Starvation

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 3 Glucose (mM) Hypo Danger zone! • 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 0 24 Time (h)

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 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)