1. Starvation
Lecture 19

2. Starvation Starvation is defined as post-absorptive period
i.e. all food digested and no glucose coming in from gut
We need to keep [glucose]blood ~5mM (>4mM)
Under normal circumstances, brain can only use glucose
Cannot use FAs which cannot cross blood-brain barrier
So uses ~120 g glucose/day
Transported into brain cells by GLUT-1
Note that these are not insulin sensitive
Although we store most of our energy as fat, we cannot convert FA into CHO
Acetyl CoA can’t be made into gluconeogenic precursors
Pyruvate  acetyl CoA is IRREVESIBLE

3. Glucose Requirements
Parts of the kidney, skin and red blood cells have obligatory requirements for glucose
ie cannot use anything else but glucose
Other tissues (such as Muscle and WAT)
can switch to fatty acids as an alternate fuel during starvation
General strategy
Glucose conservation and recycling
De novo glucose formation

4. Liver Glycogen 5 4
Glucose (mM) 3
Hypo Danger zone! 24
Time (h)
During the first few hours, the tissues are using glucose
So blood glucose concentration falls
To prevent hypoglycemia, the liver releases glucose into the bloodstream
Thus [glucose]blood stays constant – or at least levels at ~4 mM

5. Glycogen Mobilisation - Glycogenolysis
Glucose 6-phosphate
Glucose
GLUT-2
Phosphorylase
G6Pase
G6P
Carrier
Glucose
glycogen
G 6-P
GLUT-9
Glucose
Glucose 1-phosphate

6. Glycogenolysis
The pathways for glycogen synthesis and glycogen degradation are different
Different rate limiting enzymes
Phosphorylase breaks down glycogen
Phosphorolysis – cleavage using phosphates
Produces G 1-P
Rapidly converted into G 6-P
G6Pase = glucose 6-phosphatase
To allow release of glucose into bloodstream
G6Pase reaction actually happens inside vesicles
G6P needs to be transport into the vesicle to react with G6Pase

7. Activation of Phosphorylase
Regulated by reversible phosphorylation
Active when phosphorylated
Phosphorylase is phosphorylated by phosphorylase kinase
Sorry, but it gets worse…
Phosphorylase kinase is phosphorylated by cAMP-dependent protein kinase
Also known as Protein Kinase A
PKA is activated when cAMP levels are high
cAMP is produced when adenyl cyclase is activated
Which occcurs when glucagon binds to glucagon receptors on the liver cell membrane
Glucagon is released when blood glucose concentration dips below 5 mM

8. Mechanisms of Glycogen Breakdown

9. Mechanisms of Glycogen Breakdown
The breakdown of glycogen to give glucose is stimulated by the hormone glucagon
Glucagon is secreted from a-cells of pancreas whenever [glucose]blood < 4mM
The amount of ATP being used and the amount of cAMP being made are very tiny  doesn’t really affect [ATP]cell
cAMP is the 2nd messenger in the pathway
PKA (protein kinase A) is activated by removing a regulatory inhibitory subunit

10. Mechanisms of Glycogen Breakdown
Amplification through 2nd messenger and cascade, rather than direct binding
Massive response from small signal
More control over the whole process
Multisteps, each catalysed by an enzyme for many control points
cAMP  after glucagon gone
Breakdown by phosphodiesterase
Which converts the cAMP to AMP
Inactivation after removal of the cAMP signal is achieved by PPI (protein phosphatase I)

11. Starvation - Muscle Muscle is selfish with it’s glycogen!!
Muscle does not breakdown glycogen much in starvation because:
It has no glucagon receptors
It has no G6Pase,  cannot convert G6P  glucose  cannot release glucose into blood (only the liver has G6Pase)
However, some glucose residues in glycogen ARE released as neat glucose
Because debranching enzyme uses water to hydrolyse the glycosidic linkages, not phosphate
About 10% potentially released in this way
Muscle is selfish with it’s glycogen!!

12. Glycogen Depletion
Glycogen store in liver can supply glucose for brain < 24 hours
Need to persuade other tissues to use fat rather than glucose
Fat is stored in WAT (white adipose tissue)