Glycogen Metabolism

How your liver and muscle bank glucose and break it back out. Plus the 5 storage diseases that crash the system.

BIOCHEM STORAGE DISEASES boards HIGH-YIELD

A 3-month-old infant has severe hypoglycemia between feeds, a massively enlarged liver, and a doll-like chubby face. Labs: glucose 32 mg/dL, lactate elevated, uric acid elevated, triglycerides markedly elevated. Glucagon does NOT raise her blood sugar.

What is the missing enzyme?

Von Gierke disease (Type I). The glycogen IS being broken down. The liver just cannot release the free glucose.

Glycogen phosphorylase chops glucose units off as glucose-1-phosphate. That becomes glucose-6-phosphate. Normally glucose-6-phosphatase (G6Pase) strips the phosphate so free glucose can leave the cell. No G6Pase: glucose-6-phosphate piles up, gets shunted into glycolysis (high lactate), the pentose phosphate pathway (high uric acid), and lipogenesis (high triglycerides). Glucagon cannot fix it because the block is downstream of every hormonal signal.

Break it down: Von Gierke = the warehouse is full, the loading dock door is bricked shut.

Glycogen Structure

A branching glucose tree. The branches are the whole point. More branches = more free ends = faster mobilization.

Glucose (alpha-1,4 backbone)

Branch point (alpha-1,6)

Alpha-1,4 bonds form the straight backbone chains (glycogen synthase adds glucose here). Alpha-1,6 bonds are the branch points (branching enzyme creates them every ~10 residues). Glycogen phosphorylase can only chop at alpha-1,4 bonds from the non-reducing ends inward. More branch ends = phosphorylase has more places to work = faster mobilization. The branch points themselves require debranching enzyme.

Storage Mode vs Mobilization Mode

These two modes are exact opposites. Insulin runs storage. Glucagon and epinephrine run mobilization. Tap each card to reveal enzyme details.

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STORAGE MODE

Glycogenesis

Trigger: Insulin (fed state, postprandial glucose spike)
Where: Liver + Muscle
Goal: Pack glucose away, prevent blood sugar spike

tap to reveal enzymes →

Storage Mode: Key Enzymes

Glycogen synthase (rate-limiting): adds UDP-glucose via alpha-1,4 bonds. Active when dephosphorylated (insulin turns phosphatases on).
Branching enzyme: cuts ~7-glucose blocks off and reattaches via alpha-1,6, creating branch points.
UDP-glucose pyrophosphorylase: activates glucose-1-P + UTP to make UDP-glucose (the substrate).
Glucokinase (liver): traps glucose as G6P when blood glucose is high. High Km, no saturation.

Clinical correlation: Insulin dephosphorylates glycogen synthase (ON) and glycogen phosphorylase (OFF) simultaneously. One signal, two reciprocal effects.

⚡

MOBILIZATION MODE

Glycogenolysis

Trigger: Glucagon (liver, fasting) or Epinephrine + Ca++ (muscle, exercise/stress)
Where: Liver releases to blood. Muscle keeps it.
Goal: Generate glucose-6-P for energy or blood glucose

tap to reveal enzymes →

Mobilization Mode: Key Enzymes

Glycogen phosphorylase (rate-limiting): cleaves alpha-1,4 bonds releasing glucose-1-P. Active when phosphorylated (by phosphorylase kinase).
Phosphorylase kinase: activated by glucagon (cAMP-PKA pathway, liver) or calcium/epinephrine (muscle). Phosphorylates and activates glycogen phosphorylase.
Debranching enzyme: two activities in one protein: (1) 4:4 transferase moves 3 glucose residues; (2) alpha-1,6 glucosidase releases the last glucose as FREE glucose (not phosphorylated).
G6Pase (LIVER ONLY): final step. Strips phosphate from glucose-6-P to release free glucose to the blood. Muscle lacks this enzyme entirely.

Clinical correlation: In McArdle disease, glycogen phosphorylase is absent in MUSCLE only. In Von Gierke, G6Pase is absent in LIVER only. One enzyme, one tissue, two completely different presentations.

Reciprocal Regulation at a Glance

Enzyme	Fed State (Insulin)	Fasted / Stress (Glucagon / Epi)
Glycogen synthase	ON (dephosphorylated)	OFF (phosphorylated)
Glycogen phosphorylase	OFF (dephosphorylated)	ON (phosphorylated)
Phosphorylase kinase	Inactive	Active (via PKA or Ca++)

From the Attending

Two opposing pathways, one regulator. Insulin (fed) → glycogen synthase ON, glycogen phosphorylase OFF. Glucagon/epi (fasted) → phosphorylase ON, synthase OFF. The switch is phosphorylation: phosphorylated phosphorylase is ACTIVE, phosphorylated synthase is INACTIVE. Same kinase (protein kinase A), opposite enzymatic consequence. Boards love asking which form (a vs b) · the "a" form is active for both enzymes by convention. Phosphorylase a = active. Synthase a = active (the unphosphorylated form). Don't memorize a/b; memorize the physiology · fed builds glycogen, fasted breaks it.

Build the Bank: Glycogenesis

After a meal, insulin says: store this. Liver and muscle pack glucose into a branching tree. Follow each step.

Glucose

Hexokinase / Glucokinase

+ ATP consumed

Glucose-6-P

Phosphoglucomutase

isomerization

Glucose-1-P

UDP-glucose pyrophosphorylase

+ UTP (activated form)

UDP-glucose

Glycogen synthase ★

adds alpha-1,4 bonds

Glycogen chain

Linear chain

Branching enzyme

creates alpha-1,6 branches

Branched glycogen

★ Glycogen synthase is the rate-limiting enzyme of synthesis. It is active when dephosphorylated (insulin drives this). The substrate is UDP-glucose, not raw glucose. Branching enzyme transfers about 7-glucose blocks and reattaches them via alpha-1,6 linkages every ~10 residues. The tree shape allows rapid access during mobilization. Primer: glycogenin provides the initial glucose scaffold before synthase takes over.

Break It Down: Glycogenolysis

Between meals, glucagon (liver) and epinephrine (muscle) flip the switch. The tree gets pruned. Only the liver can send free glucose to the blood.

Glycogen

Glycogen phosphorylase ★

+ Pi (no ATP needed)

Glucose-1-P

Branch point

Debranching enzyme

4:4 transferase + alpha-1,6 glucosidase

Free glucose + linear chain

Glucose-1-P

Phosphoglucomutase

isomerization

Glucose-6-P

G6Pase (LIVER ONLY)

strips phosphate at ER membrane

Free glucose to blood

★ Glycogen phosphorylase is the rate-limiting enzyme of breakdown. Activated by phosphorylase kinase, which is activated by glucagon (liver: cAMP-PKA pathway) or epinephrine + Ca++ (muscle). The symmetry: insulin dephosphorylates everything to STORE, glucagon and epinephrine phosphorylate everything to BREAK DOWN. Muscle lacks G6Pase, so glucose-6-P stays trapped and enters glycolysis locally. Muscle is selfish.

Storage Mode (Fed State)

Insulin in charge

Glycogen synthase = ON (dephosphorylated)
Glycogen phosphorylase = OFF
Substrate: UDP-glucose
Goal: pack glucose away, keep blood sugar from spiking

Mobilize Mode (Fasted / Stress)

Glucagon (liver) or epinephrine (muscle)

Glycogen phosphorylase = ON (phosphorylated)
Glycogen synthase = OFF
Output: glucose-1-P then glucose-6-P
Goal: feed blood sugar (liver) or feed working muscle (muscle)

Liver vs Muscle: Two Different Banks

Same glycogen molecule. Two completely different jobs. The difference is one enzyme.

	Liver Glycogen	Muscle Glycogen
Job	Keep blood glucose stable for the brain	Power local muscle contraction
G6Pase present?	YES (free glucose can leave the cell)	NO (glucose-6-P is trapped inside)
Releases free glucose to blood?	YES	NO (selfish: keeps it for itself)
Lasts how long?	~12 to 24 hours of fasting	Used during exercise, replenished after
Main hormone trigger	Glucagon (Gs → cAMP → PKA)	Epinephrine + Ca++ (Gs and Gq, plus calcium from contraction)
Key disease	Von Gierke (no G6Pase) · Hers (no liver phosphorylase)	McArdle (no muscle phosphorylase) · Pompe (lysosomal, all tissues)

Memory Hooks (tap to reveal)

Hook 1

Why muscle can never raise blood glucose

Muscle has no G6Pase. Full stop. Phosphorylase works fine in muscle, so it can break glycogen to glucose-6-P. But without G6Pase the phosphate stays on, and glucose-6-P cannot cross the cell membrane. The liver is the team player. Muscle is the gym bro who keeps the protein shake. tap to reveal · tap again to hide

Hook 2

Synthase vs Phosphorylase: who does what

SynthASE puts it AWAY (stores). PhosphorylASE pulls it APART (breaks down). Insulin dephosphorylates both: synthase turns ON, phosphorylase turns OFF. Glucagon and epi phosphorylate both: synthase turns OFF, phosphorylase turns ON. Exact reciprocal pair. Memorize the phosphorylation state. tap to reveal · tap again to hide

Hook 3

Why glucagon fails to fix Von Gierke

Glucagon activates glycogen phosphorylase just fine. The breakdown IS happening. But the product (glucose-6-P) hits the G6Pase step and stops. The loading dock door is sealed. No signal from glucagon can bypass a missing enzyme. This is why giving glucagon to a Von Gierke infant causes zero rise in blood glucose and is actually part of the diagnostic workup. tap to reveal · tap again to hide

From the Attending

Breakdown rate-limit: glycogen phosphorylase cleaves alpha-1,4 bonds, releasing glucose-1-phosphate. Debranching enzyme (alpha-1,6-glucosidase) handles the branch points. Glucose-6-phosphatase (liver only!) dephosphorylates G6P so it can leave the hepatocyte. Muscle has phosphorylase + debrancher but NO G6Pase · that's why muscle glycogen feeds local glycolysis only, never raises blood sugar. Two enzyme combos → two storage diseases: missing phosphorylase = McArdle (muscle cramps with exercise). Missing G6Pase = Von Gierke (severe fasting hypoglycemia + huge liver).

Liver vs Muscle: Two Different Banks

Same glycogen molecule. Two completely different jobs. The difference comes down to one enzyme: G6Pase.

	Liver Glycogen	Muscle Glycogen
Primary job	Keep blood glucose stable for the brain	Power local muscle contraction
G6Pase present?	YES (free glucose can exit)	NO (glucose-6-P is trapped)
Releases free glucose to blood?	YES	NO
Reserves last how long?	12 to 24 hours of fasting	Used during exercise, replenished after
Hormone trigger	Glucagon: Gs receptor, cAMP, PKA cascade	Epinephrine + Ca++: Gs and Gq, plus calcium from SR during contraction
Key storage disease	Von Gierke (no G6Pase) · Hers (no liver phosphorylase)	McArdle (no muscle phosphorylase) · Pompe (lysosomal, all tissues)

Hook 4

McArdle vs Pompe in one sentence

McARDLE is the gym kid: muscle phosphorylase missing, exercise intolerance, second-wind phenomenon, normal heart. POMPE is the floppy baby: lysosomal acid maltase missing, glycogen builds up in EVERY tissue via lysosomes, cardiomegaly kills them by age 2 without enzyme replacement. McArdle survives. Pompe does not (without ERT). tap to reveal · tap again to hide

Hook 5

Von Gierke vs Cori: the lactate test

Both have hepatomegaly and fasting hypoglycemia. The separator is lactate. Von Gierke has sky-high lactate because glucose-6-P backs up into glycolysis. Cori has NORMAL lactate because gluconeogenesis still works and glucose-6-P does not pile up the same way. Lactate is the tiebreaker every time. tap to reveal · tap again to hide

The 5 Storage Diseases

Five enzyme defects. Five different presentations. Tap each card to flip and see the clinical details. Notice what separates them.

From the Attending

Five GSDs, five tells. Type I Von Gierke (G6Pase) · infant with severe fasting hypoglycemia + huge liver + lactic acidosis + hyperuricemia + hyperlipidemia. Type II Pompe (acid maltase) · lysosomal, hypotonic floppy infant + cardiomegaly + dies young. "Pompe wrecks the Pump." Type III Cori (debrancher) · milder Von Gierke + short outer chains on glycogen. Type IV Andersen (brancher) · abnormal long-chain glycogen + cirrhosis. Type V McArdle (muscle phosphorylase) · exercise intolerance + cramps + myoglobinuria + flat lactate on ischemic exercise test. Symptom location names the enzyme: heart = Pompe, exercise = McArdle, fasting + huge liver = Von Gierke.

Type I

Von Gierke

The Warehouse with the Bricked Door

Missing Enzyme

Glucose-6-phosphatase (G6Pase)

Liver + kidney. Glycogen structure normal. Cannot release free glucose.

tap to flip →

Type I

Hallmark Labs Severe fasting hypoglycemia · high lactate · high uric acid (gout) · high triglycerides · doll-like facies · massive hepatomegaly

Glucagon Test FLAT: glucagon given but blood glucose does NOT rise. Block is downstream of every signal.

Treatment Frequent feeds, cornstarch overnight, strict no-fasting protocol

Board Trap Von Gierke is the ONE disease with normal glycogen structure. High lactate separates it from Cori. Flat glucagon response is the board lock clue.

Type II

Pompe

The Floppy Baby with the Big Heart

Missing Enzyme

Acid alpha-glucosidase (acid maltase)

Lysosomal enzyme. Affects EVERY tissue. Cytoplasmic breakdown is intact.

tap to flip →

Type II

Hallmark Findings Cardiomegaly (massive) · hypotonia · macroglossia · hepatomegaly · respiratory failure. Death before age 2 without ERT.

Hypoglycemia? NO. Cytoplasmic glycogenolysis still works. The problem is lysosomal accumulation, not glycogenolysis failure.

Treatment Alglucosidase alfa (enzyme replacement therapy). Start early.

Board Trap Pompe trashes the heart, not just the liver. Floppy baby + giant heart on CXR + macroglossia = Pompe. No hypoglycemia distinguishes it from everything else.

Type III

Cori

The Half-Eaten Tree

Missing Enzyme

Debranching enzyme

Cannot clear alpha-1,6 branch points. Glycogen has short outer chains (limit dextrin).

tap to flip →

Type III

Hallmark Findings Fasting hypoglycemia (milder than Von Gierke) · hepatomegaly · muscle weakness in some subtypes · normal lactate

Glycogen Structure Abnormal: short outer chains, prominent branch points (limit dextrin). Biopsy finding.

Treatment Frequent meals, high-protein diet (gluconeogenesis intact)

Board Trap Cori = Von Gierke minus the lactate and uric acid. Normal lactate is the separator. Gluconeogenesis intact = less metabolic chaos.

Type V

McArdle

The Gym Kid Who Hits the Wall

Missing Enzyme

Muscle glycogen phosphorylase (myophosphorylase)

Liver enzyme is fine. Pure muscle disease. No hypoglycemia.

tap to flip →

Type V

Hallmark Findings Exercise intolerance · painful cramps with exertion · myoglobinuria (red-brown urine) · elevated CK · second-wind phenomenon

Ischemic Exercise Test Flat lactate: muscle cannot break glycogen, so no pyruvate, no lactate. Ammonia still rises (amino acid catabolism intact).

Prognosis Normal lifespan. Risk: rhabdomyolysis with heavy exertion.

Board Trap Adult or teen + cramps + dark urine after exercise + flat lactate on ischemic test = McArdle. Not Pompe. Pompe is a floppy infant with a big heart.

Type VI

Hers

The Friendly One

Missing Enzyme

Liver glycogen phosphorylase

Muscle phosphorylase is fine. Block is upstream of glucose-6-P. Mild course.

tap to flip →

Type VI

Hallmark Findings Mild fasting hypoglycemia · hepatomegaly · growth delay in childhood · normal lactate, uric acid, triglycerides

Why Normal Labs? Block is before glucose-6-P is formed. Nothing piles up downstream. Gluconeogenesis intact.

Prognosis Best of all the storage diseases. Often resolves by adolescence.

Board Trap Hers vs Von Gierke: both have hepatomegaly + hypoglycemia. Hers has normal lactate. Block location is the key: Hers = before G6P, Von Gierke = after G6P.

3-Step Diagnostic Challenge

Step 1: A 4-month-old has hepatomegaly, fasting hypoglycemia, and lactate 8 mmol/L. Glucagon does not raise blood glucose. Where is the block?

Not quite. Lysosomal block is Pompe: cardiomegaly and floppy baby, NOT lactic acidosis or hypoglycemia. Cytoplasmic glycogenolysis works fine in Pompe. Try again.

Correct. Von Gierke. Glucose-6-P piles up, gets shunted into glycolysis (lactate), pentose phosphate (uric acid), and lipogenesis (triglycerides). Glucagon cannot help because the block is downstream of every signal.

Muscle phosphorylase deficiency is McArdle. That presents in a teenager with exercise cramps and dark urine, not a hypoglycemic infant. Try again.

Step 2: A 17-year-old runner gets severe muscle cramps and red-brown urine after a race. Ischemic forearm exercise test shows NO rise in venous lactate. Diagnosis?

Late-onset Pompe causes proximal muscle weakness and respiratory problems, not exercise-triggered cramps with myoglobinuria and a flat lactate test. Try again.

Von Gierke shows up in infancy with hepatomegaly and severe fasting hypoglycemia, not in a teenager after a race. Try again.

Correct. McArdle. Flat lactate = muscle cannot break glycogen to pyruvate. Dark urine = myoglobin from rhabdomyolysis. Second-wind history clinches it.

Step 3: A toddler has hepatomegaly and mild fasting hypoglycemia. Lactate is normal. Biopsy shows glycogen with short outer chains and prominent branch points. Which enzyme is deficient?

G6Pase deficiency is Von Gierke and would give HIGH lactate, not normal. Lactate is the tiebreaker here. Try again.

Correct. Cori disease. Phosphorylase chops to within 4 sugars of a branch, then stops. No debranching enzyme = the half-eaten tree (limit dextrin) on biopsy. Normal lactate because gluconeogenesis still works.

Branching enzyme deficiency is Andersen disease (Type IV): glycogen with very LONG chains, early cirrhosis. The opposite picture. Try again.

Roll The Vignette

Glycogen Metabolism

Storage Mode (Fed State)

Mobilize Mode (Fasted / Stress)