Gluconeogenesis & Glycogen Metabolism
Biochemistry · Carbohydrates · lean revision notes
Gluconeogenesis & Glycogen Metabolism
Two tightly coupled pathways that keep blood glucose in the physiological 70–110 mg/dL band between meals and during fasting. Gluconeogenesis (GNG) makes glucose from non-carbohydrate precursors; glycogen metabolism stores and releases glucose. Together with the enzyme defects (glycogen storage diseases, GSDs) they are among the most repeatedly tested Biochemistry topics in NEET PG.
1. Orientation & big picture
- Glycogenesis = glycogen synthesis (after meals, insulin-driven).
- Glycogenolysis = glycogen breakdown (fasting, glucagon/adrenaline-driven).
- Gluconeogenesis = de-novo glucose synthesis from lactate, glucogenic amino acids, glycerol, propionate. Occurs mainly in liver (90%) and renal cortex (~10%, rises in prolonged starvation).
- Glycogen reserves are exhausted in ~12–18 hours of fasting; thereafter GNG sustains glucose for obligate glucose users (brain initially, RBCs, renal medulla, lens, cornea, exercising muscle, WBCs).
High-yield: RBCs, renal medulla, cornea, lens and WBCs are obligate glucose users because they lack mitochondria or rely on anaerobic glycolysis. Brain shifts partly to ketone bodies after ~3 days of starvation.
2. Glycogen metabolism
2.1 Structure of glycogen
- Branched polymer of glucose; α-1,4 glycosidic bonds form the linear chains, α-1,6 bonds form branches (every 8–10 residues).
- Stored in liver (up to ~10% wet weight, used to maintain blood glucose) and muscle (~1–2%, used locally — muscle lacks glucose-6-phosphatase so it cannot export free glucose).
2.2 Glycogenesis (synthesis)
Primer: Glycogen synthesis needs glycogenin, a protein that auto-glucosylates a tyrosine residue and acts as the primer (first 8 glucose units).
Flow: Glucose → Glucose-6-P (hexokinase/glucokinase) → Glucose-1-P (phosphoglucomutase) → UDP-glucose (UDP-glucose pyrophosphorylase) → glycogen
- Glycogen synthase is the rate-limiting/regulatory enzyme; it adds glucose via α-1,4 bonds. It cannot start a chain de novo — needs glycogenin primer.
- Branching enzyme = amylo-(1,4→1,6)-transglucosylase; transfers a block of ~7 residues to create α-1,6 branches. Increases solubility and number of free ends for rapid synthesis/degradation.
- UDP-glucose pyrophosphorylase reaction is driven forward by hydrolysis of pyrophosphate (PPi → 2 Pi).
High-yield: Glycogenin is the protein primer; glycogen synthase is the regulatory enzyme of glycogenesis and forms only α-1,4 bonds; branching enzyme makes α-1,6 bonds.
2.3 Glycogenolysis (breakdown)
Flow: Glycogen → Glucose-1-P (glycogen phosphorylase, uses Pi — phosphorolysis) → Glucose-6-P (phosphoglucomutase) → (liver only) Glucose (glucose-6-phosphatase)
- Glycogen phosphorylase = rate-limiting enzyme of glycogenolysis; cleaves α-1,4 bonds by phosphorolysis (not hydrolysis), releasing glucose-1-phosphate. It needs pyridoxal phosphate (vitamin B6) as cofactor. Stops 4 residues from a branch point (forms a "limit dextrin").
- Debranching enzyme is bifunctional:
- 4:4 transferase (glucan transferase) — moves 3 residues to a nearby chain.
- amylo-1,6-glucosidase — hydrolyses the α-1,6 bond, releasing free glucose (~8–10% of glycogen glucose is released free; the rest as glucose-1-P).
- Liver glucose-6-phosphatase (ER enzyme) liberates free glucose into blood. Muscle lacks it → muscle glycogen serves only muscle.
| Feature | Glycogen synthase | Glycogen phosphorylase |
|---|---|---|
| Pathway | Glycogenesis | Glycogenolysis |
| Bond acted on | Forms α-1,4 | Breaks α-1,4 |
| Cofactor | UDP-glucose donor | Pyridoxal phosphate (B6) |
| Active form | Dephosphorylated (synthase a) | Phosphorylated (phosphorylase a) |
| Activated by | Insulin, glucose-6-P | Glucagon, adrenaline, AMP, Ca²⁺ (muscle) |
High-yield: Phosphorylation has opposite effects: it activates glycogen phosphorylase but inactivates glycogen synthase. So glucagon/adrenaline (raise cAMP → PKA → phosphorylation) simultaneously promote breakdown and inhibit synthesis. Insulin (via protein phosphatase-1) does the reverse.
2.4 Hormonal control cascade
Glucagon/Adrenaline → receptor (Gs) → adenylate cyclase ↑ → cAMP ↑ → PKA → phosphorylase kinase (active) → glycogen phosphorylase a (active) → glycogenolysis
- Adrenaline acts on liver via β2/α1 and on muscle via β2 receptors; in muscle, Ca²⁺-calmodulin also activates phosphorylase kinase during contraction.
- Insulin activates protein phosphatase-1 (PP1) → dephosphorylates and reverses the cascade.
3. Gluconeogenesis
3.1 Substrates
- Lactate (Cori cycle, from RBCs and exercising muscle)
- Glucogenic amino acids — chiefly alanine (glucose–alanine cycle) and glutamine; all amino acids except pure ketogenic leucine and lysine ("Leucine and Lysine" = the only purely ketogenic).
- Glycerol (from triacylglycerol/lipolysis; enters at DHAP)
- Propionyl-CoA (from odd-chain fatty acids and some amino acids) → succinyl-CoA → enters TCA.
High-yield: Acetyl-CoA cannot be converted to glucose in humans (the pyruvate dehydrogenase step is irreversible and there is no glyoxylate cycle). Hence even-chain fatty acids are NOT glucogenic. Only the glycerol portion of fat and propionyl-CoA from odd-chain FAs yield glucose.
3.2 The four "bypass" (key irreversible) reactions
GNG largely reverses glycolysis but must bypass the 3 irreversible glycolytic steps. Four unique enzymes:
| Bypass | Reaction | Enzyme | Location |
|---|---|---|---|
| 1a | Pyruvate → Oxaloacetate | Pyruvate carboxylase (biotin, needs acetyl-CoA as +ve allosteric activator) | Mitochondria |
| 1b | OAA → Phosphoenolpyruvate | PEP carboxykinase (PEPCK) (needs GTP) | Cytosol/mito |
| 2 | Fructose-1,6-bisP → Fructose-6-P | Fructose-1,6-bisphosphatase (rate-limiting; inhibited by F-2,6-BP & AMP) | Cytosol |
| 3 | Glucose-6-P → Glucose | Glucose-6-phosphatase | ER (liver/kidney) |
Flow summary: Pyruvate → OAA → (malate shuttle out of mitochondria) → OAA → PEP → … reverse glycolysis … → F-1,6-BP → F-6-P → G-6-P → Glucose
- OAA cannot cross the mitochondrial membrane → exported as malate (via malate-aspartate shuttle), reconverted to OAA in cytosol.
- Energy cost: GNG of one glucose from 2 pyruvate consumes 6 ATP (4 ATP + 2 GTP) plus 2 NADH.
High-yield: Fructose-1,6-bisphosphatase is the rate-limiting enzyme of gluconeogenesis. Biotin is the cofactor of pyruvate carboxylase (carboxylation). Acetyl-CoA (rising in fasting from β-oxidation) allosterically activates pyruvate carboxylase, channelling pyruvate toward GNG.
3.3 Reciprocal regulation with glycolysis
- Fructose-2,6-bisphosphate (F-2,6-BP) is the master signal: stimulates PFK-1 (glycolysis) and inhibits fructose-1,6-bisphosphatase (GNG).
- F-2,6-BP is made/degraded by bifunctional PFK-2/FBPase-2:
- Fed state (insulin) → PFK-2 dephosphorylated/active → F-2,6-BP ↑ → glycolysis ↑.
- Fasting (glucagon → PKA phosphorylates the enzyme) → FBPase-2 active → F-2,6-BP ↓ → GNG ↑.
4. Cori cycle & glucose–alanine cycle
| Cycle | Carries | From → To | Purpose |
|---|---|---|---|
| Cori (lactic acid) cycle | Lactate → liver; glucose back to muscle | Muscle/RBC ↔ liver | Recycles lactate; net cost 6 ATP (liver) to regain glucose used by muscle |
| Glucose–alanine cycle | Alanine (carries amino-N) → liver; glucose back | Muscle ↔ liver | Disposes muscle nitrogen as alanine, regenerates glucose, urea made in liver |
High-yield: The Cori cycle shifts the metabolic/ATP burden from muscle to liver. RBCs (no mitochondria) feed lactate continuously into it. The glucose–alanine cycle additionally transports amino nitrogen to the liver for urea synthesis.
5. Glycogen storage diseases (GSDs) — examination favourites
| Type | Eponym | Deficient enzyme | Organ(s) | Hallmark features |
|---|---|---|---|---|
| I | Von Gierke | Glucose-6-phosphatase | Liver, kidney | Severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia (gout), hyperlipidaemia, hepatomegaly, "doll-like face", normal glycogen structure |
| II | Pompe | Acid α-1,4-glucosidase (acid maltase, lysosomal) | Generalised (heart, muscle) | Cardiomegaly, hypotonia ("floppy baby"), death by ~2 yrs; only lysosomal GSD |
| III | Cori / Forbes | Debranching enzyme (amylo-1,6-glucosidase) | Liver, muscle | Milder Von Gierke-like; short outer branches (limit dextrin); normal lactate/uric acid |
| IV | Andersen | Branching enzyme | Liver | Cirrhosis, long unbranched chains (amylopectin-like), hepatic failure |
| V | McArdle | Muscle glycogen phosphorylase (myophosphorylase) | Skeletal muscle | Exercise intolerance, muscle cramps, myoglobinuria, NO rise in blood lactate on exercise (flat ischaemic forearm test), "second wind" phenomenon |
| VI | Hers | Liver phosphorylase | Liver | Mild hypoglycaemia, hepatomegaly |
| VII | Tarui | Phosphofructokinase-1 (muscle) | Muscle, RBC | Like McArdle + haemolysis |
Mnemonic for GSD I–V order: *"Very Poor Carbohydrate And Muscle"* → Von Gierke, Pompe, Cori, Andersen, McArdle.
Mnemonic for the two purely muscle ones (no liver hypoglycaemia): McArdle (V) and Tarui (VII) present with exercise intolerance.
High-yield (very frequently asked):
- Von Gierke (I): hypoglycaemia + lactic acidosis + hyperuricaemia + hyperlipidaemia. Hypoglycaemia does NOT respond to glucagon (the released G-6-P cannot be dephosphorylated).
- Pompe (II): lysosomal acid maltase; cardiomegaly + floppy infant; ERT with alglucosidase alfa.
- McArdle (V): myophosphorylase; no lactate rise with ischaemic exercise, myoglobinuria, second-wind phenomenon.
- Andersen (IV) = branching enzyme (amylopectin-like, cirrhosis); Cori (III) = debranching enzyme (limit dextrin).
6. Clinical features & complications
Hypoglycaemia
- The unifying feature of liver-affecting GSDs (I, III, VI) and of GNG enzyme defects.
- Symptoms: adrenergic (sweating, tremor, palpitations) at moderate falls; neuroglycopenic (confusion, seizures, coma) at <45–50 mg/dL.
- Von Gierke complications: gout (uric acid), xanthomas/pancreatitis (hyperlipidaemia), hepatic adenomas, growth retardation, bleeding tendency (platelet dysfunction).
Diagnosis & investigation of choice
- Blood glucose, lactate, uric acid, lipid profile — pattern recognition (e.g., Von Gierke: low glucose, high lactate/urate/lipids).
- Glucagon stimulation test — fails to raise glucose in Von Gierke (and after exercise in McArdle, no lactate rise).
- Ischaemic (now non-ischaemic) forearm exercise test — flat lactate, exaggerated ammonia in McArdle/Tarui.
- Enzyme assay (liver/muscle biopsy) — historically confirmatory.
- Molecular/genetic testing — current confirmatory investigation of choice; non-invasive.
High-yield: A flat lactate curve with exaggerated ammonia rise on forearm exercise testing = McArdle disease (GSD V).
7. Management / drug & dietary principles
- Von Gierke (I): frequent feeds, uncooked cornstarch (slow-release glucose) at night, avoid fructose/galactose (they trap phosphate as their phosphates can't be released), allopurinol for gout, treat hyperlipidaemia.
- Pompe (II): enzyme replacement therapy — recombinant alglucosidase alfa.
- McArdle (V): avoid strenuous exercise; pre-exercise oral glucose/fructose; aerobic conditioning; recognise "second wind."
- Cori (III): high-protein diet, frequent feeds.
- General GNG support: in acute hypoglycaemia → IV dextrose; treat precipitant.
8. Key differentials / discriminators
- Von Gierke vs Cori: both hepatomegaly + hypoglycaemia, but Von Gierke has high lactate & uric acid; Cori has normal lactate/uric acid and abnormal (short-branch) glycogen.
- Pompe vs other GSDs: Pompe is the only lysosomal one; presents with cardiomegaly/floppy infant, glycogen structure is normal.
- McArdle vs Tarui: both muscle exercise intolerance; Tarui (PFK) also has haemolytic anaemia and symptoms worse after high-carbohydrate meals (out-of-wind effect).
- Ketotic vs non-ketotic hypoglycaemia: GNG/glycogenolysis defects with intact fat oxidation may be ketotic; fatty acid oxidation defects (e.g., MCAD) cause hypoketotic hypoglycaemia — a frequent distractor.
9. Recently asked / exam angle
- "Rate-limiting enzyme of gluconeogenesis" → Fructose-1,6-bisphosphatase (NOT PEPCK, which is the most regulated transcriptionally).
- "Cofactor of pyruvate carboxylase" → Biotin; "cofactor of glycogen phosphorylase" → Pyridoxal phosphate (B6).
- "Primer for glycogen synthesis" → Glycogenin.
- "Branching enzyme makes which bond?" → α-1,6.
- "Enzyme deficient in lactic acidosis + hyperuricaemia + hepatomegaly in an infant" → Glucose-6-phosphatase (Von Gierke / GSD I).
- "Floppy infant with cardiomegaly + normal glucose" → Pompe (acid maltase).
- "No rise in lactate after ischaemic forearm exercise" → McArdle (myophosphorylase).
- "Which signal molecule reciprocally regulates glycolysis & GNG?" → Fructose-2,6-bisphosphate.
- "Which amino acids are purely ketogenic (not glucogenic)?" → Leucine & Lysine.
- "Why can't fatty acids (even chain) form glucose?" → Pyruvate dehydrogenase is irreversible; acetyl-CoA cannot become pyruvate; no glyoxylate cycle in humans.
- Image-based: limit dextrin / amylopectin-like glycogen structure linking to Cori vs Andersen.
10. Rapid revision
- Glycogenin primes glycogen; glycogen synthase (regulatory) makes α-1,4 bonds; branching enzyme makes α-1,6.
- Glycogen phosphorylase (RL of glycogenolysis) needs PLP (B6); phosphorolysis releases glucose-1-P; stops 4 residues before a branch (limit dextrin).
- Debranching enzyme = transferase + amylo-1,6-glucosidase → releases free glucose.
- Muscle lacks glucose-6-phosphatase → muscle glycogen cannot raise blood glucose.
- Phosphorylation activates phosphorylase but inactivates synthase; insulin works via PP1 (dephosphorylation).
- GNG bypass enzymes: pyruvate carboxylase (biotin) → PEPCK (GTP) → fructose-1,6-bisphosphatase (RL) → glucose-6-phosphatase.
- Acetyl-CoA activates pyruvate carboxylase; even-chain fatty acids are NOT glucogenic; only glycerol & propionyl-CoA (odd chain) are.
- Leucine and Lysine are the only purely ketogenic amino acids.
- Cori cycle = lactate↔glucose (muscle/RBC ↔ liver); glucose–alanine cycle carries amino-N to liver.
- Von Gierke (I): hypoglycaemia + lactic acidosis + hyperuricaemia + hyperlipidaemia; treat with uncooked cornstarch.
- Pompe (II): lysosomal acid maltase, cardiomegaly, floppy infant; ERT = alglucosidase alfa.
- McArdle (V): myophosphorylase deficiency, exercise cramps, myoglobinuria, flat lactate on forearm test, second-wind phenomenon.