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Starvation
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
Liver Glycogen
Glucose (mM)
5
4
3
Hypo Danger zone!
0
Time (h)
24
• During the first few hours, the tissues are using glucose
– So blood glucose concentration falls
• To prevent hypoglycemia, liver releases glucose into the
bloodstream
• Thus [glucose]blood stays constant – or at least levels at ~4 mM
Glycogen Mobilisation - Glycogenolysis
Glucose 6phosphate
Glucose
GLUT-2
Phosphorylase
glycogen
G6P
Carrier
G6Pase
Glucose
G 6-P
GLUT-9
Glucose
Glucose 1phosphate
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)
Lipolysis
• Glucagon   [cAMP]
– Also, lack of insulin contributes to this by slowing
down the breakdown of cAMP
 cAMP   activity of PKA
• PKA then phosphorylates HSL
– Thus activating it
• PKA also phosphorylates perilipin
– Perilipin is in the shell surrounding the fat vacuole
– Allows the activated HSL to interact with the fat
Fatty acid oxidation
• Lipolysis releases FAs into the blood
• Note, GLUT-1 is still present in muscle
– Even though a lack of insulin has led to GLUT-4s being
endocytosed
– So muscle potentially can still do glucose uptake
• Need to preserve glucose:
– Get tissues to stop using glucose, and use FAs
instead
• FAs will be oxidised to provide the acetyl CoA for
the Krebs Cycle
– But need to avoid oxidation of glucose, which is an
irreversible reaction
PDH
Glucose-Fatty Acid Cycle
• In starvation we want PDH to be off
– PDH kinase >> PDH phosphatase
– PDH kinase is stimulated by acetyl-CoA
– PDH is inactive when phosphorylated
– Prevents wasteful oxidation of pyruvate
– Pyruvate only made into lactate
• FA released from WAT (from lipolysis), causes [FA]blood to
increase
• Uptake of FA into the muscle is also increased
• Oxidation of FA (b-oxidation) switches PDH off by
producing a lot of acetyl CoA. This stop glucose
oxidation
When PDH is off…
• Pyruvate cannot be oxidized to acetyl CoA
– Then there is only one fate for pyruvate in the muscle,
--- to be converted into lactate by LDH
• LDH = lactate dehydrogenase
• Lactate can be taken up by the liver
– Made into glucose by gluconeogenesis
• Glucose recycling (glucose conservation)
– Cori-cycle
– Muscle Glucose  Pyruvate  lactate  liver glucose (via gluconeogenesis)
 glucose to the bloodstream again
• Gluconeogenesis can also happen from glycerol
– Up to 30 g glucose per day can be made from glycerol
In Early Starvation…
Glucose Accounting
• Glycerol (from lipolysis) is the only source of
DE NOVO gluconeogenesis
– The lactate fuelled gluconeogenesis is just
recycling
– ~30g glucose from glycerol per day
• But the brain needs ~120g/day,
– not enough!
– can brain glucose consumption be reduced?
Proteolysis
• Low insulin also leads to widespread
proteolysis
• Amino acids could potentially be used for
gluconeogensis
– But often the amino acids are ‘burnt’ in the
tissues
– With the amine group coming out on pyruvate
as alanine
– Need to get the carbon skeletons to the liver
Glucogneogenesis
• Essentially a reversal of glycolysis
• Pyruvate  Glucose
• Requires three irreversible steps of glycolysis to
be bypassed
– Glucose ‘trapping’
• The first step in glycolysis
– Phosphofructokinase
• The rate limiting step in glycolysis
– Pyruvate kinase
• The final step in glycolysis
• Gluconeogenesis can only occur in the liver
– Mainly cytoplasmic
Gluconeognesis
• Requires ATP
• Stimulated in starvation
– Only happens in liver
• Control steps illustrative of
– Reversible phosphorylation
– Allosteric activation
– Gene expression
• Substrates include
– Lactate
• Enters as pyruvate at the bottom
– Glycerol
• Enters at aldolase stage (just as F16BP has split)
– Amino acid carbon-skeletons
• Mainly supplied as alanine and glutamine
Glucose Accounting
• The brain needs ~120g/day,
• Substrates for gluconeogenesis
– ~30g glucose from glycerol per day
– Glucose from lactate is just recycling
– Alanine from muscle/tissue proteolysis
• Would need to provide 90 g/day
• Or 180 g protein per day, just for the brain
• Puts a huge strain on protein
– can brain glucose consumption be reduced?
Proteolysis
• Hypoinsulinemia
– Occurs when insulin level is really low
• Especially for a long period (>24 h)
• Proteins start to breakdown – PROTEOLYSIS
• Gives rise to amino acids
• Transamination reactions shuffle amine groups
• Channeled to the liver for gluconeogenesis as
alanine/glutamine
– Not all amino acids can be made into glucose
• Glucogenic - can be made into glucose
• Ketogenic - cannot be made into glucose
– ~2 g protein  1 g glucose
Fate of –NH2
• Amine groups are channeled into urea
– Synthesised from aspartate and glutamate’s amine
groups in the urea cycle
• Urea is non-toxic
– The alternative would be conversion to ammonia,
which is toxic
• Urea cycle only occurs in the liver
Lipolysis & b-Oxidation
• After ~2-3 days of starvation, the rate of lipolysis
approaches a maximum
– FA released into bloodstream  [FA]blood  
– There is a limit to how fast muscles will use FA
• rate of b-oxidation depends on the demand of ATP by the
muscles
• Regeneration of CoA by Krebs cycle needed to keep FA
oxidation going
• BUT liver can do b-oxidation on FA even if there
is no need for ATP
– In the liver, CoA can be regenerated in a pathway other than the
Krebs cycle
Ketone Bodies
• Ketone bodies – typically acetoacetate
– Can be taken up & oxidised by the brain
– Where they are split to 2 x acetyl CoA molecules
– Tissues have to have mitochondria in order to use ketone bodies
• Ketone bodies reduce brain glucose use from 120g/day
to 30g/day
– all 30g could be provided by glycerol….
• …. If it wasn’t for the use of glucose by the other
carbohydrate-hungry tissues like skin, etc.
Extended Starvation
• After 2-3 days of starvation
– Losses are 50-100g protein/day
– Even though ketone bodies inhibit proteolysis and prevent
protein being lost too rapidly
• Proteins are lost from all tissues
– Although inactive muscles tend to slightly preferentially degraded
– From heart, liver, brain, etc, as well  may cause severe
damage to body
• Will reach equilibrium
– where the amount of protein breakdown = the amount of glucose
needed
• But the loss of body protein is ultimately what kills us