1
Gibney MJ et al. Nutrition & Metabolism. 2003
Metabolic Changes – Fed versus Fasted state
Fed State
Prevent hyperglycemia
Key pathways –
Glycolysis
TCA
PPS
Glycogen synthesis
Fatty acid synthesis
Fasted State
Prevent hypoglycemia
Key pathways –
β oxidation
TCA
Glycogenolysis
Gluconeogenesis
STORAGE of EXTRA FUEL
Minimize Glucose Use
Provide Additional Glucose
2
Glucose Needs (Daily)
Obligatory:
RBC 24 g
Brain 80-100 g #
Glucose Stores:
Blood ~10 g
Liver ~80-100 g
Muscle ~450 g
Adipocyte ?
Kidney ?
# This may be an over-estimation.
There is evidence to suggest the
brain uses lactate even under normal
condition.
Overnight fasting ~ 90% gluconeogenesis occurs in the liver
Prolong fasting ~40% contribution from kidney
Functions of muscle and liver glycogen Cleavage of an α (1->4)-glycosidic bond.
PLP=pyridoxal phosphate.
X G
Lippincott’s Illustrated Reviews : Biochemistry, 2011
Liver glycogen as readily available source
of glucose BUT NOT muscle glycogen
3
Potential carbon sources for gluconeogenesis
Lactate (Cori Cycle)
Muscle: glucose (Glycogen) 2 Lactate (+2 ATP)
Liver: 2 Lactate Glucose (- 6ATP)
Amino acids (Alanine – Glucose Cycle)
Muscle transamination followed by hepatic transamination
Glycerol α-Glycerophosphate DHAP Glucose
Glycerol
From hydrolysis of triglyceride
Tissue specificity
Muscle lacks G6Phosphatase
Adipose tissue lacks Glycerol kinase
Gylcerol generated from TG hydrolysis
can be converted to glucose in the liver
Cori Cycle
commons.wikimedia.org/wiki/File:Cori_cycle.PNG
4
Role of lactate in metabolism
Tissue production and utilization:
• RBC – weighing 2.5 kg, having ~40 g of glucose-lactate
conversion per day
• Muscle – exercising muscle produces lactate
• Liver – glucose-lactate cycle
• Brain – astrocytes and neuron
• Lactate actually plays a more significant role in normal
metabolism.
• Neurons takes uptake lactate from blood and astrocytes
under normal physiologic condition.
• Astrocytes cover ~99% cerebrovascular surface area,
therefore play a large role in shuttling lactate toward the
neurons [Astrocyte-Neuron Lactate Shuttle]
• Hence, the “actual” use of glucose (80-100 g daily) might
be less than original estimation.
BMC Systems Biol 5:162, 2011
5
BMC Systems Biol 5:162, 2011
Amino Acids
Alanine-glucose cycle
www2.ufp.pt/~pedros/bq/urea.htm
Carbon Source from Muscle
6
Pathways for production of glycerol phosphate in liver and adipose tissue
Adipose tissue
lacks Glycerol kinase
Glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the
reversible redox conversion of dihydroxyacetone phosphate (DHAP)
to glycerol 3-phosphate (G3P).
ADIPOSE TISSUE
Triacylglycerol
Glycerol Free Fatty
Acid (FFA)
Pilkis SJ et al. Diabetes Care 13:582-598, 1990
Summary of 3 key reactions that
regulate the flow of carbons
towards glucose.
7
Pilkis SJ et al. Diabetes Care 13:582-598, 1990
*
Fasting
High glucagon:insulin ratio
High cAMP
cAMP-dependent
protein kinase
Activation and transfer of CO2 to pyruvate catalyzed by pyruvate carboxylase, followed by
transport of oxaloacetate to the cytosol and subsequent decarboxylation by PEP carboxykinase.
Pyruvate Carboxylase
(only in mitochondria of
liver and kidney
BUT NOT muscle)
Phosphoenolpyruvate
Carboxykinase
8
web.virginia.edu/.../chapter23/chp23frameset.htm
Gluconeogenesis
Pilkis SJ et al. Diabetes Care 13:582-598, 1990
*
9
Fatty acids
(+)
The kinase & phosphatase
activities are different
domains in one Bifunctional
polypeptide molecule.
10
Lippincott’s Illustrated Reviews : Biochemistry, 2011
Effect of elevated glucagon on the intracellular concentration of fructose 2,6-bisphosphate
in the liver. PFK-2 = phosphofructokinase-2, FBP-2 = fructose bisphosphatase-2.
Summary of the reactions of
glycolysis and gluconeogenesis,
showing the energy requirements
of gluconeogenesis.