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🔬 Carbohydrate Metabolism - MBBS Biochemistry (Simple English)

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The Big Picture First

Glucose → Glycolysis → Pyruvate → Acetyl-CoA → TCA Cycle → Oxidative Phosphorylation → ATP (energy)

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PART 1: How Does Glucose Get Into Cells?

A. GLUT Transporters (Passive - no energy needed)

B. SGLT (Sodium-Dependent - active, needs energy)

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PART 2: GLYCOLYSIS - "Breaking Glucose in Half"

1 Glucose (6C) → 2 Pyruvate (3C) + 2 ATP + 2 NADH

The Two Phases

• You use 2 ATP to phosphorylate glucose
• This "primes the pump" - glucose is trapped in the cell and activated

• You make 4 ATP + 2 NADH
• Net gain = 4 - 2 = 2 ATP per glucose

The 10 Key Steps (Simplified)

The 3 Irreversible (Key) Enzymes - Remember "HoPK"

1. Hexokinase / Glucokinase (step 1)
2. PFK-1 (step 3) - the rate-limiting step
3. Pyruvate Kinase (step 10)

What Controls PFK-1?

• Activated by: AMP, ADP (low energy state = speed up glycolysis), Fructose-2,6-bisphosphate (most potent activator, stimulated by insulin)
• Inhibited by: ATP, citrate (high energy state = slow down)

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PART 3: WHAT HAPPENS TO PYRUVATE?

                    [WITH O2]
Pyruvate ─────────────────────────→ Acetyl-CoA → TCA Cycle
                                  (Pyruvate Dehydrogenase)

                    [WITHOUT O2]
Pyruvate ─────────────────────────→ Lactate
                                  (Lactate Dehydrogenase)

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PART 4: PYRUVATE DEHYDROGENASE COMPLEX (PDC)

Pyruvate (3C) → Acetyl-CoA (2C) + CO₂ + NADH

Cofactors needed (remember "Tender Loving Care For Nancy")

• TPP (Thiamine - Vitamin B1)
• Lipoate (Lipoic acid)
• CoA (Coenzyme A - Pantothenic acid, B5)
• FAD (Riboflavin, B2)
• NAD⁺ (Niacin, B3)

PDC Regulation

• Activated by: ADP, NAD⁺, CoA, Ca²⁺, insulin
• Inhibited by: Acetyl-CoA, NADH, ATP (products inhibit when energy is high)

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PART 5: TCA CYCLE (Krebs Cycle / Citric Acid Cycle)

The 8 Steps of TCA

Per Turn of TCA Cycle, you get:

• 3 NADH + 1 FADH₂ + 1 GTP + 2 CO₂

Regulation of TCA Cycle

• Citrate synthase - inhibited by citrate, ATP, NADH
• Isocitrate dehydrogenase - inhibited by NADH, ATP; activated by ADP
• α-KG dehydrogenase - inhibited by succinyl-CoA, NADH

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PART 6: TOTAL ATP YIELD FROM 1 GLUCOSE

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PART 7: ANAEROBIC GLYCOLYSIS - When No Oxygen is Available

Pyruvate + NADH → Lactate + NAD⁺ (enzyme: Lactate Dehydrogenase)

• RBCs - no mitochondria, always use anaerobic glycolysis
• Exercising muscle - when O₂ supply cannot keep up with demand
• Cancer cells - prefer anaerobic glycolysis even with O₂ present (Warburg effect)
• Eye lens, cornea - no blood supply

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PART 8: GLYCOGEN METABOLISM (Quick Overview)

• Stored mainly in liver (for blood glucose maintenance) and muscle (for local use)

• Insulin - promotes glycogenesis (after meals)
• Glucagon/Epinephrine - promotes glycogenolysis (fasting/stress)

• Von Gierke (Type I): Glucose-6-phosphatase deficiency → severe hypoglycemia, liver enlargement
• McArdle (Type V): Muscle phosphorylase deficiency → muscle cramps on exercise
• Pompe (Type II): Lysosomal acid maltase (GAA) deficiency → cardiomegaly in infants

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PART 9: GLUCONEOGENESIS - "Making New Glucose"

1. Lactate (from RBCs, exercising muscle)
2. Glycerol (from fat breakdown)
3. Alanine (from muscle protein)
4. Oxaloacetate (from most amino acids)

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PART 10: PENTOSE PHOSPHATE PATHWAY (HMP Shunt)

1. Makes NADPH (needed for fatty acid synthesis, steroid synthesis, and to protect RBCs from oxidative damage via glutathione)
2. Makes Ribose-5-phosphate (needed for nucleotide/DNA/RNA synthesis)

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Summary Flowchart

GLUCOSE
  │
  ↓  [Glycolysis - Cytoplasm]
PYRUVATE + 2 ATP + 2 NADH
  │
  ├──[No O2]──→ LACTATE (only 2 ATP total)
  │
  ↓  [Pyruvate Dehydrogenase - Mitochondria]
ACETYL-CoA + CO2 + NADH
  │
  ↓  [TCA Cycle - Mitochondria]
3 NADH + 1 FADH2 + 1 GTP + 2 CO2 per turn
  │
  ↓  [Oxidative Phosphorylation - ETC]
~30-32 ATP TOTAL

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High-Yield Exam Points

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• Lippincott Illustrated Reviews: Biochemistry, 8e, pp. 294-298
• Basic Medical Biochemistry: A Clinical Approach, 6e, pp. 791-793, 844
• Harper's Illustrated Biochemistry, 32e, pp. 168-170

🔬 CARBOHYDRATE METABOLISM - Complete MBBS Notes

Simple English | Textbook-Based | Exam-Ready

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📋 TABLE OF CONTENTS

1. Glucose Transport (GLUTs & SGLTs)
2. Glycolysis - All 10 Steps in Detail
3. Pyruvate's Fate - Aerobic vs Anaerobic
4. Pyruvate Dehydrogenase Complex (PDC)
5. TCA Cycle / Krebs Cycle - All 8 Steps
6. Oxidative Phosphorylation & ETC
7. Total ATP Yield
8. Gluconeogenesis
9. Glycogen Metabolism
10. Pentose Phosphate Pathway (HMP Shunt)
11. Cori Cycle & Glucose-Alanine Cycle
12. Clinical Conditions - All High-Yield Diseases

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PART 1: GLUCOSE TRANSPORT INTO CELLS

A. GLUT Transporters (Facilitated Diffusion - FREE, no ATP needed)

B. SGLT Transporters (Active Transport - needs Na+ gradient)

• Block glucose reabsorption in kidney proximal tubule
• Glucose spills into urine → lowers blood glucose
• Used in Type 2 Diabetes; also reduces cardiovascular events and protects kidneys

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PART 2: GLYCOLYSIS - ALL 10 STEPS IN DETAIL

PHASE 1: Energy-Investment Phase (Steps 1-5)

"Spend 2 ATP to prime the pump"

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Step 1 - Glucose → Glucose-6-Phosphate (G6P)

• Hexokinase: Works even at low glucose - always phosphorylates glucose. But once cells are full (G6P builds up), it stops automatically.
• Glucokinase: Only activates when blood glucose is HIGH (after a meal). Acts as a glucose-sensor in the pancreas - triggers insulin secretion. In liver, it clears excess blood glucose rapidly. Mutations in glucokinase → MODY (Maturity Onset Diabetes of the Young) Type 2.

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Step 2 - Glucose-6-P → Fructose-6-P

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Step 3 - Fructose-6-P → Fructose-1,6-bisphosphate (F1,6-bisP)

• Insulin → activates PFK-2 → F2,6-bisP increases → PFK-1 activated → glycolysis ON
• Glucagon → inhibits PFK-2 / activates F2,6-bisPhosphatase → F2,6-bisP decreases → PFK-1 inhibited → glycolysis OFF, gluconeogenesis ON

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Step 4 - Fructose-1,6-bisP → DHAP + Glyceraldehyde-3-P (GAP)

• Dihydroxyacetone phosphate (DHAP) - can go to glycerol-3-P (for fat synthesis)
• Glyceraldehyde-3-phosphate (GAP) - continues in glycolysis

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Step 5 - DHAP → GAP

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PHASE 2: Energy-Generation Phase (Steps 6-10)

"Make 4 ATP + 2 NADH (net gain = 2 ATP)"

Step 6 - GAP → 1,3-bisphosphoglycerate (1,3-BPG)

• This is an oxidation-reduction reaction - NAD+ is reduced to NADH
• The energy of oxidation is conserved in the high-energy phosphate bond of 1,3-BPG
• Arsenate (pentavalent arsenic) poisons this step: competes with phosphate, forms unstable product → bypasses ATP generation → no net ATP from glycolysis!
• This step REQUIRES NAD+. If NAD+ runs out, glycolysis stops - that's why in anaerobic conditions, pyruvate must be converted to lactate to regenerate NAD+

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Step 7 - 1,3-BPG → 3-Phosphoglycerate (3-PG)

• 2,3-BPG binds to hemoglobin and DECREASES its affinity for O2 (shifts oxygen dissociation curve RIGHT)
• This promotes O2 release to tissues
• High altitude, anemia, chronic hypoxia → increased 2,3-BPG → more O2 delivery to tissues

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Step 8 - 3-PG → 2-Phosphoglycerate (2-PG)

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Step 9 - 2-PG → Phosphoenolpyruvate (PEP)

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Step 10 - PEP → Pyruvate

• Activated by: Fructose-1,6-bisP (feedforward activation - PFK-1 goes up, so PK goes up), insulin
• Inhibited by: ATP, acetyl-CoA, alanine, glucagon (via phosphorylation)

• Most common enzyme defect of glycolysis
• RBCs cannot make ATP → RBC membrane fails → Hemolytic Anemia
• Unlike G6PD deficiency, NOT triggered by oxidative stress; it's chronic

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Glycolysis Summary

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PART 3: FATE OF PYRUVATE

                   ┌─────[O2 present]──→ Acetyl-CoA (via PDC) ─→ TCA cycle
                   │
  2 Pyruvate ──────┤
                   │
                   ├─────[No O2]────────→ Lactate (via LDH)
                   │
                   └─────[Liver/Kidney]──→ Glucose (Gluconeogenesis)

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PART 4: PYRUVATE DEHYDROGENASE COMPLEX (PDC)

Structure of PDC

• Thiamine (B1) - TPP
• Lipoic acid
• CoA (Pantothenate - B5)
• FAD (Riboflavin - B2)
• NAD+ (Niacin - B3)

1. E1 (with TPP): Pyruvate loses CO2, remaining 2C fragment binds to TPP
2. E2 (with Lipoate): 2C fragment transferred to lipoate, then to CoA → Acetyl-CoA formed, lipoate reduced
3. E3 (with FAD): Reduced lipoate is reoxidized, FAD reduced to FADH2, then FADH2 transfers electrons to NAD+ → NADH

PDC Regulation (Very Important for MBBS!)

1. Allosteric (fast, instant)
2. Covalent modification by phosphorylation (slower)

Allosteric:

• Activated by: AMP, ADP, NAD+, CoA, Ca2+ (during exercise/muscle contraction), insulin
• Inhibited by: Acetyl-CoA (product), NADH (product), ATP (high energy)

Covalent (Phosphorylation):

• PDC Kinase phosphorylates PDC → INACTIVE (when ATP, acetyl-CoA, NADH are high)
• PDC Phosphatase dephosphorylates PDC → ACTIVE (when Ca2+, insulin are high)

PDC Deficiency - Clinical

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PART 5: TCA CYCLE (Krebs / Citric Acid Cycle) - ALL 8 STEPS

The 8 Steps of TCA Cycle:

Step 1: OAA (4C) + Acetyl-CoA (2C) → Citrate (6C)

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Step 2: Citrate (6C) → Isocitrate (6C)

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Step 3: Isocitrate (6C) → α-Ketoglutarate (5C) + CO2

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Step 4: α-Ketoglutarate (5C) → Succinyl-CoA (4C) + CO2

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Step 5: Succinyl-CoA (4C) → Succinate (4C)

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Step 6: Succinate (4C) → Fumarate (4C)

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Step 7: Fumarate (4C) → Malate (4C)

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Step 8: Malate (4C) → Oxaloacetate (4C)

Per Turn Summary:

TCA Cycle Regulation

1. Citrate Synthase - inhibited by citrate, NADH, ATP, succinyl-CoA
2. Isocitrate Dehydrogenase - inhibited by NADH, ATP; activated by ADP, Ca2+
3. α-KG Dehydrogenase - inhibited by succinyl-CoA, NADH; activated by Ca2+

Anaplerosis & Cataplerosis

• Main reaction: Pyruvate + CO2 → OAA (enzyme: Pyruvate Carboxylase, needs biotin)
• Amino acids also feed in at various points

• OAA → PEP (for gluconeogenesis)
• α-Ketoglutarate → Glutamate (for amino acid synthesis)
• Succinyl-CoA → Heme synthesis

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PART 6: OXIDATIVE PHOSPHORYLATION & ELECTRON TRANSPORT CHAIN (ETC)

The 4 Complexes

Chemiosmotic Theory (Peter Mitchell, Nobel Prize 1978)

• As electrons flow through Complexes I, III, IV, protons (H+) are pumped OUT of the mitochondrial matrix into the intermembrane space
• This creates an electrochemical gradient (proton motive force, Δp) across the inner membrane
• Protons want to flow back into the matrix (down their gradient)
• They can only re-enter through ATP Synthase (Complex V / F0F1-ATPase)
• As protons flow through ATP synthase, it rotates (like a turbine) and generates ATP from ADP + Pi

ATP Yield per NADH vs FADH2

• 1 NADH → ~2.5 ATP (passes through Complexes I, III, IV - pumps 10 H+)
• 1 FADH2 → ~1.5 ATP (bypasses Complex I, only pumps 6 H+ through Complexes III & IV)

Inhibitors of ETC - Clinical Importance

Uncouplers - Separate Proton Flow from ATP Synthesis

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PART 7: TOTAL ATP YIELD FROM 1 GLUCOSE

• Aerobic: ~30-32 ATP per glucose
• Anaerobic (no O2): Only 2 ATP per glucose (only glycolysis works)

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PART 8: GLUCONEOGENESIS - Making Glucose from Scratch

The 4 Main Precursors

The 3 Bypass Steps (Most Important!)

Bypass 1: Pyruvate → PEP (Replaces Pyruvate Kinase)

• Enzyme: Pyruvate Carboxylase (requires Biotin + ATP)
• Activated by: Acetyl-CoA
• Note: Acetyl-CoA activating pyruvate carboxylase is clever - when fat is being burned (lots of Acetyl-CoA), body says "also make glucose from pyruvate"

• Enzyme: PEPCK (Phosphoenolpyruvate Carboxykinase) (needs GTP, releases CO2)
• OAA is transported out of mitochondria as malate (since OAA cannot cross the membrane)
• Induced by: Glucagon, cortisol, fasting → makes gluconeogenesis go

Bypass 2: Fructose-1,6-bisP → Fructose-6-P (Replaces PFK-1)

• Simply removes the phosphate from position 1 by hydrolysis
• Inhibited by: AMP, Fructose-2,6-bisphosphate (when fed state = glycolysis ON = gluconeogenesis OFF)
• Activated by: ATP, citrate

Bypass 3: Glucose-6-P → Glucose (Replaces Hexokinase)

• Located in ER membrane of liver and kidney only
• Muscle CANNOT release free glucose (no glucose-6-phosphatase) - muscle glycogen stays in muscle
• In liver, releases free glucose into blood to maintain blood glucose levels

Gluconeogenesis Regulation (Summary)

Energy Cost of Gluconeogenesis

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PART 9: GLYCOGEN METABOLISM

• Glucose units linked by α-1,4-glycosidic bonds (straight chain)
• Branch points: α-1,6-glycosidic bonds every 8-10 residues
• Branching increases solubility and allows rapid mobilization from many chain ends simultaneously

GLYCOGENESIS (Synthesis)

1. Glucose → Glucose-6-P (Hexokinase/Glucokinase)
2. Glucose-6-P → Glucose-1-P (Phosphoglucomutase)
3. Glucose-1-P + UTP → UDP-Glucose + PPi (UDP-glucose pyrophosphorylase)
   • UDP-glucose is the "activated" form of glucose - the "building block"
   • PPi (pyrophosphate) is hydrolyzed to 2Pi by pyrophosphatase → drives reaction forward
4. UDP-Glucose added to glycogen chain (Glycogen Synthase - key enzyme, adds α-1,4 links)
5. Branching Enzyme (Amylo-4,6-transglycosylase): moves a block of 6-7 residues from end of chain to form a new α-1,6 branch

GLYCOGENOLYSIS (Degradation)

1. Glycogen Phosphorylase cleaves α-1,4 bonds from the non-reducing ends → Glucose-1-P (NOT free glucose - phosphate comes from Pi, not water)
2. But phosphorylase STOPS 4 residues from a branch point. Then:
3. Debranching Enzyme (bifunctional):
   • Transferase activity: moves 3 of the 4 remaining residues to another chain
   • Glucosidase activity: releases the last α-1,6 branch residue as FREE glucose (not G1P!)
4. Glucose-1-P → Glucose-6-P (Phosphoglucomutase)
5. In liver/kidney: Glucose-6-phosphatase → Free glucose → blood In muscle: No G6Pase → G6P enters glycolysis directly

Hormonal Regulation

• Glycogen Phosphorylase Kinase → activates
• Glycogen Phosphorylase → ACTIVE (phosphorylated = active)
• Glycogen Synthase → INACTIVE (phosphorylated = inactive) Result: Glycogen breakdown ON, glycogen synthesis OFF

Glycogen Storage Diseases (GSDs) - High Yield

• Ask patient to exercise forearm with tourniquet (no blood flow)
• Normal: Lactate rises, ammonia rises
• McArdle: Lactate does NOT rise (muscle can't break down glycogen to make pyruvate/lactate) but ammonia rises
• Myalgia, cramps, fatigue during exercise are typical symptoms

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PART 10: PENTOSE PHOSPHATE PATHWAY (HMP SHUNT / Hexose Monophosphate Shunt)

1. NADPH (for biosynthesis and antioxidant defense)
2. Ribose-5-phosphate (for nucleotide synthesis - DNA, RNA, ATP, NAD+, etc.)

Two Phases:

Phase 1: Oxidative Phase (Irreversible) - Makes NADPH

1. Glucose-6-P → 6-Phosphoglucono-δ-lactone (G6PD - makes NADPH)
2. 6-Phosphoglucono-δ-lactone → 6-Phosphogluconate (Lactonase)
3. 6-Phosphogluconate → Ribulose-5-P + CO2 (6-Phosphogluconate dehydrogenase - makes NADPH)

Phase 2: Non-Oxidative Phase (Reversible) - Makes/uses Ribose-5-P

• Ribulose-5-P can be converted to Ribose-5-P (by isomerase) for nucleotide synthesis
• OR if nucleotides not needed, Ribose-5-P can be converted back to glycolytic intermediates (F6P and GAP) via transketolase and transaldolase reactions (these need thiamine/B1 as cofactor!)

Why NADPH is so Important

• H2O2 builds up in RBCs from oxidative metabolism
• Glutathione peroxidase destroys H2O2 using reduced glutathione (GSH)
• GSH gets oxidized to GSSG (disulfide form)
• Glutathione reductase regenerates GSH using NADPH
• HMP shunt is the ONLY source of NADPH in RBCs (no mitochondria, no malic enzyme)
• Without NADPH → cannot regenerate GSH → H2O2 accumulates → oxidizes Hb to Heinz bodies → RBC membrane damage → hemolysis

• Fatty acid synthesis (cytoplasm)
• Cholesterol/steroid synthesis
• Cytochrome P450 reactions (drug metabolism)
• NADPH oxidase in neutrophils (kills bacteria) - deficient in Chronic Granulomatous Disease

G6PD Deficiency - Most Common Enzyme Defect Worldwide

• Drugs: Primaquine, dapsone, sulfonamides, nitrofurantoin, rasburicase
• Infection (oxidative stress from immune response)
• Fava beans (broad beans - favism) - contain vicine and convicine which generate H2O2
• Naphthalene (mothballs)

• Hemolytic anemia (decreased Hb, increased reticulocytes, increased bilirubin)
• Heinz bodies on peripheral smear
• Decreased G6PD activity (best tested AFTER hemolytic crisis, not during, because young RBCs have higher G6PD activity)

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PART 11: CORI CYCLE & GLUCOSE-ALANINE CYCLE

Cori Cycle (Lactate Cycle)

       MUSCLE/RBCs                          LIVER
   Glucose ──→ Lactate ──────────────────→ Lactate
                                              ↓
                                           Pyruvate
                                              ↓ (Gluconeogenesis)
   Glucose ←──────────────────────────── Glucose

• RBCs and anaerobic muscle produce lactate
• Lactate goes to liver via blood
• Liver converts lactate → pyruvate → glucose (gluconeogenesis)
• Glucose goes back to muscle/RBCs
• Energy note: Muscle gets 2 ATP from lactate production; liver uses 6 ATP to make glucose. NET: liver subsidizes muscle energy production. The liver makes up the deficit using fat oxidation.

Glucose-Alanine Cycle

       MUSCLE                               LIVER
   Pyruvate + NH3 ──→ Alanine ──────────→ Alanine
                                             ↓ (Transamination)
                                          Pyruvate + NH3
                                             ↓          ↓
                                          Glucose    Urea
   Glucose ←──────────────────────────── Glucose

• During prolonged exercise/fasting, muscle breaks down protein
• Amino acids transaminated to alanine (safe NH3 carrier)
• Alanine sent to liver → converted back to pyruvate for gluconeogenesis + NH3 goes to urea cycle
• Glucose returns to muscle

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PART 12: CLINICAL CONDITIONS - COMPLETE SUMMARY

Inborn Errors of Metabolism

Toxin/Drug Effects

Hormonal Regulation - One-Page Summary

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🎯 MASTER MNEMONIC SHEET

10 Steps of Glycolysis - "Good Gracious! Father Franklin Did Go By Plane, Eventually"

1. Glucose → G6P (Hexokinase)
2. G6P → F6P (Phosphoglucose isomerase)
3. F6P → F1,6-bisP (PFK-1)
4. F1,6-bisP → DHAP + GAP (Aldolase)
5. DHAP → GAP (Triose phosphate isomerase)
6. GAP → 1,3-BPG (GAPDH - NADH)
7. BPG → 3PG (Phosphoglycerate Kinase - ATP)
8. PG → 2PG (Phosphoglycerate Mutase)
9. Enolase: 2PG → PEP
10. PEP → Pyruvate (Pyruvate Kinase - ATP)

TCA Cycle - "Citrate Is Krebs' Starting Substrate For Making Oxaloacetate"

1. Citrate (Citrate synthase)
2. Isocitrate (Aconitase)
3. Ketoglutarate = α-KG (Isocitrate dehydrogenase - NADH, CO2)
4. Succinyl-CoA (α-KG dehydrogenase - NADH, CO2)
5. Succinate (Succinyl-CoA synthetase - GTP)
6. Fumarate (Succinate dehydrogenase - FADH2)
7. Malate (Fumarase)
8. Oxaloacetate (Malate dehydrogenase - NADH)

Irreversible Glycolysis Steps - "HoPKins CaFe"

• Hexokinase / Glucokinase
• PFK-1
• Pyruvate Kinase

PDC Cofactors - "The Lovely Cat Found Napping"

GSDs - "Very Poor Cow Always Makes Lots"

• Von Gierke (I), Pompe (II), Cori (III), Anderson (IV), McArdle (V), Liver phosphorylase/Hers (VI)

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Quick Summary - Kya Kya Cover Kiya:

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🔬 HMP SHUNT (Hexose Monophosphate Pathway / Pentose Phosphate Pathway)

Complete MBBS Notes - Simple English

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INTRODUCTION - "Yeh Pathway Kya Hai?"

• ATP nahi banata
• NADPH banata hai (reducing power - antioxidant + biosynthesis)
• Ribose-5-Phosphate banata hai (DNA/RNA ke liye nucleotides)

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KEY FACTS AT A GLANCE

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WHERE DOES IT OCCUR? (Tissue Distribution)

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THE TWO PHASES

Phase 1 (Oxidative) = IRREVERSIBLE → makes NADPH
Phase 2 (Non-Oxidative) = REVERSIBLE → shuffles carbon skeletons

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PHASE 1: OXIDATIVE PHASE - "NADPH Factory"

Step 1: Glucose-6-P → 6-Phosphoglucono-δ-lactone

• Uses: NADP+ → makes NADPH
• This is the committed step (rate-limiting)
• Carbon 1 (aldehyde group) is oxidized
• Inhibited by NADPH (product inhibition - if NADPH is enough, pathway slows)
• This is the enzyme deficient in G6PD deficiency!

Step 2: 6-Phosphoglucono-δ-lactone → 6-Phosphogluconate

• Simple hydrolysis - adds water
• Opens the ring structure
• No coenzyme needed

Step 3: 6-Phosphogluconate → Ribulose-5-Phosphate + CO2

• Uses: NADP+ → makes NADPH
• An oxidative decarboxylation (loses one CO2)
• Similar mechanism to isocitrate dehydrogenase in TCA cycle
• Product: Ribulose-5-P (5-carbon ketose sugar)

Phase 1 Net Result (per molecule):

1 Glucose-6-P + 2 NADP+ → 1 Ribulose-5-P + 2 NADPH + CO2

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PHASE 2: NON-OXIDATIVE PHASE - "Carbon Shuffler"

First - Ribulose-5-P is converted to two products:

• Ribulose-5-P → Ribose-5-P (by Isomerase - aldose/ketose conversion) → Used for nucleotide synthesis (DNA, RNA, ATP, NAD+, FAD, CoA)
• Ribulose-5-P → Xylulose-5-P (by Epimerase - changes stereochemistry at C3) → Used in carbon-shuffling reactions below

The Two Key Enzymes of Non-Oxidative Phase:

Transketolase (Cofactor: Thiamine - Vitamin B1)

• Transfers a 2-carbon unit from a ketose to an aldose
• Reaction: ketose (shorter by 2C) + aldose (longer by 2C)
• Requires TPP (Thiamine Pyrophosphate, Vitamin B1) as cofactor!
• Clinical: B1 deficiency → transketolase fails → HMP shunt cannot recycle carbons → measured as RBC transketolase activity test (gold standard for B1 deficiency)

Transaldolase (No cofactor needed)

• Transfers a 3-carbon unit from a ketose to an aldose
• Proceeds via Schiff base intermediate (3C unit attached to lysine in enzyme)

The Non-Oxidative Reactions:

Step A (Transketolase):
Xylulose-5-P (C5) + Ribose-5-P (C5) → Sedoheptulose-7-P (C7) + Glyceraldehyde-3-P (C3)

Step B (Transaldolase):
Sedoheptulose-7-P (C7) + Glyceraldehyde-3-P (C3) → Fructose-6-P (C6) + Erythrose-4-P (C4)

Step C (Transketolase):
Xylulose-5-P (C5) + Erythrose-4-P (C4) → Fructose-6-P (C6) + Glyceraldehyde-3-P (C3)

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OVERALL EQUATION

Glucose-6-P + 12 NADP+ + 6 H₂O → 6 CO₂ + 12 NADPH + Phosphate

• Input: 3 Glucose-6-P
• Output: 6 NADPH + 3 CO2 + products that regenerate 2 Glucose-6-P (and 1 GAP → can become ½ Glucose-6-P)

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THE CELL'S CHOICES - "What Does the Cell Need?"

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WHY IS NADPH SO IMPORTANT?

In RBCs - The Most Tested!

HMP Shunt → makes NADPH
     ↓
NADPH + Glutathione Reductase → converts GSSG (oxidized) → GSH (reduced)
     ↓
GSH + Glutathione Peroxidase → destroys H₂O₂ and lipid peroxides
     ↓
Result: RBC membrane protected, Hb not oxidized

No NADPH → cannot regenerate GSH → H₂O₂ accumulates
     ↓
H₂O₂ oxidizes Hb → methemoglobin → denatured Hb = Heinz bodies
     ↓
Heinz bodies attach to RBC membrane → membrane damage → HEMOLYSIS

Complete List of NADPH Roles:

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G6PD DEFICIENCY - Complete Coverage

Basic Facts:

• Most common enzyme deficiency in the world (~400 million people)
• Gene is on X chromosome → X-linked recessive → mainly males affected
• Females are carriers (one normal X protects them usually)
• Malaria belt distribution - heterozygous females have partial malaria protection (infected RBCs are more fragile and lyse faster)

Mechanism:

No G6PD → No NADPH → No reduced glutathione (GSH)
→ Cannot remove H₂O₂ when oxidative stress occurs
→ H₂O₂ oxidizes hemoglobin → Heinz bodies
→ RBC membrane damaged → HEMOLYSIS

Triggers of Hemolytic Crisis:

Two Main Variants:

Lab Findings During Crisis:

• Decreased Hb (hemolytic anemia)
• Increased bilirubin (indirect - from Hb breakdown)
• Increased reticulocytes (bone marrow response)
• Heinz bodies on peripheral smear with methyl violet/crystal violet stain
• Normal G6PD activity may be falsely normal DURING the crisis (old cells with low G6PD have already lysed; only young cells with higher activity remain!)
• Test after crisis for reliable G6PD measurement

Treatment:

• Stop the triggering drug/exposure
• Avoid fava beans
• Supportive: fluids, folic acid (for reticulocytosis)
• Severe: blood transfusion
• NO specific enzyme replacement currently

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REGULATION OF HMP SHUNT

Inhibited by:

• NADPH (product inhibition - the most important regulator)
• If NADPH/NADP+ ratio is HIGH → pathway slows down automatically

Activated by (Gene induction):

• Insulin (post-meal, when glucose is high and cell is in "build mode")
• Induces G6PD synthesis in liver → more flux through HMP shunt
• This couples glucose availability to NADPH production for biosynthesis

Connected to Glycolysis:

• Xylulose-5-P (a product of HMP shunt) activates a phosphatase that increases Fructose-2,6-bisphosphate → activates PFK-1 → speeds up glycolysis
• So when HMP shunt is active, glycolysis also gets boosted!

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THIAMINE (B1) DEFICIENCY AND HMP SHUNT

• Measure RBC transketolase activity WITH and WITHOUT added TPP
• If B1 deficient: baseline activity is LOW, adding TPP gives a BIG BOOST (>15-20% stimulation = deficient)
• If B1 sufficient: adding TPP has little effect (enzyme already saturated)

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CHRONIC GRANULOMATOUS DISEASE (CGD) - Related Condition

NADPH + O₂ → NADPH Oxidase → O₂•⁻ (superoxide) → H₂O₂ → HOCl → kills bacteria

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HMP SHUNT vs GLYCOLYSIS - COMPARISON TABLE

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IMPORTANT INTERMEDIATES - REMEMBER THESE

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HIGH-YIELD EXAM POINTS - MUST KNOW!

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CLINICAL SCENARIO - QUICK MCQ APPROACH

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🔬 HMP SHUNT (Hexose Monophosphate Pathway / Pentose Phosphate Pathway)

Complete MBBS Notes — Pure English, Simple Language

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WHAT IS THE HMP SHUNT?

1. NADPH — a molecule that provides reducing power for antioxidant defense and biosynthesis
2. Ribose-5-Phosphate — a 5-carbon sugar needed to make DNA, RNA, and nucleotides

Think of it this way: Glycolysis is the "energy factory." HMP Shunt is the "supply factory" — it makes raw materials the cell needs to build things and protect itself.

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KEY COMPARISON WITH GLYCOLYSIS

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WHERE DOES IT OCCUR? (Tissue Distribution)

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THE TWO PHASES

• Phase 1 — Oxidative Phase → Irreversible → Produces NADPH
• Phase 2 — Non-Oxidative Phase → Reversible → Rearranges carbon skeletons

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PHASE 1: OXIDATIVE PHASE

"The NADPH Factory"

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Reaction 1: Glucose-6-P → 6-Phosphoglucono-δ-Lactone

• NADP+ accepts electrons → becomes NADPH
• Carbon-1 of glucose-6-P (the aldehyde carbon) is oxidized
• This is the rate-limiting, committed step of the entire pathway
• The reaction is irreversible
• Strongly inhibited by NADPH — when the cell already has enough NADPH, the pathway slows down automatically (product inhibition)
• This is the enzyme that is deficient in G6PD deficiency disease

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Reaction 2: 6-Phosphoglucono-δ-Lactone → 6-Phosphogluconate

• A simple hydration reaction — water is added, the ring structure opens
• No coenzyme is needed
• No energy is produced or consumed

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Reaction 3: 6-Phosphogluconate → Ribulose-5-Phosphate + CO2

• This is an oxidative decarboxylation — oxidation happens AND one carbon is lost as CO2
• NADP+ accepts electrons → becomes NADPH (second NADPH of this phase)
• The product is Ribulose-5-Phosphate, a 5-carbon ketose sugar
• The mechanism is similar to isocitrate dehydrogenase in the TCA cycle

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Phase 1 Summary:

1 Glucose-6-P + 2 NADP+ → 1 Ribulose-5-P + 2 NADPH + 1 CO2

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PHASE 2: NON-OXIDATIVE PHASE

"The Carbon Shuffler"

• Ribulose-5-P → Ribose-5-P (enzyme: Isomerase — converts ketose to aldose form) → Ribose-5-P goes directly into nucleotide synthesis (for DNA, RNA, ATP, NAD+, FAD, CoA)
• Ribulose-5-P → Xylulose-5-P (enzyme: Epimerase — flips the OH group at carbon-3) → Xylulose-5-P enters the carbon-shuffling reactions below

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The Two Key Enzymes of Phase 2:

1. Transketolase

• Transfers a 2-carbon unit from a ketose sugar to an aldose sugar
• Cofactor required: Thiamine Pyrophosphate (TPP) — Vitamin B1
• Without B1, this enzyme does not work → HMP shunt cannot complete Phase 2
• Clinical test: RBC transketolase activity is used to diagnose Vitamin B1 deficiency — if B1 is low, adding TPP in the test tube will strongly boost the enzyme activity

2. Transaldolase

• Transfers a 3-carbon unit from a ketose sugar to an aldose sugar
• No cofactor is required
• The 3-carbon unit forms a Schiff base with a lysine residue inside the enzyme

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The 3 Non-Oxidative Reactions:

Reaction A — Transketolase:
Xylulose-5-P (5C) + Ribose-5-P (5C) → Sedoheptulose-7-P (7C) + Glyceraldehyde-3-P (3C)
[2-carbon unit transferred]

Reaction B — Transaldolase:
Sedoheptulose-7-P (7C) + Glyceraldehyde-3-P (3C) → Fructose-6-P (6C) + Erythrose-4-P (4C)
[3-carbon unit transferred]

Reaction C — Transketolase:
Xylulose-5-P (5C) + Erythrose-4-P (4C) → Fructose-6-P (6C) + Glyceraldehyde-3-P (3C)
[2-carbon unit transferred]

• 2 Fructose-6-P and 1 Glyceraldehyde-3-P
• Both of these are glycolytic intermediates — they re-enter glycolysis
• No carbon is wasted!

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THE COMPLETE PATHWAY DIAGRAM

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THE CELL'S FOUR CHOICES

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REGULATION OF HMP SHUNT

Inhibition:

• NADPH is the primary inhibitor — when NADPH levels are high, G6PD is inhibited, and the pathway slows down automatically. This is classic product inhibition.

Activation (Gene induction):

• Insulin induces G6PD gene expression in the liver — after a carbohydrate-rich meal, insulin rises, G6PD synthesis increases, and more flux goes through the HMP shunt. This makes sense because the cell is in "build mode" and needs NADPH for fatty acid synthesis.

Connection to Glycolysis:

• Xylulose-5-Phosphate (a product of the HMP shunt) activates a phosphatase that increases Fructose-2,6-bisphosphate → this activates PFK-1 → this speeds up glycolysis.
• So when the HMP shunt is running fast, it also boosts glycolysis simultaneously.

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WHY IS NADPH SO CRITICAL?

In Red Blood Cells — The Most Exam-Tested Concept

HMP Shunt makes NADPH
        ↓
Glutathione Reductase uses NADPH to convert:
        GSSG (oxidized glutathione) → GSH (reduced glutathione)
        ↓
Glutathione Peroxidase uses GSH to destroy:
        H₂O₂ and lipid peroxides → water
        ↓
RBC membrane is protected. Hemoglobin stays intact.

No NADPH → cannot regenerate GSH
        ↓
H₂O₂ accumulates when oxidative stress occurs
        ↓
H₂O₂ oxidizes hemoglobin → Methemoglobin → denatures further → Heinz bodies
        ↓
Heinz bodies attach to inner membrane → membrane rigid and fragile
        ↓
RBC destroyed in spleen → HEMOLYTIC ANEMIA

All Roles of NADPH — One Complete List

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G6PD DEFICIENCY — Full Details

Basic Facts

• Most common enzyme deficiency in the world (~400 million carriers)
• Inheritance: X-linked recessive
• Mainly affects males (one X chromosome — if it carries the mutant gene, no backup)
• Females are usually carriers (two X chromosomes — one normal X is enough)
• Distribution overlaps with malaria-endemic regions — heterozygous females have partial protection against Plasmodium (infected RBCs are more oxidatively fragile and lyse faster, limiting parasite spread)

Triggers of Hemolytic Crisis

Two Main Variants

Laboratory Findings During Crisis

Treatment

• Identify and remove the trigger (stop the drug, treat infection)
• Avoid fava beans, naphthalene, triggering drugs permanently
• Supportive care — IV fluids, folic acid supplementation
• Blood transfusion for severe anemia
• No enzyme replacement therapy available currently

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THIAMINE (VITAMIN B1) DEFICIENCY AND HMP SHUNT

• Transketolase cannot transfer 2-carbon units
• Phase 2 fails — carbon skeletons pile up as Ribulose-5-P
• Cannot convert HMP intermediates back to glycolytic intermediates
• Also affects PDC and alpha-KG dehydrogenase (which also need TPP)

• Measure RBC transketolase activity BEFORE and AFTER adding TPP in the test tube
• If B1 is sufficient: adding TPP causes less than 15% increase in activity (enzyme already saturated with TPP)
• If B1 is deficient: adding TPP causes more than 15-20% increase (enzyme was starved of its cofactor)
• This test can detect deficiency even before symptoms appear — it is more sensitive than direct thiamine measurement

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CHRONIC GRANULOMATOUS DISEASE (CGD)

NADPH + O₂ → NADPH Oxidase → Superoxide (O₂•⁻)
        ↓
Superoxide dismutase → H₂O₂
        ↓
Myeloperoxidase → Hypochlorous acid (HOCl) — bleach — kills bacteria

• Staphylococcus aureus (most common)
• Aspergillus species (most common fungal cause)
• Serratia, Nocardia, Burkholderia

• Normal neutrophils reduce yellow NBT dye to blue-purple formazan using superoxide
• CGD neutrophils: cannot make superoxide → NBT remains yellow/colorless

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IMPORTANT INTERMEDIATES TO KNOW

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COMPLETE HIGH-YIELD EXAM TABLE

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ONE-PAGE SUMMARY

Glucose-6-Phosphate
        │
        ▼  [G6PD — Rate-limiting, needs NADP+]        → NADPH #1
6-Phosphoglucono-δ-Lactone
        │
        ▼  [Gluconolactonase — adds water]
6-Phosphogluconate
        │
        ▼  [6-PGD — oxidative decarboxylation]         → NADPH #2 + CO2
Ribulose-5-Phosphate (5C)
        │
   ─────┴──────────────────
   │                       │
[Isomerase]            [Epimerase]
   ↓                       ↓
Ribose-5-P           Xylulose-5-P
(nucleotides)              │
                 [Transketolase + Transaldolase]
                           ↓
               Fructose-6-P + Glyceraldehyde-3-P
                           ↓
                   RE-ENTER GLYCOLYSIS

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🩸 BLOOD GLUCOSE REGULATION

Complete MBBS Notes — Simple English

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WHY DOES BLOOD GLUCOSE NEED TO BE REGULATED?

• The brain, retina, and gonads rely almost exclusively on glucose for energy. They cannot easily switch to fats.
• Severe hypoglycemia → coma → death

• High glucose creates osmotic pressure → cellular dehydration
• Glucose spills into urine (glycosuria) → osmotic diuresis → dehydration + electrolyte loss
• Long-term high glucose damages blood vessels → heart attack, stroke, kidney failure, blindness

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THE NORMAL GLUCOSE CURVE AFTER A MEAL

Blood Glucose
(mg/dL)
    140 │       ╭───╮
    120 │      ╱     ╲
    100 │─────╱       ╲────────── ← Fasting level restored
     80 │ Fasting       ╲_______
        └────────────────────────── Time
          0    1hr   2hrs   3hrs

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THE FOUR MAIN DEFENDERS OF BLOOD GLUCOSE

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SECTION 1: THE LIVER — THE GLUCOSE BUFFER

• After a meal, when blood glucose is HIGH: The liver takes up glucose from the portal blood and stores it as glycogen (glycogenesis) and fat. Up to two-thirds of absorbed glucose can be stored in the liver this way.
• During fasting, when blood glucose is LOW: The liver breaks down its glycogen (glycogenolysis) and makes new glucose (gluconeogenesis) and releases it into the blood.

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SECTION 2: INSULIN — THE "FED STATE" HORMONE

What is Insulin?

• A polypeptide hormone made of 51 amino acids (two chains — A and B — linked by disulfide bonds)
• Made by beta (β) cells of the Islets of Langerhans in the pancreas
• Secreted as proinsulin → C-peptide is cleaved → active insulin released
• Think of insulin as the "hormone of abundance" — it is released when nutrients are plenty, and it tells every cell: "Store energy now"

The Insulin Receptor

• α subunits: Outside the cell. They bind insulin. Connected to each other by disulfide bonds.
• β subunits: Span the cell membrane. Have intrinsic Tyrosine Kinase activity on their inner (cytoplasmic) end.

How Insulin Works — Step by Step:

1. Insulin binds to the α subunits → causes a conformational change in the whole receptor
2. This activates tyrosine kinase in the β subunits → they phosphorylate themselves (autophosphorylation)
3. Activated tyrosine kinase then phosphorylates other proteins inside the cell (kinases, phosphatases, G proteins)
4. These activated proteins produce all the metabolic effects of insulin
5. The insulin-receptor complex is internalized by endocytosis → insulin is degraded inside the cell
6. Down-regulation: Chronic high insulin → fewer insulin receptors on cell surface. This is why obese patients and Type 2 diabetics become less sensitive to insulin

The insulin receptor is a Receptor Tyrosine Kinase (RTK) — this is an exam favorite. Contrast this with glucagon which uses a GPCR → cAMP pathway.

What Triggers Insulin Secretion?

What Does Insulin Do?

On Glucose (most important):

On Fat:

On Protein:

On Potassium:

• Insulin drives K+ into cells by stimulating Na+/K+ ATPase
• Clinically important: Insulin is used to treat hyperkalemia (high potassium) in emergency medicine
• Diabetic ketoacidosis: When insulin is replaced, K+ shifts into cells → watch for hypokalemia

One-Line Summary of Insulin's Effect on Blood Levels:

Insulin lowers blood glucose, blood fatty acids, blood ketoacids, blood amino acids, and blood K+.

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SECTION 3: GLUCAGON — THE "FASTING STATE" HORMONE

What is Glucagon?

• A 29 amino acid polypeptide hormone (molecular weight 3485)
• Made by alpha (α) cells of the Islets of Langerhans
• The "hyperglycemic hormone" — its job is to RAISE blood glucose
• Even 1 µg/kg of glucagon can increase blood glucose by ~20 mg/dL within 20 minutes

What Triggers Glucagon Secretion?

The Glucagon Receptor — Signal Cascade

Glucagon binds GPCR on liver cell
        ↓
G protein activates Adenylyl Cyclase
        ↓
ATP → cAMP (cyclic AMP)
        ↓
cAMP activates Protein Kinase A (PKA)
        ↓
PKA phosphorylates:
  • Phosphorylase Kinase → ACTIVE
  • Glycogen Phosphorylase → ACTIVE (glycogen breakdown ON)
  • Glycogen Synthase → INACTIVE (glycogen synthesis OFF)
  • PEPCK induced → Gluconeogenesis ON
        ↓
Glucose released into blood → blood glucose rises

What Does Glucagon Do?

Primary Effects (at normal concentrations):

• Breaks down liver glycogen → releases glucose into blood
• Infusion of glucagon for 4 hours can completely deplete all liver glycogen stores

• Even after glycogen is depleted, glucagon continues to raise blood glucose
• Stimulates amino acid uptake by liver
• Activates enzymes for gluconeogenesis, especially PEPCK (Pyruvate → PEP step)

Secondary Effects (at high concentrations):

• Activates Hormone-Sensitive Lipase in adipose tissue → releases fatty acids from fat → provides fuel for gluconeogenesis
• Inhibits triglyceride storage in liver → more fatty acids available for other tissues
• Strengthens heart contraction (pharmacological doses)
• Inhibits gastric acid secretion

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SECTION 4: THE FOUR-HORMONE ORCHESTRA

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EPINEPHRINE (Adrenaline) — Emergency Glucose Raiser

1. In liver: activates glycogenolysis (same cAMP cascade as glucagon) → glucose floods into blood within minutes
2. In adipose tissue: activates Hormone-Sensitive Lipase → releases fatty acids → provides fuel + reduces glucose use by other tissues

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CORTISOL — Slow but Sustained Glucose Raiser

1. Promotes gluconeogenesis — induces PEPCK and other gluconeogenic enzymes in the liver
2. Promotes protein breakdown in muscle → amino acids released as gluconeogenic precursors
3. Inhibits glucose uptake by peripheral tissues (anti-insulin effect)
4. Promotes fat breakdown — provides glycerol for gluconeogenesis

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GROWTH HORMONE — The Other Slow Glucose Raiser

• Inhibits glucose uptake and utilization by peripheral tissues → cells switch to fat burning instead
• Promotes lipolysis → fatty acids become the preferred fuel
• These effects develop over hours, not minutes

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SOMATOSTATIN — The Brake Pedal

• Released from delta (δ) cells of pancreatic islets
• Inhibits BOTH insulin AND glucagon secretion
• Also inhibits GH secretion from pituitary
• Acts as a paracrine regulator — fine-tunes the insulin-glucagon balance locally within the islet
• Pharmacological analogs: Octreotide — used to treat acromegaly, glucagonoma, carcinoid syndrome, and some types of severe hypoglycemia (e.g., insulinoma)

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SECTION 5: WHAT HAPPENS AT DIFFERENT PHYSIOLOGICAL STATES

Fed State (After a Meal)

Fasting State (4–12 Hours Without Food)

Prolonged Fasting / Starvation (24–48+ Hours)

Exercise

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SECTION 6: THE INSULIN/GLUCAGON RATIO — THE MASTER SWITCH

High Insulin / Low Glucagon  =  Fed State  =  BUILD and STORE
Low Insulin / High Glucagon  =  Fasting State  =  BREAK DOWN and RELEASE

• Insulin → activates PFK-2 → increases F2,6-bisP → activates PFK-1 → glycolysis ON; FBPase-1 OFF → gluconeogenesis OFF
• Glucagon → activates PKA → phosphorylates PFK-2/FBPase bifunctional enzyme → F2,6-bisP falls → PFK-1 OFF; FBPase-1 ON → gluconeogenesis ON

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SECTION 7: WHAT HAPPENS WHEN REGULATION FAILS

Hypoglycemia (Blood Glucose < 70 mg/dL)

• Too much insulin (diabetic taking excess dose)
• Insulinoma (insulin-secreting tumor)
• Alcohol (blocks gluconeogenesis)
• Addison's disease (no cortisol)
• Prolonged starvation

1. Insulin secretion stops (first and fastest)
2. Glucagon rises (within minutes)
3. Epinephrine rises (triggers: glucose < 60 mg/dL) → causes sweating, tremor, palpitations, anxiety
4. Cortisol and GH rise (glucose < 55 mg/dL) → slower, sustained response
5. Hypothalamus detects low glucose → activates sympathetic nervous system → hunger, sweating

• Adrenergic (from epinephrine): Sweating, palpitations, tremor, anxiety, pallor
• Neuroglycopenic (brain starved of glucose): Confusion, headache, seizures, coma

1. Symptoms of hypoglycemia
2. Blood glucose < 55 mg/dL at time of symptoms
3. Symptoms relieved by giving glucose

Hyperglycemia (Blood Glucose > 126 mg/dL fasting)

• Osmotic effects: Cellular dehydration, glycosuria, polyuria (osmotic diuresis), polydipsia
• Non-enzymatic glycation: Glucose attaches to proteins non-enzymatically → HbA1c (diagnostic marker), glycated LDL, glycated basement membranes
• Diabetic complications: Microangiopathy (retinopathy, nephropathy, neuropathy), macroangiopathy (heart attack, stroke)
• DKA (Type 1): No insulin → no glucose uptake → fat burned → ketone bodies → metabolic acidosis, Kussmaul breathing, acetone breath
• HHS (Type 2): Extreme hyperglycemia → severe dehydration → coma without significant ketosis (some residual insulin prevents ketogenesis)

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SECTION 8: GLUCOSE DIAGNOSTIC THRESHOLDS

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EXAM HIGH-YIELD TABLE

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ONE-PAGE VISUAL SUMMARY

                    BLOOD GLUCOSE CONTROL

   HIGH GLUCOSE                        LOW GLUCOSE
   (After meal)                        (Fasting/starvation)
        ↓                                     ↓
  β cells secrete                     α cells secrete
    INSULIN                               GLUCAGON
        ↓                                     ↓
  Liver: stores glucose as          Liver: breaks down glycogen
  glycogen, stops gluco-            and makes new glucose via
  neogenesis                        gluconeogenesis
        ↓                                     ↓
  Muscle: GLUT-4 inserts →          Muscle: uses fatty acids
  takes up glucose                  and ketones instead
        ↓                                     ↓
  Adipose: stores fat,              Adipose: releases fatty
  stops lipolysis                   acids (HSL activated)
        ↓                                     ↓
  Blood glucose FALLS ←──────── If still low ──────────→
                                  Epinephrine released
                                  (glycogenolysis + lipolysis)
                                  If persistent:
                                  Cortisol + GH released
                                  (reduces peripheral glucose use)

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