Metabolism in the fed and starved states Flashcards
Fed state
During meals and for several hours afterwards
Characterised by high insulin and low glucagon
Absorptive phase
Fasting state
6-12 hours after a meal
Fasting that lasts in excess of 12 hours is prolonged fasting or starvation
Characterised by low insulin and high glucagon
Post- absorptive state
Metabolism in the fed state
Food intake stimulates insulin release; this inhibits glucagon secretion
This affects metabolism in the liver, adipose tissue and muscle
Glucose utilisation in the brain remains unchanged
Metabolism in the fed state- liver
High concentrations of nutrients leads to an increase in insulin: glucagon ration
High blood glucose enters the liver, converted to glycogen and triacylglycerols which are secreted as VLDL, some enter TCA cycle
Lactate returning from rbcs and muscle and glycerol from peripheral tissues also converted to triacylglycerols
Excess amino acids entering from the gut are converted to pyruvate and metabolised via the TCA for energy or converted to triacylglycerols
Metabolism in the fed state- muscle
Glucose enters the muscle via insulin stimulated Glut-4 transport system- converted to glycogen or metabolised via glycolysis and TCA cycle
Fatty acids enter muscle both from diet via chylomircons and from the liver via VLDL; oxidised via B-oxidation to acetyl CoA to produce energy to support contraction
Amino acids are incorporated into proteins
Metabolism in the fed state- adipose tissue and brain
Glucose enters adipose tissue by the insulin dependent Glut 4 transport system- converted via glycolysis and PDH into acetyl CoA and then to fatty acids and triacylglycerol
Fatty acids enter from VLDL and chylomicrons and are converted to triacyglycerol
Glycerol released from TAGs is returned to liver for re-use
Brain takes up glucose via Glut 1 and 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce energy
Metabolism in the early fasting state
During fasting, the liver switches from a glucose utilising to a glucose producing organ
Decrease in glycoen synthesis and increase in glycogenolysis
Gluconeogenesis
The early fasting state- liver
Plasma glucose falls, no longer enters liver as Glut 2 transport has low affinity, liver changes from user to exporter of glucose
Reduced insulin glucagon ration activates glycogenolysis and gluconeogenesis via cAMP production in response to glucagon
Protein in liver and other tissues are broken down to amino acids to fuel gluconeogenesis
Fatty acids from lipolysis enter the liver and produce energy via B-oxidation; citrate and acetyl CoA produced from oxidation of fatty acids activte gluconeogenesis and inhibit glycolysis
The early fasting state- adipose tissue
Entry of glucose into adipose tissue via Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited
Mobilsation of TAGS occurs in response to the reduced insulin: glucagon ration and activation of the sympathetic NS by release of noradrenaline
Some of the fatty acids are used directly in tissue to produce energy, remainder released into bloodstream to support glucose independent production in muscle and other peripheral tissues
Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis
The early fasting state- muscle
Fall in insulin reduced glucose entry, glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle to cause activation
Muscle and other peripheral tissues switch to fatty acid oxidation as a source of energy which inhibits glycolysis and glucose utilisation
Proteins are broken down to amino acids and the carbon skeletons can be used for energy or exported to the liver in the form of alanine
The early fasting state- brain
Continues to take up glucose because of the high affinity of Glut 1 and Glut 3 transport system and independence from insulin
Glucose continues to be metabolised despite the fact that no glucose is provided in the brain
Brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier
Metabolism in the late fasting state
Chronic low- insulin, high glucagon state
Accompanied by decrease in concentration of thyroid hormones- decrease metabolic rate
Free fatty acids become the major energy source
The late fasting state- liver
No glucose enters liver and glycogen stores are depleted within 24 hours
Plasma glucose dependent on gluconeogenesis from lactate, glycerol and alanine from fat and protein breakdwon; the kidney also becomes an important source of gluconeogenesis
Urea synthesis stimulated to cope with increases amino groups entering liver
Glycogen synthesis and glycolysis are inhibited
Fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies
The late fasting state- adipose tissue
Little glucose entry with fall in insulin secretion
Body switches to using fatty acids from triacylglycerol to supply all the energetic needs of the major tissues
Lipolysis is greatly activated because of the low insulin: glucagon ratio and blood levels of fatty acids rise 10 fold
Glycerol exported to the liver to be converted into glucose
The late fasting state- muscle
Little glucose entry with fall in insulin and switch to fatty acids as the fuel
Fatty acid oxidation supplies the energy needed for muscle contraction
Ketone bodies are taken up by muscle and other peripheral tissues and used as a further source of fuel in heart and muscle conserving glucose
Protein breakdown (proteolysis) stimulated by noradrenaline and cortisol supply carbon skeletons for net glucose synthesis in the form of alanine
Ketone bodies reduce proteolysis and decrease muscle wasting
The glucose fatty acid cycle
Mobilsation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation in peripheral tissues to acetyl CoA
Excess acetyl CoA converted to citrate in TCA cycle which build up in cytoplasm and inhibits PFK-1
Build up of G6P inhibits hexokinase and prevents glucose phosphorylation
Increase in glucose prevents further glucose entry and so conserves glucose
The late fasting state- brain
Although fatty acids cannot be used by the brain, as levels of ketone bodies rise in the plasma, these can cross the blood brain barrier and enter the brain as a source of energy sparing use of glucose
Ketone bodies cannot completely replace the need for glucose and therefore brain continues to take up glucose and metabolise through glycolysis- net glucose synthesis during starvation is essential
Glucose utilisation in various metabolic states
Fed state- glucose provided by diet
Fasted state- most glucose provided by the breakdown of liver glycogen, increasing amounts by gluconeogeneis
Starved state- most glucose comes from gluconeogenesis, the breakdown of protein and fats provide amino acids and glycerol as substrates
Hormonal control of glycogenolysis and glycogen synthesis
Enzymes involved in glycogenolysis/ synthesis are subject to allosteric control
Enzymes are also subject to hormonal control by glucagon, adrenaline, cortisol and insulin
Hormonal control is mediated by changes in phosphorylation
Hormonal regulation of glycogen mobilisation
Hormones glucagon and epinephrine are released in response to low blood glucose so increase glucose from glycogen in the liver
Epinephrine is also part of fight or flight response, levels rise greatly during exercise when metabolic demands of muscle are high and glycogen breakdown is required to support muscle contraction
Prepares the muscle for strenuous activity
Reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation
Glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation and phosphorylase and glycogen synthase
Mimicked by increasing Ca2+ during contraction
Insulin activates protein phosphatase to reverse these effects
cAMP PK phosphorylates glycogen switching it off, phosphorylates phosphorylase kinase leading to activated which can also phosphorylate glycogen synthase ensuring it is inactive
Phosphorylase kinase
Exists in a and b form
Phosphorylated form is the active a form
Phosphorylase kinase phosphorylates phosphorylase switching it ON, allows glycogen degradation at the same time that it inhibits synthesis
Can be activated allosterically by Ca2+ ions linking muscle contraction with glycogen breakdown ensuring adequate ATP
Control of glycogen metabolism by adrenaline
Adrenaline stimulates glycogenolysis in muscle via B-oxidation receptors and cAMP formation, but in liver uses a1- adrenergic receptors and Ca2+ and diacylglycerol as second messengers
Regulation of glycogen metabolism
Coordinated regulation of both phosphorylase and glycogen synthase actvity to prevent futile cycling of intermediates (allosteric and covalent modification)
During exercise glycogen stimulated to provide energy for muscle contraction while glycogen synthesis is inhibited
Epinephrine stimulates breakdown and inhibits synthesis in skeletal muscle to prepare the body for physical work
In liver glycogen breakdown is stimulated by epinephrine and glucagon, whereas glycogen synthesis is inhibited in order to elevate blood glucose
Insulin stimulates glycogen synthesis in response to feeding and high blood glucose whereas simultaneously switches off glycogen breakdown in both liver and muscle
