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.