04 - Overview of Carbohydrate Metabolism

TARGET DECK: MED::I::Signaling Pathways in Health and Disease::Metabolic Biochemistry::04 - Overview of Carbohydrate Metabolism

Topics Covered

• Digestion and absorption
• General scheme: role of liver and extra-hepatic tissues
• Glycogen synthesis and breakdown
• Glycolysis
• Pyruvate oxidation
• Tricarboxylic Acid (TCA) Cycle
• Gluconeogenesis
• Pentose phosphate shunt

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Key Dietary Carbohydrates

Molecule	SMILES
Glucose	OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Fructose	OC[C@@H]1OC(O)(CO)[C@@H](O)[C@@H]1O
Glycogen	Branched polymer of α-D-glucose (α-1,4 and α-1,6 linkages)
Starch	Linear (amylose) and branched (amylopectin) α-D-glucose polymer

franz

aggiungi come smiles o metti foto delle slide…

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Digestion and Intestinal Absorption

Major dietary carbohydrates and their products:

Carbohydrate	Type	Products
Starch	Polysaccharide	Glucose
Lactose	Disaccharide	Galactose + Glucose
Sucrose	Disaccharide	Fructose + Glucose

• Digestion: Amylases from saliva and pancreas
• Absorption: Through intestinal microvilli via secondary active transport

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Glucose Absorption

Energetics of Intestinal Co-transport

$\Delta G_{glucose}>0[\text{Glucose}{]}_{out}\to [\text{Glucose}{]}_{in}$

$\Delta G_{N{a}^{+}}\ll 0[{\text{Na}}^{+}{]}_{out}\to [{\text{Na}}^{+}{]}_{in}$

$\Delta G_{cotransport}<0\text{Glucose}+2{\text{Na}}^{+}\text{ (net favorable)}$

Transport Steps

1. Secondary active transport → Glucose + 2 Na⁺ enter the enterocyte (SGLT1)
2. Primary active transport → Na⁺/K⁺-ATPase maintains the Na⁺ gradient
3. Passive transport → Glucose exits via GLUT2 into portal blood

How is glucose absorbed from the intestine?

Glucose enters enterocytes by secondary active transport with Na⁺ via SGLT1, then exits to portal blood via GLUT2.

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Glucose Transport in Blood (GLUT Transporters)

GLUT	Location	Features	$K_m$ (substrate) mM
GLUT1	Ubiquitous (RBCs, brain)	High affinity, basal uptake	5 (glucose)
GLUT2	Liver, pancreatic β-cells, intestine	Low affinity, high capacity	10-15 (glucose, [galactose & fructose])
GLUT3	Neurons	Very high affinity	1-2 (glucose)
GLUT4	Muscle, adipose tissue	Insulin-dependent	3-5 (glucose)
GLUT5			6 (fructose)

GLUT4

GLUT 4 can be regulated by insulin.

Which GLUT transporter is insulin-dependent?

GLUT4 in muscle and adipose tissue.

1. Storage (The “Waiting Room”)

Normally, GLUT4 transporters aren’t on the cell’s surface. They are tucked away inside the cell in small bubbles called vesicles. They are basically “off-duty” and waiting for a signal.

2. The Insulin Signal (The “Green Light”)

When you eat, your pancreas releases insulin.

• Binding: Insulin binds to an insulin receptor on the cell membrane (the pink structure in your image).
• Translocation: This sends a signal that tells the GLUT4 vesicles to move toward the surface and fuse with the plasma membrane.
• Action: Now that the “doors” are open on the surface, glucose can flood into the cell to be used for energy.

3. Removal (The “Closing Time”)

Once your blood sugar levels drop, insulin levels also decrease.

• Endocytosis: The cell pinches the membrane back inward, swallowing the GLUT4 transporters.
• Recycling: These transporters are pulled back into the cell, forming new vesicles (Steps 4 and 5) where they stay until the next meal.

Anatomical Route of Absorbed Glucose

1. Intestinal microvilli
2. Portal circulation blood
3. Hepatic sinusoids → glucose enters hepatocytes postprandially
4. Centrolobular vein
5. General circulation

Glycaemic Regulation

A glycaemic peak follows a carbohydrate-rich meal. Regulation is primarily mediated by insulin (↑ uptake) and glucagon (↑ production).

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General Scheme of Carbohydrate Metabolism

• Metabolic tasks are distributed between the liver and peripheral tissues (muscle, brain, etc.) via the bloodstream
• The kidney plays a key role through ultrafiltration and reabsorption of glucose, governed by the renal threshold

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Glucose Reabsorption in the Kidney

Sites and Transporters

Segment	Transporter	Affinity	Capacity	% Glucose Reabsorbed
Early PCT	SGLT2	Low	High	~90%
Late PCT	SGLT1	High	Low	~10%

• Basolateral exit into the bloodstream: via GLUT2 and GLUT1
• Driving force: Na⁺/K⁺-ATPase maintains the electrochemical gradient required for SGLT activity

Renal Threshold for Glucose (RTG)

Renal Glucose Threshold

In healthy individuals, the RTG is approximately 180–200 mg/dL. Below this concentration, virtually all filtered glucose is reabsorbed. Above it, glucose appears in the urine (glucosuria).

What is the renal threshold for glucose in healthy individuals?

About 180–200 mg/dL; above this, glucose appears in urine.

Transport Maximum (Tm) for glucose reabsorption:

$T_m=375\text{mg/min (men)},300\text{mg/min (women)}$

RTG variability:

Condition	RTG
Healthy adult	180–200 mg/dL
Pregnancy / Children	< 126 mg/dL
Type 2 Diabetes	200–250 mg/dL

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Effects of Insulin and Glucagon

Summary Table

Hormone	Pathways Activated	Net Effect
Insulin	Glycogen synthesis, Glycolysis, Pentose phosphate pathway, Lipid synthesis	↓ Blood glucose
Glucagon	Glycogenolysis, Gluconeogenesis	↑ Blood glucose

What is the main metabolic effect of insulin versus glucagon?

Insulin promotes glycogen synthesis, glycolysis, PPP, and lipid synthesis; glucagon promotes glycogenolysis and gluconeogenesis.

Postprandial State (Insulin Active)

Glucose → Glucose-6-P → Glycogen (liver & muscle)
                      → Glycolysis → Pyruvate → CO₂ + H₂O (+ ATP)
                      → Lipid synthesis

Fasting State (Glucagon Active – Liver)

Glycogen → Glycogenolysis → Glucose-6-P → Glucose (→ blood)
Amino acids → Gluconeogenesis → Glucose-6-P → Glucose (→ blood)

Skeletal Muscle (No Glucagon Receptors)

Blood Glucose → (Insulin ↑) → Glucose-6-P
                              → Glycogen
                              → 2 Pyruvate → CO₂ + H₂O (25 ATP)
                                           → Lactate (→ blood)
Net: 2 ATP (substrate level) + 25 ATP (oxidative) per glucose

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Kinases and Phosphatases

Kinase = phosphotransferase:

$X+ATP\to X\text{-}P+ADP$

Note

In protein kinases, X is a Ser, Thr, or Tyr residue. Many kinase reactions are irreversible; the reverse is catalysed by a phosphatase:
$X\text{-}P+H_{2}O\to X+P_i$

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Glucose Phosphorylation

Key Reactions

$\text{Glucose}+ATP\stackrel{\text{Hexokinase/Glucokinase}}{\to }\text{Glucose-6-P}+ADP$

$\text{Glucose-6-P}+H_{2}O\stackrel{\text{Glucose-6-Phosphatase}}{\to }\text{Glucose}+P_i$

Futile Cycle

Running both reactions simultaneously results in:
$\text{Glucose}+ATP+H_{2}O\to \text{Glucose}+ADP+P_i$
This is energetically wasteful and is largely prevented by hormonal regulation.

Why is the glucose/glucose-6-phosphatase pair considered a futile cycle?

Because running both reactions at once wastes ATP without changing the glucose pool.

Hormonal Transcriptional Control

Enzyme	Induced by	Inhibited by	Effect on Glycaemia
Glucokinase	Insulin	Glucagon	↓
Glucose-6-Phosphatase	Glucagon	Insulin	↑

Hexokinase vs. Glucokinase

Property	Glucokinase (GK)	Hexokinase (HK)
Location	Liver, pancreatic β-cells	All other tissues
Affinity	Low (high Km)	High (low Km)
Substrate specificity	Glucose only	Glucose, fructose, mannose
Product inhibition	Not inhibited by G6P	Inhibited by G6P
Insulin induction	Yes	No
Kinetics	Sigmoidal (cooperative)	Hyperbolic (Michaelis-Menten)

Glucokinase Regulatory Protein (GKRP)

GKRP Regulation

• Fasting: GKRP sequesters GCK in the nucleus, creating a reserve pool
• Postprandial (high glucose): GCK is released into the cytoplasm → phosphorylates glucose → supports glycogen synthesis
• F6P stabilises the GCK–GKRP complex → enhanced inhibition
• F1P disrupts the complex → releases active GCK into the cytosol

Downstream Fates of Glucose-6-Phosphate

(All stimulated by insulin, inhibited by glucagon)

Glucose-6-P ──→ Glycogen synthesis
            ──→ Glycolysis
            ──→ Pentose phosphate pathway

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TLDR - 04 - Overview of Carbohydrate Metabolism

TLDR – Overview of Carbohydrate Metabolism

Digestion & Absorption:
Dietary carbohydrates (starch, lactose, sucrose) are broken down by salivary and pancreatic amylases into monosaccharides (glucose, fructose, galactose). These are absorbed in the intestine via secondary active transport (SGLT1, driven by the Na⁺ gradient maintained by Na⁺/K⁺-ATPase) and exit into the portal blood via GLUT2.

Glucose Transport:
GLUT transporters mediate tissue-specific glucose uptake. GLUT4 in muscle and adipose tissue is insulin-dependent. GLUT2 in the liver acts as a glucose sensor (low affinity, high capacity).

Renal Handling:
The kidney reabsorbs ~90% of filtered glucose via SGLT2 (early PCT) and ~10% via SGLT1 (late PCT). The renal threshold is ~180–200 mg/dL; above this, glucosuria occurs. Tm is 375 mg/min (men) and 300 mg/min (women).

Insulin vs. Glucagon:

• Insulin (postprandial): activates glycogen synthesis, glycolysis, pentose phosphate pathway, and lipid synthesis → lowers blood glucose
• Glucagon (fasting): activates glycogenolysis and gluconeogenesis → raises blood glucose
• Skeletal muscle has no glucagon receptors; glucose metabolism there is primarily insulin-driven

Glucose Phosphorylation:
Glucose is trapped in cells as Glucose-6-Phosphate by hexokinase (all tissues, high affinity, inhibited by G6P) or glucokinase (liver/pancreas, low affinity, not inhibited by G6P, insulin-induced). G6P can be released back to glucose only in liver and kidney (glucose-6-phosphatase). Running both enzymes simultaneously creates a futile cycle, prevented hormonally.

GKRP sequesters glucokinase in the nucleus during fasting; high glucose and F1P release it into the cytosol, while F6P enhances its nuclear retention.

G6P fates (all insulin-stimulated, glucagon-inhibited): glycogen synthesis, glycolysis, pentose phosphate pathway.