Starvation Lecture 19 Starvation Starvation is defined as

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 ~5 m. M (>4 m. M) • 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 Co. A can’t be made into gluconeogenic precursors – Pyruvate acetyl Co. A 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 (m. M) 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, the liver releases glucose into the bloodstream • Thus [glucose]blood stays constant – or at least levels at ~4 m. M

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

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 • G 6 Pase = glucose 6 -phosphatase – To allow release of glucose into bloodstream – G 6 Pase reaction actually happens inside vesicles – G 6 P needs to be transport into the vesicle to react with G 6 Pase

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 c. AMPdependent protein kinase – Also known as Protein Kinase A • PKA is activated when c. AMP levels are high • c. AMP 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 m. M

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 < 4 m. M • The amount of ATP being used and the amount of c. AMP being made are very tiny doesn’t really affect [ATP]cell • c. AMP is the 2 nd messenger in the pathway • PKA (protein kinase A) is activated by removing a regulatory inhibitory subunit

Mechanisms of Glycogen Breakdown • Amplification through 2 nd 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 • c. AMP after glucagon gone – Breakdown by phosphodiesterase – Which converts the c. AMP to AMP • Inactivation after removal of the c. AMP 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 G 6 Pase, cannot convert G 6 P glucose cannot release glucose into blood (only the liver has G 6 Pase) – 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)