon/Epinephrine: Bind to receptors, activate adenylyl cyclase → cAMP → activate Protein Kinase A (PKA). PKA phosphorylates and activates Glycogen Phosphorylase, leading to glycogenolysis. PKA also phosphorylates and inactivates Glycogen Synthase.

• Insulin: Activates phosphodiesterase (decreases cAMP) and protein phosphatases. This leads to dephosphorylation, inactivating Glycogen Phosphorylase and activating Glycogen Synthase, promoting glycogenesis.

• Allosteric Regulation:

• AMP: Activates muscle Glycogen Phosphorylase (energy demand).

• Calcium (Ca²⁺): Activates Phosphorylase Kinase (muscle contraction).

Glycogen Storage Disorders (GSDs)

GSDs are genetic defects in glycogen metabolism enzymes, causing abnormal glycogen accumulation.

Summary of Key Glycogen Storage Disorders

Hexose Monophosphate (HMP) Shunt / Pentose Phosphate Pathway (PPP)

The HMP Shunt is an alternative glucose oxidation pathway primarily producing:

1. NADPH: Crucial reducing agent.

2. Ribose-5-Phosphate: Precursor for nucleotide synthesis.

Functions of NADPH:

• Reductive Biosynthesis: Fatty acid, cholesterol synthesis.

• Antioxidant Defense: Regenerates reduced glutathione, protecting cells (especially RBCs) from oxidative damage.

• Respiratory Burst in phagocytes.

Oxidative Phase (Irreversible):

Glucose-6-Phosphate is oxidized by Glucose-6-Phosphate Dehydrogenase (G6PD) (the rate-limiting step), producing NADPH and CO₂.

Clinical Correlation: G6PD Deficiency

An X-linked genetic disorder, G6PD deficiency leads to decreased NADPH production. RBCs become vulnerable to oxidative damage because the HMP shunt is their only NADPH source. This causes hemolytic anemia triggered by oxidant stressors (e.g., antimalarial drugs like primaquine, sulfonamides, fava beans - favism, infections).

Galactose and Fructose Metabolism

Galactose Metabolism:

Galactose is converted to glucose via: Galactose → Galactose-1-phosphate (by Galactokinase) → UDP-galactose (by Galactose-1-Phosphate Uridyltransferase (GALT)) → UDP-glucose.

Clinical Correlation: Classical Galactosemia

An autosomal recessive disorder caused by GALT deficiency. Leads to accumulation of galactose-1-phosphate (toxic) and galactitol. Clinical features include hepatomegaly, jaundice, hypoglycemia, mental retardation, and cataracts (due to galactitol).

Fructose Metabolism:

Fructose is metabolized primarily in the liver: Fructose → Fructose-1-phosphate (by Fructokinase) → Dihydroxyacetone phosphate (DHAP) + Glyceraldehyde (by Aldolase B). This bypasses the PFK-1 regulatory step of glycolysis.

Clinical Correlation: Hereditary Fructose Intolerance (HFI)

An autosomal recessive disorder caused by Aldolase B deficiency. Accumulation of fructose-1-phosphate is toxic, causing severe hypoglycemia, hepatomegaly, and jaundice after fructose ingestion. Symptoms appear upon weaning.

Polyol Pathway (Sorbitol Pathway)

Significant in hyperglycemia (e.g., Diabetes Mellitus).

1. Glucose → Sorbitol: By Aldose Reductase (NADPH-dependent).

2. Sorbitol → Fructose: By Sorbitol Dehydrogenase (NAD+-dependent).

Clinical Significance in Diabetes: Tissues with low Sorbitol Dehydrogenase activity (e.g., lens, retina, kidney, Schwann cells) accumulate sorbitol in hyperglycemia. This osmotic effect leads to cellular damage and diabetic complications like cataracts, retinopathy, and neuropathy.

Blood Glucose Regulation

Blood glucose regulation balances sources and utilization.

Sources of Blood Glucose:

1. Dietary carbohydrate absorption.

2. Glycogenolysis.

3. Gluconeogenesis.

Pathways that Utilize Glucose:

1. Glycolysis & TCA Cycle.

2. HMP Shunt.

3. Glycogenesis & Lipogenesis.

Normal Blood Glucose Ranges:

• Fasting: 70–110 mg/dL.

• Post-prandial: 110–140 mg/dL.

Hormonal Control:

• Hypoglycemic: Insulin (only one hormone).

• Increases glucose uptake (GLUT4), promotes glycolysis/glycogenesis, inhibits glycogenolysis/gluconeogenesis.

• Hyperglycemic: Glucagon, Epinephrine, Growth Hormone, ACTH, Thyroxine.

• Glucagon/Epinephrine: Stimulate glycogenolysis and gluconeogenesis via a cAMP-PKA cascade.

Clinical Case Studies

• Lactose Intolerance: Lactase deficiency causes GI symptoms (flatulence, bloating) after consuming lactose due to bacterial fermentation of undigested sugar.

• Von Gierke's Disease (GSD Type I): Deficiency of Glucose-6-Phosphatase leads to severe fasting hypoglycemia, hepatomegaly, lactic acidosis, and hyperlipidemia.

• Pompe's Disease (GSD Type II): Deficiency of lysosomal α-1,4-glucosidase results in massive cardiomegaly, hypotonia, and early death due to heart failure.

• McArdle's Disease (GSD Type V): Deficiency of muscle glycogen phosphorylase causes exercise intolerance and muscle cramps, but no hypoglycemia as liver glycogenolysis is unaffected.

HbA1c (Glycated Hemoglobin): Reflects the average blood glucose level over the preceding 8-12 weeks.

Why This Chapter Important for MBBS 1st Year?

Understanding carbohydrate metabolism is the cornerstone of clinical biochemistry, bridging the gap between cellular energy production and the diagnosis of systemic metabolic disorders.

• Foundation of Energy Homeostasis: It explains how the body maintains a steady blood glucose level via a delicate balance between insulin and glucagon.

• Clinical Diagnostics: Knowledge of pathways like Glycolysis and the HMP Shunt is essential for interpreting common tests, such as blood glucose levels preserved with sodium fluoride or HbA1c for long-term monitoring.

• Critical Disease Pathways: It provides the biochemical basis for high-yield medical conditions, including Diabetes Mellitus, G6PD Deficiency, and various Glycogen Storage Disorders.

• Organ-Specific Physiology: It details why certain tissues have unique requirements, such as the brain’s reliance on glucose and the RBCs’ use of the Rapoport-Luebering Cycle to regulate oxygen delivery via 2,3-BPG.

• Metabolic Integration: The TCA Cycle acts as the final common oxidative pathway, illustrating how carbohydrates, lipids, and proteins intersect to generate ATP.