Biol2171

REGULATION OF GLUCOSE METABOLISM

GLUCOSE LEVELS ARE TIGHTLY REGULATED

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 THE FED STATE
Pancreas
CO2 + H2O
Gut

Insulin
Glucose Glucose Glycogen
Amino Amino Urea
acids acids Pyruvate

Portal vein Protein Acetyl-CoA Lactate

Fat
Fat

Adipose tissue

Lymphatics

Chylomicrons CO2 Glucose

Glucose
VLDL +
Glycogen
H2O

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HOW IS GLUCOSE REMOVED FROM THE CIRCULATION BY INSULIN?

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 EARLY FASTING STATE
Pancreas
CO2 + H2O
Gut

Glucagon
Glucagon Glucose Glycogen

Portal vein Lactate

Glycerol

Adipose tissue

Lymphatics
Pyruvate Fatty acids

Chylomicrons CO2 Alanine

+
VLDL H2O

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 EXERCISE
Pancreas
CO2 + H2O
Gut

Glucagon

Glucagon Glucose Glycogen

Portal vein Lactate

Adrenaline
Glycerol
Fatty
Pyruvate acids

Lactate
CO2
Glycogen +
H2O
Adipose tissue TEQSA PROVIDER ID: PRV12002 (AUSTRALIAN UNIVERSITY) CRICOS PROVIDER CODE: 00120C
MAJOR ACTIONS OF GLUCAGON AND INSULIN
Insulin Glucagon

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Regulation of glycogen breakdown, how does this work?

Insulin Glucagon Adrenaline

(liver) (muscle)

Insulin receptor
G-protein coupled receptor
Glycogen
PI-3 Kinase cAMP

GSK3 GSK3 Protein kinase A

P Glycogen Phosphorylase
phosphorylase kinase
Glycogen Glycogen
synthase synthase

P Protein phosphatase 1

Glucose-1-Phosphate

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 THE INSULIN SIGNALLING CASCADE
First Insulin
messenger resistance
2nd
messenger

Receptor
Protein
kinase

Protein
kinase

Target Down-regulation
enzyme of glycogen
breakdown

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MOBILIZATION OF TRIACYLGLYCEROLS

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 INTER-TISSUE CYCLES

Glucose-Alanine cycle Cori cycle

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 ARTERIO-VENOUS DIFFERENCE

Ala Ala Ala Ala

Ala-Ala=-ve Ala-Ala=+ve

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AMINO ACIDS ARE USED FOR GLUCONEOGENESIS

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 Preparation for stress (dawn)
Pancreas
Gut

Glucose Glucose Glycogen

Cortisol Lactate

Glucose
Glycerol

Adipose tissue
Pyruvate
Fatty acids
Alanine
Glutamine

Protein
CO2+H2O

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GLUCOCORTICOIDS AT WORK

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METABOLIC REGULATION VIA TRANSCRIPTION

PEPCK
promoter

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 DIABETES

Type 1 Diabetes: Type 2 Diabetes:

Autoimmune disease Acquired disease caused by nutrient oversupply
Destruction of β –cells by the Causing insulin resistance
Immune system Compensation by elevated insulin release
Inability to store glucose as glycogen Eventually β-cell failure
Elevated glucose after a meal
Appearance:
Appearance: Late onset
Young onset Typically obese body shape
Starvation-like body shape
Treatment:
Treatment: Drugs to enhance insulin sensitivity and to reduce
Insulin replacement Hyperglycemia, diet and lifestyle changes

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Factors contributing to insulin resistance
• High lipolytic activity of adipose tissue results in
the release of fatty acids which inhibit glucose
metabolism.
• Elevated Leptin antagonizes insulin action
• Adipocyte hypoxia damages cells and stimulates
macrophage invasion
• Macrophage numbers increase in adipose tissue
releasing cytokines, which cause insulin
resistance
• Adipose tissue produces cytokines which cause
insulin resistance
• Increased release of exosomes containing
bioactive compounds
• Increased fat in liver resulting in elevated levels
of bioactive lipid species (ceramides,
Diacylglycerol)
• Exhaustion and death of beta cells

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Long-term damage in diabetes

Glucose is a reactive molecule,

particularly its aldehyde group.

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Advanced glycation end products
(AGE’s)

Reminder: Schiff base formation

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 WHAT HAPPENS IF YOU CAN’T MAKE INSULIN?

Without insulin With insulin

injection injection

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 Advanced fasting state and diabetes
Pancreas
CO2 + H2O
Gut

Glucagon Protein

Glucagon Amino acids

Lactate
Urea Glucose Glycerol

Portal vein Ketone bodies

Alanine

BCKA

Fatty Glycerol
Lymphatics acids
Amino
Glutamine acids

Chylomicrons CO2
+
VLDL Protein H2O
BCKA: branched chain keto acids Adipose tissue

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INCREASE OF KETONE BODIES DURING STARVATION

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 THE EARLY REFED STATE
Pancreas
CO2 + H2O
Gut

Insulin
Glucose Glucose
Amino
acids Amino Glycogen
acids

Portal vein Urea Lactate

Protein
Fat
Amino acids
(all tissues)

Lymphatics

CO2
Chylomicrons + Adipose tissue
VLDL H2O Glycogen

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Summary
After a meal glucose, lipids and amino acids are derived from the nutrition. Insulin
controls the metabolism under these conditions, the insulin/glucagon ratio is high.
When fasting, the insulin/glucagon ratio is low. This changes metabolism.
Initially glycogen is used up, subsequently amino acids and fatty acids are used as fuels
and to generate glucose.
Extended starvation causes ketone body levels to rise. Low blood glucose also causes the
release of cortisol, which promotes gluconeogenesis. Type 1 diabetes is a pathogenic
state of starvation.
Exercise causes the release of adrenalin, which up-regulates pathways that provide
energy.
Several inter-organ cycles run to provide nutrients. The production of lactate by muscle
which is used to generate glucose in liver for muscle metabolism is called the Cori
cycle. The glucose alanine cycle refers to the exchange of glucose and alanine between
liver and muscle.
Insulin resistance occurs when fat is deposited in cells that are insulin-regulated.
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