Obj 1: Integration of Metabolic Pathways during Fed and Fasting States

The human body maintains energy homeostasis by regulating metabolic pathways depending on the
availability of nutrients.

The fed state (absorptive state) occurs after a meal when nutrients are abundant, while fasting state(
post-absorptive state) occurs several hours after eating when stored energy is utilised

Fed State = Absorptive Phase ( influx of nutrients > energy requirement)

Hormone of abundance: Insulin (secreted by beta cells of pancreas)

Time Frame: 0-4 h after a meal

Insulin promotes efficient storage of excess nutrients (carbohydrates, lipids & proteins) + inhibits their
degradation and release into the circulation

Insulin stimulates the uptake of glucose, A.A, FA into cells & increases expression/activity of enzymes
that catalyse glycogen, lipid and lipid synthesis while inhibiting the expression/activity of those that
catalyse their degradation

Main target tissues: Liver, muscle & adipose tissue

Key features:
1.​ Glucose utilisation: Blood glucose is used as the primary energy source
2.​ Glycogenesis: Excess glucose stored as glycogen in liver and muscles
3.​ Lipogenesis: Excess glucose and A.A converted to FA & stored as TG in adipocytes
4.​ Protein synthesis: A.A used for protein synthesis rather than energy production
1.​ CARBOHYDRATE METABOLISM

●​ ⊕ Glycolysis
-​ Insulin causes translocation of glucose transporters (GLUT4 only) on cell membranes of
liver, muscle cells & adipocytes = allow intracellular glucose uptake.
-​
-​ Insulin does not influence the number GLUT2, similarly to GLUT1 and GLUT3 which are
present in the brain, RBC and almost all other cells
-​
-​ Glycolysis is the major energy-producing pathway in RBC and brain.
-​
-​ Phosphofructokinase 1 PFK1 is the rate-limiting step and is activated by
Phosphofructokinase 2 PFK2 which itself is activated by insulin and inhibited by
glucagon.
●​ ⊕ Glycogenesis
-​ Excess glucose during the fed state is stored as glycogen in liver and muscle, a
cytosolic process activated by insulin.
-​
-​ Glycogen synthase is the rate-limiting step.

●​ ⊕ Pentose phosphate pathway

-​ Excess glucose also enters the pentose phosphate pathway (Hexose monophosphate
shunt), a cytosolic process which generates NADPH, for the synthesis of fatty acids,
cholesterol, nucleotides and coenzymes of antioxidant enzymes, and ribose, for the
synthesis of DNA and RNA.
-​
-​ Glucose-6-phosphate dehydrogenase G6PD is the rate-limiting step.

2.​ LIPID METABOLISM

●​ ⊕ Lipogenesis & TG storage
-​ During the fed state, the increased glucose and insulin levels stimulate lipogenesis, i.e. the
synthesis of fatty acid and triacylglycerol, a process which occurs in the cytosol.
-​
-​ Acetyl CoA has to be transported into the cytosol as citrate, which is then converted back to
acetyl CoA in the cytosol by citrate lyase.
-​
-​ The rate-limiting step is acetyl CoA carboxylase, activated by insulin. It catalyses the
transformation of acetyl CoA into malonyl CoA.
-​
-​ Another important enzyme is fatty acid synthase which uses NADPH derived from the pentose
phosphate pathway.​

-​ The newly-synthesized fatty acids are combined with glycerol-3-phosphate (a glycolytic

intermediate) to generate triacylglycerol, which is then transported into the bloodstream and
peripheral tissues in the forms of lipoprotein VLDL.
-​
-​ During the fed state cholesterol is also increased due to the action of insulin and the availability
of acetyl-CoA in the cytosol.
-​ HMG CoA reductase is the rate-limiting step. This enzyme is activated by insulin and inhibited
by antilipidemic drugs (statins).
-​ Cholesterol is transported into the bloodstream and peripheral tissues in the forms of lipoprotein
VLDL.
3.​ PROTEIN METABOLISM
●​ ⊕ Protein synthesis
-​ Insulin stimulates amino acid uptake.
-​
-​ Unlike glucose or fatty acids, amino acids are not stored. After being used for the
synthesis of proteins and nitrogenous compounds (heme, creatine, purine, pyrimidine,
histamine, epinephrine), the excess amino acids undergo transamination and
deamination, resulting in the production of α-keto acids, i.e. intermediates in the
metabolic pathways (glycolysis, Krebs cycle, fatty acid synthesis and lipogenesis).
-​
-​ The carbon skeleton of amino acids can be used during the fed state for energy
production and synthesis of triacylglycerol.
Fasting State (High Glucagon, Low Insulin)
Main counterregulatory hormone of insulin: glucagon secreted by alpha cells of pancreas

Other implicated hormones are epinephrine, growth hormone and cortisol

Time frame: 4-24 h after a meal (early fasting), prolonged fasting (>24 h)

Key features:

1.​ Glycogenolysis: Breakdown of glycogen into glucose

2.​ Gluconeogenesis: Glucose synthesis from non-carb sources (lactate, a.a, glycerol etc)
3.​ Lipolysis: TG breakdown into FA + glycerol
4.​ Ketogenesis (during prolonged fasting): Liver produces ketone bodies from FA as alternative to
glucose (used by brain)

1.​ CARBOHYDRATE METABOLISM

●​ ↑ Glycogenolysis
-​ Glycogen is broken down in the cytosol to release glucose into the bloodstream, preventing the
blood glucose from dropping too low.
-​
-​ Although glycogenesis from glycogenolysis occurs both in liver and muscle, the muscle glycogen
is stored and used only within the muscle (in house use) because the muscle lacks the enzyme
glucose-6-phosphatase and thus is unable to release glucose into the bloodstream.
-​
-​ The rate-limiting enzyme glycogen phosphorylase is activated by glucagon and epinephrine.

●​ ↑ Gluconeogenesis
-​ Glycogen stores are low & to keep up the blood glucose level, new glucose must be synthesized
from other compounds (e.g. amino acids, lactate, glycerol) by gluconeogenesis, both a cytosolic
and mitochondrial process which is activated by glucagon and epinephrine.​
Note that acetyl CoA (derived from the beta-oxidation of fatty acid) cannot be used as a
substrate for gluconeogenesis.
-​
-​ The rate limiting enzyme is fructose-1,6-bisphosphatase.
-​
-​ Other important enzymes are pyruvate carboxylase, PEP carboxykinase (PEPCK), and
glucose-6-phosphatase.
2.​ LIPID METABOLISM
●​ ↑ Lipolysis and beta-oxidation of fatty acids
-​ Counterregulatory hormones stimulate lipolysis by activating hormone sensitive lipase,
which releases fatty acids and glycerol from triglycerides into the bloodstream.
-​
-​ Peripheral tissues such as muscle, heart, and liver can use fatty acids as fuel,
preserving glucose for the important organs like the brain.
-​
-​ Beta oxidation of fatty acid occurs in the mitochondria.
-​
-​ The rate-limiting enzyme is carnitine acyltransferase which facilitates fatty acid transport
into mitochondria and glycerol kinase which catalyzes the transformation of glycerol into
dihydroxyacetone phosphate (DHAP).
●​ ↑ Ketogenesis (during prolonged fasting)
-​ The liver produces ketone bodies for other tissues but cannot use them (ketolysis) due
to the lack of enzyme beta-ketoacyl CoA transferase.
-​
-​ Neurons cannot use fatty acids directly. However, they can adapt to use ketone bodies
during prolonged fasting or starvation and provide an alternative to glucose as an
energy source for the brain.
-​
-​ Ketogenesis is normally low and increases in case of shortage of carbohydrates and
excessive oxidation of fatty acids, e.g. unbalanced diabetes mellitus: fat is broken down
into acetyl-CoA in order to get energy, thus preserving glucose for important organs.
-​
-​ Acetyl-CoA cannot be recycled through the Krebs cycle because the citric acid cycle
intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis
pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.
3.​ PROTEIN METABOLISM
●​ ↑ Protein breakdown
-​ The carbon skeletons of glucogenic amino acids are an important source of energy production,
of substrates for gluconeogenesis and ketogenesis.
-​
-​ They are broken down as a result of a counterregulatory hormone corticosteroid action into one
of the following metabolites: pyruvate, α- ketoglutarate, succinyl CoA, fumarate or oxaloacetate.
 Ketogenesis

Role of Ketone Bodies

• Ketone bodies provide "cheap" energy when glucose is insufficient.

• This is especially important for the brain, which cannot use lipids for energy.
• Advantages of ketone bodies:
o Water-soluble, making them easy to transport in the blood.
o Cross cell membranes easily.
o Act as shuttles to transfer acetyl-CoA between cells for energy production.

Synthesis and Degradation of Ketone Bodies

Synthesis (Ketogenesis)

• Location: Liver mitochondria (exclusive site of synthesis).

• Main Ketone Bodies:
o Acetoacetate
o β-hydroxybutyrate
• Precursor: Derived from acetyl-CoA.
• Triggers for Ketogenesis:
o Carbohydrate shortage (fasting, low-carb diet).
o Excessive fatty acid oxidation (as in diabetes mellitus).
o Uncontrolled diabetes:
▪ Cells experience glucose fasting despite high blood glucose.
▪ Fat breakdown increases, producing acetyl-CoA.
▪ Oxaloacetate depletion (due to gluconeogenesis) prevents acetyl-CoA from
entering the Krebs cycle.
▪ Excess acetyl-CoA is diverted to ketone body formation.
• Protein catabolism also contributes by releasing keto-forming amino acids.

Degradation (Ketolysis)

• Location:
o Peripheral tissues: Muscle, brain, myocardium (heart), renal cortex (kidney).
• Process:
o Ketone bodies are converted back to acetyl-CoA.
o Acetyl-CoA enters the Krebs cycle for ATP production.
• Red Blood Cells (RBCs):
o CANNOT use ketone bodies due to the absence of mitochondria.
Regulation of Ketogenesis

Hormonal Control

• Ketone production increases in fasting and uncontrolled diabetes.

• Key hormonal trigger: Change in the glucagon-to-insulin ratio.
o ↓ Insulin, ↑ Glucagon → Increased Ketogenesis
o Glucagon stimulates fatty acid oxidation and ketogenesis in the liver.

Glucagon’s Role in Ketogenesis

↑ Glucagon ⟶ ↑ Lipolysis ⟶ ↑ FFAs released in blood and sent to liver

⟶ Glucagon ↓ malonyl-CoA levels by inhibiting acetyl-CoA carboxylase (Glycolytic pathway) ⟶

CPT-1 activates ⟶ Allows long-chain fatty acids to enter mitochondria for β-oxidation ⟶ ↑ β-oxidation ⟶ ↑
acetyl-CoA ⟶ ↑ ketogenesis (HMG-CoA Synthase activated)

Rate-Limiting Step of Ketogenesis

• Hset states that CPT-1 (Carnitine Palmitoyltransferase 1) is the rate-controlling step.

• However, the true rate-limiting enzyme in ketogenesis is mitochondrial HMG-CoA Synthase
(commits acetyl-CoA to ketone body formation).
• CPT-1 is the rate-limiting step for fatty acid β-oxidation, indirectly controlling ketogenesis by
regulating fatty acid entry into mitochondria.
• HMG-CoA Lyase is the slowest step, making it the rate-determining step.

Summary
Aspect Details
Main Function of Ketone Bodies Provide alternative energy, especially for the
brain
Main Ketone Bodies Acetoacetate, β-hydroxybutyrate
Synthesis Location Liver mitochondria
Degradation Location Peripheral tissues (muscle, brain, heart,
kidney)
Triggers for Ketogenesis Fasting, low carb intake, diabetes, high fat
oxidation
Key Hormone Glucagon (↑ ketogenesis) vs. Insulin (↓
ketogenesis)
Rate-Limiting Enzyme of HMG-CoA Synthase
Ketogenesis
Indirect Control via Fatty Acid CPT-1 (Carnitine Palmitoyltransferase 1)
Oxidation
Ketogenesis Pathway
The ketone bodies are: acetone, acetoacetate and β-hydroxybutyrate.
1. 2 molecules of acetyl-CoA condense to form acatoacetyl-CoA. (Catalysed by enzyme thiolase)
2. Catalysed by enzyme HMG-CoA synthase: Acetoacetyl-CoA combines with another molecule of acetyl-
CoA to produce HMG-CoA (ß-hydroxy ß-methyl glutaryl-CoA).
3. HMG-CoA lyase cleaves HMG-CoA to produce acetoacetate and acetyl-CoA.
4. Acetoacetate can undergo spontaneous decarboxylation to form acetone.
5. Acetoacetate can be reduced by a dehydrogenase to
ß-hydroxybutyrate.
The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation -
PMC
 GLYCOLYSIS
• Glycolysis or Embden-Myerhof is the metabolic pathway that converts glucose(C6) into pyruvate(C3).
• Occurs in the cytoplasm of all cells.
• Involves 10 enzymatic rxns and produce ATP + NADPH.
• The pathway functions under both : aerobic and anaerobic conditions.
• Glycolysis: 2 phase
1- Investment phase(-2 ATP for 1 glucose)
2- Output phase, energy generation (+4 ATP for 1 glucose)
 Mnemonic:

Step 1: Energy Investment Phase (Uses 2 ATP) The molecules:

Glucose → Pyruvate (via 10 reactions) Girls- Glucose
1. Glucose phosphorylation (by hexokinase/glucokinase) Get- G6P
→ G-6-P (irreversible)
Fine- F6P
2. Isomerization → Fructose-6-P
Foods- F16BP
3. Phosphorylation (by phosphofructokinase-1;
rate-limiting step) → Fructose-1,6-DP (irreversible) Gentlemen- G3P
4. Cleavage into 2 three-carbon molecules → Dine- DP
Dihydroxyacetone-P + Glyceraldehyde-3-P Girls- G3P
Boys- 1,3BPG
Step 2: Energy Generation Phase (Produces 4 ATP) Prefer- 3PG
• High-energy phosphate bonds from intermediates Pick- 2PG
generate ATP. Pepperoni- PEP
• Key reactions: Pizza-P
1. Glyceraldehyde-3-P → 1,3-DP-Glycerate
(NADH production)
2. 1,3-DP-Glycerate → 3-P-Glycerate
(ATP produced) The enzymes:
3. 3-P-Glycerate → 2-P-Glycerate
4. 2-P-Glycerate → Phosphoenolpyruvate (PEP) High- Hexokinase + glucokinase
5. PEP → Pyruvate (by pyruvate kinase, Profile- Phosphoglucose isomerase
irreversible, ATP production) People- Phosphofructokinase-1
Act- Aldolase
Aerobic vs Anaerobic Glycolysis Too- Triose phosphate isomerase
1. Aerobic Glycolysis (With Oxygen)- AEROBIOSIS Glamorous- Glyceraldehyde 3 PD
• Final step: Pyruvate kinase catalyzes an irreversible reaction Picture- Phosphoglycerate kinase
forming pyruvate. Posing- phosphoglycerate mutase
• Energy yield: Every- Enolase
o 2 ATP (net) per glucose molecule. Place – Pyruvate kinase
o 2 NADH molecules (contain ~15% of glucose's original energy).
o 80% of glucose’s energy remains in pyruvate.
• Pyruvate fate:
o Transported into mitochondria.
o Oxidized by Pyruvate Dehydrogenase (PDH).
o Converted to Acetyl-CoA, which enters the Krebs cycle for further ATP production.
• PDH Reaction:
Pyruvate + Coenzyme A + NAD⁺ → Acetyl-CoA + CO₂ + NADH + H⁺
• Energy efficiency:
o Only ~2% of glucose’s energy is captured in ATP during glycolysis.
o Remaining energy (~95%) is stored in NADH and pyruvate for later use.
o ~3% is lost as heat, helping maintain body temperature.

2. Anaerobic Glycolysis (Without Oxygen)- ANAEROBIOSIS

• Final step: Glycolysis extends beyond pyruvate to produce lactate.
• Lactate formation prevents pyruvate accumulation and regenerates NAD⁺ for continued glycolysis.
• No mitochondrial oxidation:
o Pyruvate does not enter the Krebs cycle.
o No additional ATP beyond glycolysis is produced.
• Energy yield:
o 2 ATP per glucose molecule (same as aerobic glycolysis).
o No further ATP from NADH (since it is used to reduce pyruvate to lactate).
• Advantage: Allows ATP production without oxygen, important for muscle activity during intense
exercise.
• Disadvantage: Less efficient energy production compared to aerobic metabolism.
Energy Distribution from Glucose
• 95% of glucose energy remains in NADH (~15%) and
pyruvate (~80%).
• Only 2% of energy is captured as ATP (rest released as heat).

Glycolysis
oCatabolic process of glucose hydrolysis.
oProvides:
▪ Energy (ATP production) – Critical for maintaining ATP levels.
▪ Biosynthetic intermediates – Used for fatty acid, cholesterol, and nucleotide
synthesis.
• Regulation of Glycolysis Allosteric: refer to a regulatory
o Enzymatic reactions are tightly controlled. mechanism where a molecule binds
o Regulatory mechanisms with different response times: to a site other than the active site of
▪ Allosteric effectors → Fast response (milliseconds). an enzyme, causing a change in its
▪ Covalent modification → Fast response (seconds), activity.
often via reversible phosphorylation.
▪ Transcriptional control → Slow response (hours), influenced by hormones and
growth factors.
• Key Control Points: Irreversible Reactions
o Enzymes catalyzing irreversible steps serve as main regulatory sites:
▪ Hexokinase (HK)
▪ Phosphofructokinase-1 (PFK1)
▪ Pyruvate kinase (PK)
• Other Important Regulators
o Glucokinase (GK) – Liver-specific form of hexokinase.
o Pyruvate dehydrogenase (PDH) – Links glycolysis to the TCA cycle.
o PDH kinase (PDHK) – Regulates PDH activity.
o Fructose 1,6-bisphosphatase (F1,6-BPase) – Opposes glycolysis in gluconeogenesis.
o Fructose 2,6-bisphosphate (F2,6-BP) – A key regulator of PFK1 and F1,6-BPase.

Remember the irreversible rxns are: steps: 1, 3, 10

- These steps have large -ve ΔG( free energy change) values making them one-way rxns under
physiological conditions.
 Enzyme Function Regulation

Phosphorylates glucose to
- Allosterically inhibited by G6P.
glucose-6-phosphate (G6P),
- If PFK1 is inactive → ↑ F6P → ↑ G6P → Inhibits HK.
Hexokinase (HK) committing it to glycolysis.
- PFK1 inhibition indirectly inhibits HK.
Always activated.
- Regulated by lysine acetylation.
High affinity for glucose

Liver/pancreatic isoform of HK,

- Escapes allosteric control.
specific for glucose.
Glucokinase (GK) - In fasting: captured by GKRP (GK regulatory protein).
Glucose sensor.
- In postprandial state: released to capture glucose in the liver.
Weak affinity for glucose.

- Most important control point of glycolysis.

- Allosteric inhibition by ATP & citrate.
Converts fructose-6-phosphate - Allosteric activation by F2,6-BP.
Phosphofructokinase-
(F6P) + ATP → fructose-1,6- - Exists in T ⇔ R states (inactive ⇔ active).
1 (PFK1)
bisphosphate (F1,6-BP) + ADP. - ATP inhibits PFK1 at inhibitor site (only in T state).
- Inhibition reversed by AMP → AMP/ATP ↓ → ↑ PFK1 →
stimulates glycolysis.

- Allosterically inhibited by ATP, acetyl-CoA, and alanine (liver

only).
- Allosterically activated by F1,6-BP.
Converts phosphoenolpyruvate - Covalently inactivated by phosphorylation (via glucagon-activated
Pyruvate kinase (PK) (PEP) → pyruvate, generating kinase).
ATP. - Covalently activated by dephosphorylation (via insulin-activated
phosphodiesterase).
- Lysine acetylation at Lys305 reduces activity and promotes
degradation via autophagy/lysosomes.

- Activated by NAD+ & acetyl-CoA.

Pyruvate - Inhibited by pyruvate.
Converts pyruvate → acetyl-CoA
Dehydrogenase - Covalently inactivated by phosphorylation (via PDH kinase).
for entry into the TCA cycle.
(PDH) - Covalently activated by dephosphorylation (via PDH
phosphatase).

- Allosterically activated by ATP, NADH, and acetyl-CoA.

Inactivates PDH via - Inhibited by pyruvate.
PDH Kinase (PDHK)
phosphorylation. - Mitochondrial enzyme, not regulated by cAMP/cytoplasmic
kinases.

Fructose 1,6-
Converts F1,6-BP → F6P - Inhibited by AMP (signals low energy, promotes glycolysis).
bisphosphatase (F1,6-
(gluconeogenesis). - Activated by citrate (signals energy abundance, inhibits glycolysis).
BPase)

- Activates PFK1 (increases affinity for F6P & counteracts ATP

inhibition).
- Inhibits F1,6-BPase (prevents gluconeogenesis).
- Controlled by bifunctional enzyme PFK-2/F2,6-BPase.
Fructose 2,6-
Key allosteric regulator of - Glucagon & insulin regulate balance of PFK-2/F2,6-BPase
bisphosphate (F2,6-
glycolysis & gluconeogenesis. activity:
BP)
- Liver: Unphosphorylated = PFK2 (glycolysis active), Phosphorylated
= F2,6-BPase (gluconeogenesis active).
- Muscle/Heart: Opposite regulation (e.g., adrenaline activates PFK2 to
promote glycolysis).

T-state(tensed) and R-state(relaxed) refer to the conformational states of allosteric enzymes.

T state: enzyme is in low affinity conformation for substrate.;less active;often stabilised by inhibitors/-ve regulators.
R state: enzyme is in a high affinity conformation for substrate; more active; stabilised by activators/ +ve regulators.
Gluconeogenesis

Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors

such as pyruvate, lactate, glycerol, Krebs cycle intermediates, and certain amino acids.

It primarily occurs in the liver (90%) and to a smaller extent in the kidney and intestine.

Gluconeogenesis is essential for maintaining glucose levels, especially for the brain, during
periods of glucose shortage.

The key steps of gluconeogenesis involve reversing the glycolytic pathway, except for three
irreversible steps that are bypassed with specialized enzymes:
1. Conversion of pyruvate to PEP via oxaloacetate, catalyzed by pyruvate carboxylase and
PEP carboxykinase

• in the mitochondria: formation of

oxaloacetate (OAA) from pyruvate
by pyruvate carboxylase.

o Oxaloacetate then follows

the malate shuttle to exit the
mitochondria:

▪ oxaloacetate is reduced →
malate
▪ by mitochondrial
malate dehydrogenase
▪ NADH is oxidized → NAD+

• in the cytoplasm:

o malate exits the mitochondria and is oxidized back:

▪ malate → OAA
▪ by cytoplasmic malate
dehydrogenase
▪ NAD+ is reduced → NADH

o OAA is decarboxylated:

▪ OAA → PEP (phosphoenolpyruvate)

by PEPCarboxyKinase (PEPCK: an
important regulator for
gluconeogenesis).
▪ GTP is hydrolyzed → GDP

2. Conversion F-1-6-DP to fructose-6P

• in the cytoplasm

o fructose-1,6-BP is dephosphorylated

▪ fructose-1.6-BP → fructose-6P by FDP phosphatase.

▪ Pi is produced

3. Conversion of G-6-P to glucose

• in the endoplasmic reticulum

o glucose-6-P is is dephosphorylated:

▪ glucose-6-P → glucose by G6 phosphatase.

▪ Pi is produced.
▪ This enzyme is liver and kidney specific.

NON GLUCONIC PRECURSORS (SUBSTRATES) OF GLUCONEOGENESIS

• lactate, synthesized from pyruvate in muscle and erythrocytes (anaerobic glycolysis)
In the liver lactate is transformed into pyruvate (primary substrate for gluconeogenesis)
by LDH (lactate dehydrogenase) with NADH production (Cori cycle)
Lactate + NAD+ → Pyruvate + NADH

• glycerol, a product of degradation of triglycerides in adipocytes

In the liver: glycerol is transformed into dihydroxyacetone phosphate (DHAP) (glycerol
kinase)
Glycerol → Glycerol-3-phosphate → DHAP

• alanine and other aminoacids can produce pyruvate or Krebs cycle intermediates by
transamination (alanine aminotransferase)
Alanine + α-cetoglutarate → Glutamate + Pyruvate

• Krebs Cycle Intermediates – Intermediates from the citric acid cycle (like
oxaloacetate) can also serve as substrates for gluconeogenesis.
 COORDINATED REGULATION OF STEPS OF GLUCOSE
METABOLISM BY INSULIN AND GLUCAGON

Insulin (Fed Enzymes Glucagon Enzymes

state) (Fasting
state)
Source Secreted by Secreted by
beta cells of the alpha cells of
pancreas the pancreas
Stimulus for High blood Low blood
Secretion glucose levels glucose levels
(after a meal) (between
meals,
fasting)
Main Effect Lowers blood Raises blood
glucose levels glucose levels
by promoting by promoting
glucose uptake glucose
and storage release
Glucose Promotes No significant
Uptake glucose uptake effect on
by muscle and glucose
fat cells (via uptake
GLUT4)
Glycogenesis Stimulates Glycogen Inhibits Glycogen
(Glucose glycogen synthase glycogenesis synthase
Storage) synthesis in by inhibiting (inhibited)
liver and muscle glycogen
by activating synthase
glycogen
synthase
Glycogenolys Inhibits Glycogen Stimulates Glycogen
is (Glycogen glycogen phosphorylas glycogen phosphoryl
Breakdown) breakdown by e (inhibited) breakdown ase
inhibiting by activating (stimulated)
glycogen glycogen
phosphorylase phosphoryla
se
Gluconeogen Inhibits PEPCK Stimulates PEPCK,
esis (Glucose gluconeogenes (phosphoenolp gluconeogen G6Pase
Production) is in liver by yruvate esis by (stimulated
suppressing key carboxykinase) activating key by
enzymes: , G6Pase enzymes: glucagon)
PEPCK, (glucose-6- PEPCK,
G6Pase phosphatase) G6Pase
Glycolysis Stimulates Hexokinase, Inhibits PFK-1
(Glucose glycolysis by PFK-1 glycolysis by
Pyruvate
Breakdown to activating key (phosphofructo reducing
kinase
Pyruvate) enzymes like kinase-1) activity of
(both are
hexokinase and PFK-1 and
inhibited by
PFK-1 pyruvate
glucagon)
kinase
Lipogenesis Stimulates fat Acetyl-CoA Inhibits Hormone-
(Fat storage by carboxylase, lipogenesis; sensitive
Synthesis) promoting Fatty acid suppresses lipase
conversion of synthase fat storage (inhibited by
glucose into fatty insulin,
acids in adipose activated by
tissue via glucagon)
acetyl-CoA
carboxylase
and fatty acid
synthase
Lipolysis (Fat Inhibits Hormone- Stimulates Hormone-
Breakdown) lipolysis in sensitive lipolysis in sensitive
adipose tissue lipase adipose tissue lipase
by decreasing (inhibited) by activating (stimulated)
hormone- hormone-
sensitive lipase sensitive
activity lipase
Protein Promotes Inhibits
Synthesis protein protein
synthesis in synthesis
muscle and through the
other tissues by activation of
activating mTOR PKA; favors
pathway protein
breakdown in
prolonged
fasting
Ketogenesis Inhibits Acetyl-CoA Stimulates HMG-CoA
(Ketone Body ketogenesis by carboxylase ketogenesis reductase
Production) promoting (inhibited) in liver to (stimulated)
glucose use for provide an
energy via alternative
insulin energy source
signaling via HMG-CoA
pathways reductase
Effect on Decreases Increases
Blood blood glucose blood
Glucose levels by glucose
increasing levels by
uptake and stimulating
storage glucose
release
andproduction
Main Target Liver, muscle, Liver, adipose
Organs adipose tissue tissue
[Hepatocytes
are rich in
glucagon
receptors]
Overall Anabolic: Catabolic:
Metabolic Promotes Promotes
Effect storage of breakdown of
nutrients stored
(glucose, fat, nutrients for
protein) energy

SUMMARY
● Glycogenesis:
o Insulin activates glycogen synthase, promoting glucose storage.
o Glucagon inhibits glycogen synthase, preventing glucose storage.
● Glycogenolysis:
o Insulin inhibits glycogen phosphorylase, reducing glycogen
breakdown.
o Glucagon activates glycogen phosphorylase, promoting glycogen
breakdown.
 ● Gluconeogenesis:
o Insulin inhibits PEPCK and G6Pase, blocking glucose production from
non-carbohydrate sources.
o Glucagon activates PEPCK and G6Pase, promoting glucose
production.
● Lipogenesis and Lipolysis:
o Insulin promotes fat storage through activation of acetyl-CoA
carboxylase and fatty acid synthase, and inhibits hormone-
sensitive lipase.
o Glucagon promotes fat breakdown by activating hormone-sensitive
lipase and inhibits fat storage.
● Protein synthesis
o Insulin stimulates protein synthesis through the activation of mTOR
pathway which increases ribosomal activity.
o Glucagon inhibits protein synthesis through the activation of adenylyl
cyclase that activates PKA which phosphorylates and hence,
inactivates proteins involved in protein synthesis.
● Ketogenesis:

o Insulin inhibits ketogenesis by regulating acetyl-CoA carboxylase.

o Glucagon stimulates ketogenesis by activating HMG-CoA reductase.

COORDINATED REGULATION AND BALANCED ACTION TO MAINTAIN

GLUCOSE HOMEOSTASIS

Coordinated regulation: Insulin vs. Glucagon

The secretion and action of insulin and glucagon are regulated in a highly
coordinated manner to maintain glucose homeostasis. When blood glucose levels
are high, insulin secretion predominates, promoting the storage of glucose and other
nutrients. Conversely, when blood glucose levels drop, glucagon secretion increases
to release stored glucose and stimulate gluconeogenesis.
When Glucose levels are high (after a meal):
● Insulin is secreted.
● Insulin promotes glucose uptake by cells and storage as glycogen and fat.
● Glycogenolysis and gluconeogenesis are suppressed.
● Glucagon secretion is inhibited.
When Glucose levels are low (between meals or during fasting):
 ● Glucagon is secreted.
● Glucagon promotes glycogen breakdown and glucose production through
gluconeogenesis in the liver.
● Insulin secretion decreases, and its effects are suppressed.
● Lipolysis is promoted to provide alternative energy sources.

Balanced action to maintain blood glucose homeostasis

● The insulin-glucagon ratio is key to regulating glucose metabolism. When
the ratio is high (insulin dominates), glucose is stored. When the ratio is low
(glucagon dominates), glucose is released.
● The liver plays a central role in regulating glucose levels in response to both
insulin and glucagon. Insulin promotes glucose storage (as glycogen), while
glucagon triggers glucose release into the bloodstream.
Tissue-Specific Effects of Insulin in the Fed State

General Role of Insulin

● Hormone of abundance: promotes storage of excess nutrients and inhibits endogenous

substrate mobilization.
● Main target tissues: liver, muscle, and adipose tissue.

Metabolic Pathway Regulation by Insulin

● ↑ Glycolysis: Enhances glucose uptake via GLUT4 (muscle, adipose), increases

glucokinase (liver), and activates PFK-2, which stimulates PFK-1.
● ↑ Glycogenesis: Promotes glycogen storage in liver and muscle via glycogen synthase
activation.
● ↑ Pentose Phosphate Pathway: Generates NADPH (for fatty acid, cholesterol,
nucleotide synthesis) and ribose (for DNA/RNA synthesis); rate-limiting enzyme: G6PD.
● ↑ Lipogenesis & Fatty Acid Synthesis: Acetyl-CoA converted to fatty acids in the cytosol;
key enzymes: acetyl-CoA carboxylase (rate-limiting), fatty acid synthase. Fatty acids
are stored as triacylglycerol and transported via VLDL.
● ↑ Cholesterol Synthesis: Stimulated by insulin, using cytosolic acetyl-CoA; rate-limiting
enzyme: HMG-CoA reductase (target of statins).
● ↑ Protein Synthesis: Stimulates amino acid uptake and protein formation; excess amino
acids enter glycolysis, Krebs cycle, or lipogenesis.

Tissue-Specific Effects of Glucagon in the Fasting State

General Role of Glucagon

● Main counterregulatory hormone of insulin during fasting.

● Other supporting hormones: epinephrine, growth hormone, cortisol.
● Promotes energy mobilization by increasing gluconeogenesis, glycogenolysis,
lipolysis, ketogenesis, and protein breakdown.

Metabolic Pathway Regulation by Glucagon

● ↑ Glycogenolysis:
○ Liver glycogen is broken down to release glucose into the bloodstream.
○ Muscle glycogen is used only within muscle (lacks glucose-6-phosphatase).
○ Rate-limiting enzyme: glycogen phosphorylase (activated by glucagon and
epinephrine).
● ↑ Gluconeogenesis:
○ New glucose is synthesized from amino acids, lactate, and glycerol when
glycogen stores are depleted.
○ Key enzymes: fructose-1,6-bisphosphatase (rate-limiting), pyruvate
carboxylase, PEPCK, glucose-6-phosphatase.
○ Acetyl-CoA (from fatty acid β-oxidation) cannot be used as a gluconeogenic
substrate.
● ↑ Lipolysis & β-Oxidation:
○ Hormone-sensitive lipase releases fatty acids and glycerol from triglycerides.
○ Fatty acids are used by peripheral tissues (muscle, heart, liver) as an energy
source, preserving glucose for the brain.
○ Carnitine acyltransferase (rate-limiting) transports fatty acids into mitochondria
for β-oxidation.
● ↑ Ketogenesis:
○ Liver converts acetyl-CoA (from fatty acid oxidation) into ketone bodies
(alternative brain fuel).
○ Brain neurons cannot use fatty acids directly but adapt to ketone bodies in
prolonged fasting.
○ Beta-ketoacyl-CoA transferase is absent in the liver, preventing ketone usage
there.
● ↑ Protein Breakdown:
○ Glucogenic amino acids provide energy, gluconeogenesis, and ketogenesis
substrates.

Breakdown occurs via corticosteroid action, producing intermediates: pyruvate, α-

ketoglutarate, succinyl-CoA, fumarate, oxaloacetate.
Effects of Insulin on Glucose transport, tissue specificity.

• Insulin is called the "hormone of

abundance."

• It is released when there are more nutrients

than the body needs (fed state).

• Main job: Helps store extra nutrients and

prevents the breakdown of the body’s stored
energy.

• Main target tissues:

o Liver

o Muscle

o Adipose (fat) tissue

Tissue specific effects of insulin:

↑ Glucose
results in
↑ Insulin
(↓ Counterregulatory hormones)
Effects of Insulin on Blood Glucose:
Uptake of Glucose by Cells &
Storage of Triacylglycerol and Glycogen
Metabolic effect Target enzyme or hormone
LIVER
↑ Glucose uptake ↑ Glucokinase activation
↑ Glycogen synthesis ↑ Glycogen synthase
↓ Glycogen breakdown ↓ Glycogen phosphorylase
↑ Glycolysis ↑ PFK-1 & PFK-2
↑ Acetyl-CoA production ↑ Pyruvate dehydrogenase complex
↓ Pyruvate carboxyase
↓ Gluconeogenesis ↓ PEP carboxykinase,
↓ F1,6 biphosphatase
↑ Fatty acid synthesis ↑ Acetyl-CoA carboxylase
↑ Amino acids synthesis ↑ Amino acids uptake
↑ Glycogenesis ↓ Glucagon
MUSCLE
↑ Glucose uptake ↑ Glucose transporter GLUT4
↑ Acetyl CoA ↑ Pyruvate dehydrogenase
↑ Glycogen synthesis ↑ Glycogen synthase
↑ Amino acids synthesis ↑ Amino acids uptake
ADIPOSE TISSUE
↑ Glucose transporter GLUT4
↑ Triacylglycerol synthesis
↑ Lipoprotein lipase
↑ Acetyl CoA ↑ Pyruvate DH
Carbohydrate metabolism

↑ Glycolysis

• Glucose transporters (GLUTs) help glucose enters cells.

• Insulin increases GLUT4 on the surface of muscle and fat cells, boosting glucose
uptake.

• In the liver, insulin increases glucokinase (which helps trap glucose inside the cell),
but doesn't affect GLUT2, which is always present and insulin independent.

• GLUT1 and GLUT3, found in the brain, RBCs, and most other cells, also work
independently of insulin.

↑ Glycogenesis
Excess glucose during the fed state is stored as glycogen in liver and muscle, a cytosolic process activated
by insulin.

↑ Pentose phosphate pathway

Excess glucose also enters the pentose phosphate pathway (Hexose monophosphate shunt), a
cytosolic process which generates NADPH, for the synthesis of fatty acids, cholesterol,
nucleotides and coenzymes of antioxidant enzymes, and ribose, for the synthesis of DNA and
RNA.

↑ Fatty acid synthesis and lipogenesis

During the fed state, the increased glucose and insulin levels stimulate lipogenesis, i.e. the
synthesis of fatty acid and triacylglycerol, a process which occurs in the cytosol. Therefore,
acetyl CoA must be transported into the cytosol as citrate, which is then converted back to
acetyl CoA in the cytosol by citrate lyase. During the fed state cholesterol is also increased due
to the action of insulin and the availability of acetyl-CoA in the cytosol.
 1. Skeletal Muscle and Adipose Tissue

• Transporter Involved: GLUT4

• Mechanism:

o Insulin binds to its receptor (a tyrosine kinase receptor) on muscle and fat cells.

o This triggers a signalling cascade (involving IRS, PI3K, Akt), which leads to the
translocation of GLUT4-containing vesicles to the plasma membrane.

o More GLUT4 on the membrane = increased glucose uptake from the blood.

• Purpose:

o In muscle, glucose is used for energy (via glycolysis) or stored as glycogen.

o In adipose tissue, glucose provides glycerol for triglyceride synthesis and can
be stored as fat.

GLUT4 is insulin-dependent and only expressed in muscle and adipose tissue.

2. Liver

• Transporter Involved: GLUT2

• Mechanism:

o GLUT2 allows bidirectional, passive glucose transport based on

concentration gradients.

o It is insulin-independent, meaning insulin doesn't increase GLUT2 expression

or activity.

• Insulin's Role in the Liver:

o Increases glucokinase synthesis, which phosphorylates glucose to glucose-6-

phosphate, trapping it in the cell.

o Promotes glycogen synthesis (via activation of glycogen synthase).

o Inhibits gluconeogenesis and glycogenolysis.

Insulin controls glucose metabolism in the liver through enzyme regulation, not by affecting
glucose transport.

3. Brain and Red Blood Cells (RBCs)

• Transporters Involved: GLUT1 and GLUT3

• Mechanism:

o These transporters allow constant glucose uptake, essential for tissues highly
dependent on glucose.

o GLUT1: Found in RBCs and the blood-brain barrier.

o GLUT3: Primarily in neurons.

• Insulin Independence:

o Glucose transport in these tissues does not depend on insulin.

The brain and RBCs always require glucose, so their uptake is regulated by glucose
concentration, not insulin.

Insulin
Tissue Transporter Effect of Insulin
Dependence?

Skeletal ↑ GLUT4 translocation

GLUT4 Yes
Muscle → ↑ glucose uptake

Adipose ↑ GLUT4 translocation

GLUT4 Yes
Tissue → ↑ glucose uptake

↑ Glucokinase
Liver GLUT2 No synthesis, promotes
glycogen storage

Constant glucose
GLUT1 /
Brain No uptake for energy
GLUT3
needs

Constant glucose
RBCs GLUT1 No uptake for glycolysis
(no mitochondria)

• Insulin resistance in muscle and fat cells leads to reduced GLUT4 translocation →
hyperglycaemia.

• In the brain and RBCs, glucose uptake stays normal unless blood glucose levels drop
dangerously low (hypoglycaemia), which can impair brain function.
Synthesis and degradation of glycogen

▪ Glycogen is the storage form of glucose

▪ Formed in the liver and muscle.
- The liver regulates blood sugar by absorbing and releasing glucose in response to hormonal
signals. While muscles store more glycogen, they cannot release glucose into the bloodstream
due to the absence of glucose-6-phosphatase.

How is glycogen accumulated and released?

- Glycogen is a polymer consisting of highly branched glucose chains.

- These chains are composed by α-1,4 glycosidic bonds (linear form) which are branched by α-1,6
glycosidic bonds.
- This structure provides high solubility and many access points to the glycogenolytic enzymes,
which can hydrolyze (break) glycogen easily when appropriate.
- Main chain formation(linear): Glucose units are linked by α-1,4-glycosidic bonds (between C1 of
one glucose and C4 of another).
- Branching: Every 8–10 glucose units, a branch forms via an α-1,6-glycosidic bond (between C1
and C6).
- Branching enzyme(only work when chain has min 11 units): This enzyme moves a 6–7 glucose
residue segment from the non-reducing end and attaches it to a deeper C6 hydroxyl group in the
glycogen molecule.
Glycogen storage:

1. Muscle: in granules called β particles that contain up to 60.000 glucose residues.

2. Liver glycogen: large granules called α-rosettes that are aggregates of β particles.

- Glycogen synthesis starts from G6P (also present at the start of glycolysis and pentose
phosphate pathway).

- G6P → G1P → uridine diphosphate glucose (UDP-glucose) → chain elongation (11-15 glucose) →
creation of a branching point which can be elongated.
 - Glycogen synthase forms a linear chain and a branching enzyme adds up branches.
- Glycogen synthase can be:
➢ dephosphorylated by phosphatase 1 in an active form, or
➢ phosphorylated by protein kinase in an inactive form.
- Glycogen synthase is regulated indirectly by insulin, glucagon and adrenalin and also by G6P
(allosteric regulation).

Glycogen is released by degradation:

- Glycogenolysis is the breakdown of glycogen (n) to glucose-6-phosphate and glycogen (n-1).

Degradation of the polymer is mediated by glycogen phosphorylase and debranching enzyme.
The end step of degradation is glucose-6-phosphate. In the lysosomes release involves the
activity of lysosomal α-glucosidase.

1. The first step is a shortening of the chain by cleavage of α-(1,4) bonds.

This reaction is catalyzed by glycogen phosphorylase, which can be:
➢ phosphorylated as an active form, or
➢ dephosphorylated as an inactive form.

The activation of this phosphorylase involves a cascade of successive phosphorylation’s initiated by an

increase in cAMP.

This glycogen phosphorylase is also allosterically regulated by several factors (AMP, ATP, G6P, creatine
phosphate...).

Important regulators of glucogenesis or glycogenesis

Glucogenesis = glucose production = glycogen degradation

Glycogenesis = storage of glucose = synthesis of glycogene

Glycogen phosphorylase - regulated by allosteric control and covalent control

Glycogen phosphorylase is regulated by allosteric control and covalent control.

- It exists as tense T form, with low affinity for its substrate phosphate and low activity, or relaxed
R (high affinity for its substrate phosphate and high activity).
- The T form can be phosphorylated: equilibrium is shifted to the T-form
and dephosphorylated: R-form

- The phosphorylase kinase is itself activated by phosphorylation by PKA (protein-kinase A).

- It is dephosphorylated by protein phosphatase 1 (PP1)
➢ PP1 is inhibited by an inhibitor activated by PKA and directly inactivated by PKA
➢ Insulin has a positive effect on PP1
 - In the liver: glucose promotes the T allosteric state, which allows the inactivation by
phosphorylation
- In the muscle: AMP favors state R (energy requirement); ATP and G6P promote state T.

Glycogen synthase

- exists in T tense (less active) or R relaxed (more active) form

T-FORM
Phosphorylated Dephosphorylated
Leads to inactivation Leads to activataion
-glucagon in the liver or -insulin via mitogen-activated protein kinase
-adrenalin in the liver and muscles, (MAPK), which activates PP1.
via cAMP and PKA which inactivate protein -The dephosphorylation of glycogen kinase 3 also
phosphatase 1 (PP1) and activate the kinases phosphorylates the synthase

In fasting state in the liver, -In post-prandial state in the liver, glucose acts
-glucagon acts to activate degradation and inhibit directly to suppress degradation and indirectly via
synthesis, and inhibition by glucose is lifted. insulin to promote synthesis.
-In G6P muscle activates synthase and insulin
promotes the entry of glucose, which makes more
glycogen than glycolysis by inhibition of PFK1.

calcium active phosphorylase, which inactivates the degradation is activated by the ratio AMP / ATP
the synthase and adrenaline via kinases
 Glycogenosis

Glycogen storage disorders (GSD) are a group of inborn errors of metabolism characterised by
accumulation of glycogen in various tissues.

GSD can develop at any age, ranging from neonatal life to adulthood.

These disorders typically arise from a de ciency in speci c enzymes responsible for glycogen
breakdown, leading to abnormal glycogen accumulation in the liver or skeletal muscles.

There are eleven distinct diseases that are commonly classi ed as GSD:
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 Von Gierke Disease

Glycogen storage disease type I (GSD I), also known as Von Gierke disease, is an autosomal recessive
disorder caused by de ciencies of speci c enzymes in the glycogen metabolism pathway.

GSD I consists of 2 subtypes:

• GSD Ia
De ciency in the enzyme glucose-6-phosphatase (G6Pase) which cleaves glycogen to glucose thus
leading to hypoglycemia and lactic acidosis.

• GSD Ib
Normal G6Pase enzyme activity.
De ciency of the transporter enzyme, glucose-6-phosphate translocase, responsible for transporting
glucose-6-phosphate from the cytoplasm into the ER lumen.

Clinical Presentations
• Hypoglycemia
• Hepatomegaly
• Renomegaly
• Doll-like face with fat cheeks
• Thin extremities
• Short stature
• Protuberant abdomen
• Xanthoma and diarrhoea may be present *Xanthoma:Build-up of fat underneath the skin
• Frequent epistaxis due to impaired platelet function

Untreated infants present at age 3-4 months with hepatomegaly, lactic acidosis, hyperuricemia,
hyperlipidemia, hypertriglyceridemia and/or hypoglycaemic seizures.

Untreated GSD Ib patients present with recurrent bacterial infections due to neutropenia.

Long-term complications:
• Failure to thrive along with delayed motor development
• Osteoporosis
• Delayed puberty
• Gout- A form of in ammatory arthritis that occurs when there is uric acid build up in blood.
• Renal disease
• Pulmonary hypertension
• Hepatic adenomas with the possibility of developing into cancer
• Polycystic ovaries
• Pancreatitis
• Abnormal cognitive function due to cerebral damage

Pathophysiology

The liver loses its ability to release free glucose.

• Hepatocytes are saturated with glucose-6-phosphate which alternatively acts as a substrate for
glycolysis and produces lactate —> lactic academia —> acidosis and increased anion gap

• rephosphorylation of adenine nucleotides is inhibited by the immense increase in the

intracellular phosphorylated intermediate compounds of glycolysis --> activation of the nucleic
acid degradation pathway --> hyperuricemia --> nephrolithiasis
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• Hypoglycemia activates epinephrine secretion --> activation of lipoprotein lipase --> release of
free fatty acids --> increased triglyceride synthesis exported as very-low-density
lipoproteins (VLDL) --> increased VLDL

• Lipid abnormalities include hypercholesterolemia, characterized by low levels of high-density

lipoprotein (HDL) cholesterol and elevated levels of low-density lipoprotein (LDL) cholesterol, along
with hypertriglyceridemia. However, there are no signs of premature atherosclerotic lesions

• Muscle waste due increased protein breakdown

• Von Willebrand-like disease (possibly alterations in membrane glycoprotein synthesis) -->

nosebleeds
• Neutrophils from patients with glycogen-storage disease Ib show a much weaker respiratory-burst
response to stimuli compared to those with type Ia. This impaired response reduces their ability to
produce superoxide, a key defense against gram-positive bacteria, leading to neutropenia and a
decreased ability to ght infections

• Despite experiencing hypoglycemia, patients with glycogen-storage disease I don't develop signi cant
ketosis. This is because excess acetyl CoA from glycolysis activates an enzyme that produces malonyl
CoA, which inhibits fatty acid transport into the mitochondria. As a result, fatty acid breakdown (beta-
oxidation) doesn't occur to provide energy, leading to a further decline in blood glucose and preventing
the production of ketone bodies

Work-up

Laboratory studies:
- Measure blood glucose levels with electrolyte
- Measurement of liver function, plasma uric acid levels, and urinary creatinine clearance.
- Perform a Complete Blood Count(CBC)
- Perform a coagulation pro le to include bleeding time tests
Glucagon stimulation test should be avoided as it increases the risk of acute acidosis.
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Molecular Genetic Testing
Non invasive molecular genetic testing that includes full gene sequencing is preferred for con rming the
diagnosis.

Imaging
Abdominal ultrasonography can enable reasonable estimates of liver and kidney size.

Management
Medical Care:
- Young infants require nasogastric(NG) tube feedings to sustain blood sugar level.
- Older children can typically be switched to raw cornstarch feedings, which help maintain blood
glucose levels for 4-6 hours.
- It is important to carefully monitor the dental and oral health of patients with GSD Ib to help prevent
infections.
- Any intercurrent infection that causes decreased intake requires intravenous (IV)
glucose support until resolution.

Diet:
- Diet requires close monitoring and adjustments by a professional nutritionist.
- Ensure su cient calories and protein for growth while avoiding excessive carbohydrates and overall
calorie intake.
- Counsel the patient to avoid high lipid intake.
- Liver size can be reduced by maintaining glucose balance through overnight feeding.
- Once pancreatic amylase activity is adequate in children over 2-3 years old, overnight feeding is
typically substituted with raw cornstarch before bedtime and in the early morning.
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