Enhance your knowledge with our comprehensive guide and curated study materials.
• Dietary carbohydrates include starch, glycogen, sucrose, and lactose.
• Digestion starts in the mouth by salivary α-amylase but stops in the stomach due to acidity.
• Pancreatic α-amylase in the small intestine breaks α-1,4 linkages → maltose, isomaltose, dextrins.
• Brush border enzymes—sucrase, maltase, isomaltase, lactase—convert disaccharides to monosaccharides.
• Caused by lactase deficiency.
• Leads to lactose accumulation → irritation, flatulence, diarrhea.
• May be congenital or acquired.
• Only monosaccharides are absorbed.
• Absorption rate: galactose > glucose > fructose.
• Located on the intestinal mucosal side.
• Transports glucose + sodium (secondary active transport).
• Sodium pump indirectly provides energy.
• Defect causes glucose-galactose malabsorption.
• Present in kidney proximal tubule.
• Defect results in congenital renal glycosuria.
• Found in intestine (blood side), liver, pancreatic β-cells, kidney.
• Facilitated diffusion (uniport).
• High Km → acts as glucose sensor and helps regulate insulin release.
• Located in skeletal muscle and adipose tissue.
• Insulin-dependent transporter.
• Reduced membrane GLUT-4 in Type 2 DM → insulin resistance.
• Present in RBCs, brain, kidney, colon, retina, placenta.
• Maintains basal glucose uptake.
• Located in neurons.
• High affinity → ensures continuous glucose supply to brain.
• Found in small intestine, testis, and sperm.
• Fructose transporter.
• Located on the liver ER membrane.
• Moves glucose from ER lumen → cytoplasm.
• Glucose & galactose: SGLUT-1 (active).
• Fructose: GLUT-5 (facilitated).
• Exit into blood: GLUT-2.
According to a document from your file vasu biochem.pdf, blood glucose is maintained within narrow limits because the brain, RBCs, and renal medulla require a continuous glucose supply.
When a meal is taken:
• Glucose is absorbed into blood → blood glucose rises.
• Insulin secretion increases from pancreatic β-cells.
• Insulin promotes:
– Glucose uptake in extrahepatic tissues (via GLUT-4)
– Glycogen synthesis
– Lipogenesis
High glucose → high insulin → lowering of blood sugar by:
• Tissue utilization
• Glycogen formation
• Fat synthesis
(Shown in Fig. 24.2B).
About 2–2.5 hours after a meal, glucose falls toward fasting levels.
Maintained by:
• Hepatic glycogenolysis for ~3 hours
• Later by gluconeogenesis
In fasting:
• Glucagon is high.
• Adipose tissue releases free fatty acids as alternate fuel (Fig. 24.2A).
(Box 24.1)
• Intestinal absorption
• Glycogenolysis
• Gluconeogenesis
• Hyperglycemic hormones: glucagon, steroids, epinephrine, GH, ACTH, thyroxine.
• Glucose utilization in tissues
• Glycogen synthesis
• Lipogenesis
• Insulin (hypoglycemic hormone).
Glycolysis is the sequence of reactions where one molecule of glucose is converted into two molecules of pyruvate (aerobic) or two molecules of lactate (anaerobic) with the production of ATP and NADH.
Occurs entirely in the cytoplasm of all cells.
• Only pathway that occurs in all human tissues.
• Primary and only ATP source for RBCs.
• Major ATP source during strenuous exercise.
• Provides intermediates for amino acid and glycerol synthesis.
• Several reversible steps are shared with gluconeogenesis.
Enzyme: Hexokinase / Glucokinase
Irreversible; traps glucose inside the cell.
Enzyme: Phosphohexose isomerase
Enzyme: PFK-1 (Rate-limiting step)
Irreversible.
Enzyme: Aldolase
Enzyme: Triose phosphate isomerase
Enzyme: G3P dehydrogenase
Generates NADH.
Enzyme: Phosphoglycerate kinase
Produces ATP (substrate-level phosphorylation).
Enzyme: Phosphoglycerate mutase
Enzyme: Enolase
Enzyme: Pyruvate kinase
Produces ATP.
Irreversible.
Hexokinase / Glucokinase
Phosphofructokinase-1 (PFK-1)
Pyruvate kinase
• Net gain: 2 ATP and 2 NADH
• Total ATP yield (after ETC reoxidation): 7 ATP per glucose
• Pyruvate → Lactate
• Net gain: 2 ATP
• NADH is reoxidized to NAD⁺ by lactate dehydrogenase.
• Hexokinase: inhibited by glucose-6-phosphate
• Glucokinase: active when blood glucose is high; induced by insulin
Most important control point
• Activated by: AMP, Fructose-2,6-bisphosphate
• Inhibited by: ATP, citrate
• Activated when energy demand is high
• Inhibited when ATP is abundant
• Also regulated by phosphorylation/dephosphorylation depending on hormonal status
• Formed by PFK-2
• Most powerful activator of PFK-1
• High glucose → ↑F-2,6-BP → ↑glycolysis
• Low glucose → ↓F-2,6-BP → ↓glycolysis
• Insulin stimulates glycolysis (increases key enzyme activities).
• Glucagon inhibits glycolysis (via cAMP → enzyme phosphorylation).
• Counterregulatory hormones (epinephrine, cortisol) also reduce glycolytic flux when needed.
Cori’s Cycle explains how lactate produced in muscles and RBCs is recycled by the liver to maintain blood glucose.
• During anaerobic glycolysis (exercise, hypoxia), pyruvate → lactate.
• Lactate enters blood and is carried to the liver.
• Liver converts lactate → pyruvate → glucose via gluconeogenesis.
• Newly formed glucose is released back into blood and reused by muscle.
• Prevents lactic acidosis.
• Supplies glucose during prolonged exercise.
• Allows continued glycolysis in tissues lacking mitochondria (RBCs).
• Excessive lactate production → lactic acidosis (shock, sepsis, hypoxia).
• Essential for RBC metabolism since they rely only on glycolysis.
This pathway operates exclusively in RBCs to regulate oxygen delivery.
• 1,3-Bisphosphoglycerate is diverted from glycolysis → forms 2,3-BPG.
• 2,3-BPG binds to deoxygenated hemoglobin, decreasing its affinity for oxygen.
• Enhances oxygen unloading to tissues.
• Shifts oxygen–hemoglobin dissociation curve to the right.
• High altitude
• Chronic hypoxia
• Anemia
• Stored blood → reduced O₂ delivery capacity
• Fetal hemoglobin (HbF) binds 2,3-BPG poorly → higher O₂ affinity
Pyruvate is the central metabolic junction connecting glycolysis with multiple pathways.
Pyruvate → Acetyl-CoA
Enzyme: Pyruvate dehydrogenase complex (PDH)
Requires thiamine, lipoic acid, CoA, FAD, NAD⁺.
• Enters TCA cycle
• Fatty acid synthesis
• Ketone body synthesis (liver)
• Lactic acidosis
• Neurological defects
• Treated with thiamine supplementation
Pyruvate → Lactate
Enzyme: Lactate dehydrogenase
Purpose: regenerate NAD⁺ for glycolysis.
• RBCs
• Exercising muscle
• Hypoxic tissues
Enzyme: Pyruvate carboxylase
Requires biotin.
• First step of gluconeogenesis
• Replenishes TCA intermediates (anaplerosis)
Enzyme: Alanine transaminase (ALT)
• Part of glucose–alanine cycle between muscle and liver
• Transports amino nitrogen to the liver for urea synthesis
Occurs in yeast and bacteria
Enzyme: pyruvate decarboxylase → alcohol dehydrogenase
(Not in humans)
• Cori’s cycle conserves glucose during anaerobic conditions.
• 2,3-BPG regulates oxygen delivery by modifying hemoglobin affinity.
• Pyruvate connects glycolysis with TCA, gluconeogenesis, amino acid metabolism, and lactate formation.
• PDH is inhibited by ATP, NADH, and acetyl-CoA; activated by ADP and pyruvate.
• Lactate production allows glycolysis to continue without oxygen.
• Oxaloacetate formation is essential during fasting for gluconeogenesis.
Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors such as lactate, glucogenic amino acids, glycerol, and propionyl-CoA.
• Mainly in the liver
• Partly in the renal cortex
• Reactions occur in both mitochondria and cytosol
These replace the irreversible steps of glycolysis:
Pyruvate carboxylase
PEP carboxykinase (PEPCK)
Fructose-1,6-bisphosphatase
Glucose-6-phosphatase
Enzyme: Pyruvate carboxylase
• Occurs in mitochondria
• Requires ATP and biotin
• Activated by acetyl-CoA
Oxaloacetate must move to cytosol via:
• Malate shuttle, or
• Aspartate shuttle
Enzyme: PEP carboxykinase (PEPCK)
• Uses GTP
• Removes CO₂
• First major bypass of glycolysis
PEP → Fructose-1,6-bisphosphate using steps 8, 7, 6, 5, and 4 of glycolysis (all reversible).
Enzyme: Fructose-1,6-bisphosphatase
• Major regulatory step of gluconeogenesis
• Inhibited by AMP and fructose-2,6-bisphosphate
• Activated during fasting
Enzyme: Phosphohexose isomerase
Enzyme: Glucose-6-phosphatase
• Present in liver, kidney, and intestine
• Absent in muscle, so muscle cannot release free glucose
• From muscle and RBCs
• Converted to pyruvate → enters pathway
• Part of Cori’s cycle
• Alanine, glutamate, aspartate, etc.
• Alanine is the major substrate (glucose–alanine cycle)
• Increased proteolysis in starvation or uncontrolled diabetes
• From triglyceride breakdown
• Converted to DHAP in the liver
• From odd-chain fatty acids
• Converted to succinyl-CoA
• Minor source
Important: Even-chain fatty acids cannot form glucose.
To form one glucose molecule, gluconeogenesis uses:
• 6 ATP equivalents
– 2 ATP (pyruvate → oxaloacetate)
– 2 GTP (oxaloacetate → PEP)
– 2 ATP (3-phosphoglycerate → 1,3-BPG)
Gluconeogenesis and glycolysis are reciprocally regulated.
• Glucagon
• Cortisol
• Epinephrine
• Acetyl-CoA
• Insulin
• High AMP
• High fructose-2,6-bisphosphate
1. Pyruvate Carboxylase
• Activated by acetyl-CoA
2. PEPCK
• Induced by fasting hormones (glucagon, cortisol)
• Inhibited by insulin
3. Fructose-1,6-bisphosphatase
• Inhibited by AMP
• Inhibited by fructose-2,6-bisphosphate
4. Glucose-6-phosphatase
• Active only in tissues capable of releasing glucose
• Maintains blood glucose during fasting, starvation, and exercise
• Essential for tissues requiring glucose (brain, RBCs, kidney medulla)
• Prevents hypoglycemia when glycogen stores are depleted
• Complements Cori’s cycle and glucose–alanine cycle
• Occurs in liver and partly kidney
• Not a simple reversal of glycolysis
• Four bypass enzymes overcome irreversible steps
• Alanine and lactate are major substrates
• Requires 6 ATP per glucose
• Insulin inhibits; glucagon stimulates
• Muscle lacks glucose-6-phosphatase → cannot contribute to blood glucose
The glucose–alanine cycle transfers amino nitrogen from muscle to liver and returns glucose back to muscle.
It connects protein catabolism in muscle with gluconeogenesis in liver.
• Muscle → production of alanine
• Liver → conversion of alanine to glucose
• Cycle repeats during fasting, exercise, and muscle protein breakdown
• During exercise or fasting, muscle proteolysis releases amino acids.
• Pyruvate (from glycolysis) accepts amino group from glutamate via ALT (alanine transaminase).
• This produces alanine.
• Alanine is released into bloodstream.
• Alanine circulates from muscle to liver.
• This safely transports ammonia in a nontoxic form.
• Alanine → Pyruvate via ALT
• Amino group enters urea cycle → converted to urea for excretion
• Pyruvate enters gluconeogenesis → forms glucose
• Produced glucose is sent back to muscle → enters glycolysis → forms pyruvate again
• Cycle continues
• Removes ammonia safely from muscle
• Provides glucose to muscle during exercise and fasting
• Supports gluconeogenesis in liver
• Helps maintain blood glucose when glycogen stores are depleted
• Prevents buildup of pyruvate and lactate in muscle
| Feature | Glucose–Alanine Cycle | Cori’s Cycle |
|---|---|---|
| Transported substance | Alanine | Lactate |
| What is removed from muscle? | Ammonia (NH₃) | Lactic acid |
| Liver uses for gluconeogenesis? | Pyruvate from alanine | Pyruvate from lactate |
| Additional effect | Detoxifies ammonia | Prevents lactic acidosis |
• Elevated ALT indicates muscle or liver injury (cycle enzyme).
• Increased in fasting, trauma, burns, sepsis, due to increased muscle proteolysis.
• Important in maintaining glucose in prolonged starvation or uncontrolled diabetes.
• Transfers nitrogen from muscle → liver.
• Alanine carries both nitrogen and carbon skeleton.
• Liver converts alanine → glucose; glucose returns to muscle.
• ALT is key enzyme in both tissues.
• Helps prevent hyperammonemia and provides fuel during fasting.
Glycogenolysis is the breakdown of glycogen into glucose units.
All enzymes involved are cytoplasmic.
• Removes glucose units as glucose-1-phosphate (phosphorolysis).
• Acts only on α-1,4 linkages.
• Stops 3–4 residues before a branch point.
• Requires pyridoxal phosphate (PLP) as cofactor.
Two enzymatic activities:
• Transfers block of 3 glucose residues to another chain.
• Cleaves the remaining α-1,6-linked glucose, releasing free glucose.
• Converts glucose-1-phosphate → glucose-6-phosphate.
• Contains glucose-6-phosphatase → releases free glucose into blood.
• Lacks glucose-6-phosphatase → retains G6P for glycolysis and ATP production.
• From glycogen-derived glucose: 3 ATP (no ATP required for Step 1 of glycolysis).
• From free glucose: 2 ATP.
• Activated by AMP and Ca²⁺–calmodulin, and by epinephrine.
• Glucagon has no effect.
• Controlled mainly by glucagon and epinephrine (via cAMP cascade).
Glycogenesis is not the reverse of glycogenolysis; it has distinct enzymes.
• Core protein = glycogenin, attaches first glucose and forms an oligosaccharide of 7 glucose units per monomer.
• Glucose-1-P + UTP → UDP-glucose
(Activation step)
• Adds glucose from UDP-glucose to non-reducing ends of glycogen via α-1,4 linkages.
• Amylo-[1,4]→[1,6]-transglucosidase creates α-1,6 branches.
• Transfers block of 6–8 glucose residues to form a branch.
• Glycogen synthase is active when dephosphorylated.
• Glucose-6-P activates dephosphorylated glycogen synthase.
• Hormonal regulation via cAMP, affecting both synthase & phosphorylase reciprocally.
(Based on the clinical sections of the glycogen metabolism chapter)
GSDs are inherited disorders caused by enzyme defects in glycogen metabolism.
Below is the high-yield clinically relevant list following standard classification.
• Enzyme: Glucose-6-phosphatase deficiency
• Affected tissue: Liver, kidney
• Features:
– Severe fasting hypoglycemia
– Lactic acidosis
– Hyperuricemia
– Hepatomegaly
• Reason: Impaired release of glucose from liver.
• Enzyme: Lysosomal α-1,4-glucosidase (acid maltase)
• Generalized, including cardiac muscle
• Features:
– Cardiomegaly
– Heart failure in infancy
– Muscle hypotonia
• Enzyme: Debranching enzyme deficiency
• Accumulation of limit dextrins
• Features:
– Mild hypoglycemia
– Hepatomegaly
– Muscle weakness
• Enzyme: Branching enzyme deficiency
• Very long, unbranched glycogen → liver fibrosis
• Features:
– Cirrhosis
– Failure to thrive
– Death in childhood
• Enzyme: Muscle glycogen phosphorylase deficiency
• Features:
– Exercise intolerance
– Muscle cramps
– “Second wind” phenomenon
– Myoglobinuria
• Enzyme: Liver phosphorylase deficiency
• Features:
– Mild fasting hypoglycemia
– Hepatomegaly
• Liver glycogen maintains blood glucose; muscle glycogen fuels contraction.
• Glycogen phosphorylase removes G1P; debranching enzyme removes branch residues.
• Muscle cannot release glucose due to absence of glucose-6-phosphatase.
• Glycogen synthase builds α-1,4 chains; branching enzyme makes α-1,6 linkages.
• Glycogen metabolism is reciprocally regulated by cAMP.
• GSDs involve specific enzyme defects → characteristic presentations.
• Liver glycogen maintains blood glucose during fasting; muscle glycogen supplies local energy only.
• Glycogen synthase forms α-1,4 linkages; branching enzyme forms α-1,6 linkages.
• Glycogen phosphorylase removes glucose as glucose-1-phosphate (not free glucose).
• Debranching enzyme has two activities: transferase + α-1,6-glucosidase.
• Muscle lacks glucose-6-phosphatase, so it cannot release free glucose into blood.
• Glycogen metabolism is regulated by phosphorylation:
– Glycogen phosphorylase → active when phosphorylated
– Glycogen synthase → active when dephosphorylated
• cAMP stimulates glycogen breakdown via phosphorylase activation.
• PLP (vitamin B6) is a cofactor for glycogen phosphorylase.
• Glycogenesis and glycogenolysis are reciprocally regulated.
• In glycogenolysis, glycolysis yields 3 ATP per glucose (because hexokinase step is bypassed).
• Most GSDs are autosomal recessive disorders.
• Pompe disease is the only GSD involving a lysosomal enzyme.
• McArdle disease presents with exercise intolerance and second-wind phenomenon.
• Von Gierke disease causes severe hypoglycemia, lactic acidosis, hyperuricemia, hepatomegaly.
Because muscle lacks glucose-6-phosphatase, so G6P cannot be converted into free glucose.
To maintain blood glucose between meals and during early fasting.
Branching increases solubility, storage efficiency, and allows faster synthesis and breakdown.
Glycogen phosphorylase.
Debranching enzyme releases it as free glucose, not G1P.
Different enzymes catalyze the forward and reverse pathways; several steps are irreversible.
• AMP (low energy)
• Ca²⁺–calmodulin (muscle contraction)
• Epinephrine
In liver:
• Increases cAMP → activates phosphorylase → promotes glycogenolysis
• Inhibits glycogenesis
It has no effect on muscle (muscle lacks glucagon receptors).
Glycogen can be rapidly converted to glucose anaerobically, while fat oxidation requires oxygen and is slower.
Pompe disease (Type II) — deficiency of lysosomal acid maltase.
McArdle disease (Type V) — muscle phosphorylase deficiency.
Blocked glucose-6-phosphatase causes glucose-6-phosphate to be shunted into glycolysis → lactate.
Andersen disease (Type IV) — branching enzyme deficiency.
Glycogenin, which serves as the primer.
Because gluconeogenesis is intact even though liver phosphorylase is deficient.
A. Glucose
B. Glucose-1-phosphate
C. Glucose-6-phosphate
D. Free glucose only from branches
A. Biotin
B. Thiamine
C. Pyridoxal phosphate (PLP)
D. FAD
A. Glucose-1-phosphate
B. UDP-glucose
C. Free glucose
D. Fructose-6-phosphate
A. Phosphoglucomutase
B. Glucose-6-phosphatase
C. Glycogen synthase
D. Debranching enzyme
A. Glycogen phosphorylase
B. Branching enzyme
C. Glycogen synthase
D. Glucokinase
A. α-1,4
B. α-1,6
C. β-1,4
D. β-1,6
A. Dephosphorylating phosphorylase kinase
B. Phosphorylating glycogen phosphorylase
C. Inhibiting glycogen synthase only
D. Activating branching enzyme
A. Glycogen synthase
B. UDP-glucose pyrophosphorylase
C. Glycogen phosphorylase
D. Glucose-6-phosphatase
A. Glucagon
B. Epinephrine
C. Cortisol
D. Thyroxine
A. Pompe
B. Cori
C. Andersen
D. McArdle
A. McArdle disease
B. Pompe disease
C. Von Gierke disease
D. Andersen disease
A. Hers disease
B. Pompe disease
C. Cori disease
D. McArdle disease
A. Type I
B. Type III
C. Type V
D. Type IV
A. Andersen disease
B. Cori disease
C. Von Gierke disease
D. McArdle disease
A. Von Gierke disease
B. Hers disease
C. McArdle disease
D. Pompe disease
A. Phosphorylated
B. Ubiquitinated
C. Dephosphorylated
D. Bound to AMP
A. Glycogenin
B. Glycogen synthase
C. Branching enzyme
D. UDP-glucose pyrophosphorylase
A. 0 ATP
B. 1 ATP
C. 2 ATP
D. 3 ATP
A. Type I
B. Type II
C. Type III
D. Type VI
A. Ca²⁺–calmodulin
B. Glucagon
C. Epinephrine only
D. Insulin
1-B
2-C
3-C
4-B
5-C
6-B
7-B
8-C
9-B
10-B
11-C
12-B
13-C
14-A
15-B
16-C
17-A
18-D
19-B
20-A
To maintain blood glucose during fasting.
To provide rapid local ATP for muscle contraction.
Glucose-1-phosphate.
Pyridoxal phosphate (PLP).
Because muscle lacks glucose-6-phosphatase.
α-1,6-glucosidase activity of the debranching enzyme.
α-1,6 linkage.
Glycogen synthase.
Glycogenin.
When phosphorylated.
When dephosphorylated.
Stimulates glycogenolysis; inhibits glycogenesis.
Epinephrine.
Glucagon (and epinephrine).
3 ATP per glucose.
Limit dextrins.
Glucose-6-phosphatase deficiency.
Because glucose cannot be released from G6P.
Pompe disease (Type II).
Exercise intolerance with second-wind phenomenon.
Andersen disease (Type IV).
Liver phosphorylase deficiency causing mild hypoglycemia.
To increase solubility and allow rapid synthesis & degradation.
Ca²⁺–calmodulin complex.
α-1,4 = linear chain
α-1,6 = branch point
Get the full PDF version of this chapter.
Continue with Google