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

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

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

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 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

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 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!!

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)