Starvation

Lecture 19

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

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

Hypo Danger zone!

Liver Glycogen

• 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

4

3

Time (h) 240

Glu

cose

(m

M)

Glycogen Mobilisation - Glycogenolysis

glycogen

Glucose 1-phosphate

Glucose 6-phosphate

Glucose

Glucose

Glucose

Phosphorylase

GLUT-2

G6PCarrier

GLUT-9

G6Pase

G 6-P

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

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

Mechanisms of Glycogen Breakdown

Mechanisms of Glycogen Breakdown

• The breakdown of glycogen to give glucose is stimulated by the hormone glucagon

• Glucagon is secreted from -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

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)

Starvation - Muscle

• 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!!

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)