Glycogen Metabolism

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• Topic: Glycogen Metabolism
• Lecturer: Amy M. Hicks, PhD, MPH (VCOM – Carolinas Campus)
• Recommended Reading: Lieberman & Peet – Chapter 23

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Lecture Objectives
A. Explain why excess glucose is stored as glycogen instead of being entirely converted to triacylglycerols (TAGs).
B. Clarify the rationale for large glycogen stores in liver & muscle versus small stores in other tissues.
C. Recall glycogen structure; distinguish \alpha-1,4 and \alpha-1,6 linkages.
D. Analyze the biochemical logic behind glycogen’s highly branched design.
E. Trace glycogen synthesis (glucose → glycogen) & degradation (glycogen → glucose-1-phosphate).
F. Contrast insulin vs. glucagon effects on glycogenesis vs. glycogenolysis.
G. Explain why glucose-1-phosphate must be activated to UDP-glucose for polymerization.
H. Describe liver-specific handling of glucose-6-phosphate vs. muscle handling.
I. Outline lysosomal glycogen degradation and the disorder caused by its failure.
J. Relate AMP-mediated activation of muscle glycogen phosphorylase to PKA-mediated activation by epinephrine.
K. Describe common therapies for glycogen storage diseases and their biochemical basis.

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Glucose Homeostasis
• Daily adult requirement: 160\,\text{g} glucose, of which \approx 60\% (≈96\,\text{g}) is used by the brain.
• Circulating pool: 4\text{–}20\,\text{g} glucose in plasma.
• Steady concentration is protected across fed & fasting states via: neural, hormonal & dietary signals acting on liver, muscle, adipose, pancreas.

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Fates of Glucose
• Many tissues switch to fat; brain & nerves remain glucose-dependent.
• Glycogen vs. TAG:
– Glycogen yields ATP rapidly (supports anaerobic metabolism).
– Fatty acids cannot be oxidized anaerobically & cannot be converted to glucose.

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Glycogen’s Role in Homeostasis
Liver (≈100\text{–}120\,\text{g} glycogen)
• Central regulator of blood glucose.
• Insulin (post-prandial): glycogen synthesis; excess beyond glycogen → FA & TAG export to adipose.
• Glucagon (fasting): glycogenolysis; stores sustain blood glucose ≈18 h.
Muscle (≈300\text{–}400\,\text{g} glycogen)
• Stores glucose for intrinsic use only.
• Insulin stimulates uptake & storage; glycogen fuels contraction regardless of fed/fasted state.
• Fast-twitch fibers hold more glycogen than slow-twitch.

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Glycogen vs. Fatty Acids (Objectives A & B)
• Liver glycogen covers 12\text{–}24\,\text{h} of fasting; exhausted by \approx 30\,\text{h}.
• Muscle glycogen supports:
– Minutes-hours (light activity).
– Seconds (high intensity).
• Glycolytic muscle depends on rapid glycogenolysis (can be anaerobic).
• Slow-twitch/oxidative fibers rely on fatty acids; possess less glycogen.
• Fasting liver oxidizes fatty acids for its own ATP while exporting glucose.

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Glycogen Structure (Objectives C & D)
• Branched homopolysaccharide of glucose.
• Linear chains: \alpha-1,4 glycosidic bonds; branches every 8\text{–}10 residues via \alpha-1,6 bonds.
• Single reducing end covalently attached to glycogenin.
• Numerous non-reducing ends allow simultaneous enzymatic access → rapid synthesis & degradation plus compact storage.
• Molecular weight: 10^{7}\text{–}10^{8}\,\text{g/mol}; aggregates into glycogen particles with bound metabolic enzymes & regulators.

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Glycogen Synthesis – Hormonal Trigger (Objectives E, F)
• Post-meal hyperglycemia → pancreatic insulin release.
• Liver uptake via GLUT2/4; phosphorylation by glucokinase.
• Muscle uptake via GLUT1/4.
• Adipose diverts glucose to TAG synthesis.

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Detailed Steps of Glycogenesis (Objectives E, G)

  1. Glucose entry: transporters GLUT1/2/4.

  2. Phosphorylation (hexokinase or glucokinase) → \text{G-6-P} (trapping).

  3. Isomerization by phosphoglucomutase → \text{G-1-P}.

  4. Activation: \text{G-1-P} + \text{UTP} \xrightarrow{UDP\text{-G} \text{pyrophosphorylase}} \text{UDP-Glc} + \text{PP}{\text{i}}. – \text{PP}{\text{i}} hydrolysis drives reaction forward.

  5. Primer formation: glycogenin autoglucosylates (≈8 residues).

  6. Elongation: glycogen synthase adds \alpha-1,4 linked glucose from UDP-Glc.

  7. Branching: branching enzyme forms \alpha-1,6 linkages.

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Glycogen Storage Diseases (GSD) – Overview (Objective K)
• ≥19 hereditary disorders affecting enzymes of glycogen metabolism.

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Clinical Case #1 (Fanconi-Bickel Syndrome)
• 9-month-old female, severe hypoglycemia, hepatomegaly, galactosemia, normal muscle tone.
• Deficient protein: GLUT2.
• Recommended treatments:
– Rehydration & electrolyte replacement.
– Very low-dairy diet.
– Night-time feeding.
– (All of the above.)

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Therapy Principles for GSD (Objective K)
Liver-based GSD
• Maintain euglycemia with frequent small snacks; raw cornstarch as slow-release glucose.
Muscle-based GSD
• Limit strenuous exercise to avoid cramps; supplement carbs & amino acids.
Other Options
• Symptomatic meds, enzyme replacement, liver transplant.

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Glycogenolysis – Hormonal Pathway (Objectives F, E)
• Low glucose + low insulin → pancreatic glucagon release.
• Glucagon binds liver & adipose GPCRs:
\text{GPCR} \to G_{\alpha s} \to \text{adenylate cyclase} \to \uparrow\text{cAMP} \to \text{PKA}.
• Cascade activates phosphorylase kinase → glycogen phosphorylase → cleavage of glycogen to \text{G-1-P}.
• Adipose: PKA also activates hormone-sensitive lipase → FA release.

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Insulin Antagonizes Glucagon (Objective F)
• Insulin receptor tyrosine kinase → insulin-sensitive protein kinase & PP1.
• Effects:
– Dephosphorylation/activation of glycogen synthase.
– Dephosphorylation/inactivation of phosphorylase kinase & glycogen phosphorylase.
– Enhanced glucose uptake & phosphorylation (↑ glucokinase).
– Increased cAMP degradation via phosphodiesterase.

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Enzymatic Reactions of Glycogenolysis (Objective E)

  1. Glycogen phosphorylase: \alpha-1,4 bond cleavage using \text{P}_{\text{i}} → \text{G-1-P}.

  2. Debranching enzyme: transfers trisaccharide + hydrolyzes \alpha-1,6 bond.

  3. Phosphoglucomutase: \text{G-1-P} \leftrightarrow \text{G-6-P}.
    4a. Muscle: \text{G-6-P} → glycolysis → ATP.
    4b. Liver: glucose-6-phosphatase hydrolyzes \text{G-6-P} \to \text{glucose} + \text{P}_{\text{i}} → exported via GLUT2.

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Liver-Specific Points (Objective H)
• Glucagon is primary activator; epinephrine provides additional stimulation.
• Only liver & kidneys possess glucose-6-phosphatase, enabling glucose release.
• Gluconeogenesis intersects at \text{G-6-P}, integrating with glycogenolysis.
• PPP & other sugar pathways also connect via \text{G-6-P}.

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Muscle Glycogenolysis & Regulation (Objectives H & J)
• Main trigger: ↑AMP during contraction (allosteric activator of phosphorylase b).
• Muscle lacks glucagon receptors & glucose-6-phosphatase.
• Catecholamines (epi/norepi) enhance glycogen breakdown via PKA & via Ca^{2+}/calmodulin → phosphorylase kinase.
• Combined signals (AMP, phosphorylation, Ca^{2+}) maximize glycogenolysis during intense exercise or “fight-or-flight.”

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Liver Catecholamine Signaling (Objective J)
• \beta-adrenergic liver receptors mimic glucagon pathway (cAMP-PKA).
• \alpha-adrenergic pathway → PLC → IP_{3} → Ca^{2+} → calmodulin → more phosphorylase kinase activation & glycogen synthase inhibition.
• Net effect: massive glucose output with simultaneous block of glycogenesis.

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Two Degradation Pathways (Objective I)

  1. Cytosolic: glycogen phosphorylase/debranching (major).

  2. Lysosomal: \alpha-1,4-glucosidase (acid maltase) hydrolyzes entire glycogen to glucose.
    – Supplies immediate energy in neonates.
    – Defect → Pompe disease (GSD II): glycogen accumulation in lysosomes → cardiomegaly, hepatomegaly, muscle weakness.
    – Severity: infantile vs. late-onset variants.

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Clinical Case #2 (McArdle Disease)
• 15-year-old male, exertional muscle pain, myoglobinuria (red urine), genetic confirmation.
• Enzyme deficiency: muscle glycogen phosphorylase.
• Management:
– Avoid intense exercise; warm-up gradually to utilize blood-borne glucose & FAs.
– Carb-rich diet or pre-exercise glucose.
– Monitor renal function (myoglobinuria risk).

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(End of slide deck – summary)
• Comprehensive integration of glycogen synthesis, degradation, regulation, pathology & therapy.
• Emphasize hormonal control (insulin ↔ glucagon) and tissue-specific nuances (liver vs. muscle).