Metabolism in the fed and starved states Flashcards
What is the ‘switch’ that determines metabolic changes?
The molar ratio of insulin to glucagon in the blood
Define what is meant by the fed state
During meals and for several hours afterwards
Characterized by high insulin and low glucagon (a high insulin/glucagon ratio)
Define what is meant by the fasting state
6-12 hr after a meal
Fasting that lasts in excess of 12 hr is ‘prolonged fasting’ or starvation
Characterized by low insulin and high glucagon (a low insulin/glucagon ratio)
How does food intake affect insulin and glucagon?
Food intake stimulates insulin release; this inhibits glucagon secretion
What occurs in the absorptive phase?
Molecules of storage are built up
What occurs in the post-absorptive phase?
Storage compounds are broken down
In the fed state what happens to glucose utilisation in the brain?
Remains unchanged
Describe metabolism in the fed state in the liver
High concentrations of nutrients lead to an increase in the insulin:glucagon ratio
High blood glucose enters the liver and is converted to glycogen and triacylglycerols which are secreted as VLDL. Some enters TCA cycle
Lactate returning from rbcs and muscle and glycerol from peripheral tissues are 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
Describe metabolism in the fed state in the muscles
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 the diet via chylomicrons and from the liver via VLDL. These are oxidised via β-oxidation to acetyl CoA to produce energy to support contraction
Amino acids are incorporated into proteins
Describe metabolism in the fed state in the adipose tissue
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 triacylglycerol
Glycerol released from TAGs is returned to liver for re-use
Describe metabolism in the fed state in the brain
Brain takes up glucose via Glut 1 & 3 transporters and metabolises it oxidatively by glycolysis and the TCA cycle to produce energy
Describe metabolism in the early fasting state
During fasting, the liver switches from a glucose-utilizing to a glucose-producing organ
Decrease in glycogen synthesis and increase in glycogenolysis
Gluconeogenesis
What occurs in the liver during the early fasting state?
As plasma glucose falls no longer enters liver as Glut 2 transporter has low affinity. Liver changes from a user to exporter of glucose
Reduced insulin: glucagon ratio activates glycogenolysis and gluconeogenesis (from lactate and alanine) 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 activate
gluconeogenesis and inhibit glycolysis
What happens in the adipose tissue during the early fasting state?
Entry of glucose into adipose tissue via the Glut 4 transport system is reduced in response to the lowered insulin and metabolism of glucose via glycolysis is severely inhibited
Mobilisation of TAGS occurs in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline
Some of the fatty acids are used directly within the tissue to produce energy - remainder are released into the bloodstream to support glucose-independent energy production in muscle and other peripheral tissues
Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis
What occurs in the early fasting phase in the muscle?
The fall in insulin reduces 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
What occurs in the early fasting phase in the brain?
Continues to take up glucose because of the high affinity of Glut1 and Glut3 transport system and independence from insulin
Glucose continues to be metabolised despite the fact that no glucose is provided in the diet
Brain cannot switch to fatty acids as a source of fuel as free fatty acids do not cross the blood brain barrier
Define metabolism in the late fasting state
Chronic low-insulin, high glucagon state
Accompanied by decrease in concentration of thyroid hormones – decreases metabolic rate
Free fatty acids become the major energy source
Describe what happens during the late fasting state in the liver
No glucose enters liver and glycogen stores are depleted within 24 hours
Plasma glucose dependent on gluconeogenesis from lactate, glycerol & alanine from fat and protein breakdown. The kidney also becomes an important source of gluconeogenesis
Urea synthesis stimulated to cope with increasing 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 (acetoacetate and β-hydroxybutyrate). These are not used by the liver but released for oxidation by other tissues (muscle, brain)
Describe what happens in the late fasting state in adipose tissues
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
Describe the late fasting state in the 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
What is the purpose of the glucose-fatty acid cycle?
Spares glucose during fatty acid oxidation
Describe the glucose fatty acid cycle
Mobilisation 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 builds up in cytoplasm and inhibits PFK-1
Build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
Increase in glucose prevents further glucose entry and so conserves glucose
Describe what happens in the brain during the late fasting state
Although fatty acids cannot be used by brain, as the 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 so net glucose synthesis during starvation is essential
State the metabolic utilization of glucose in (a) Fed state, (b) Fasted state and (c) Starved state
(a) Glucose provided by diet
(b) Most glucose provided by the breakdown of
liver glycogen, increasing amounts by
gluconeogenesis
(c) Most glucose comes from gluconeogenesis, the
breakdown of protein and fats provide amino acids and
glycerol as substrates
What is hormonal control mediated by?
Changes in phosphorylation
How are enzymes involved in glycogenolysis and glycogen synthesis controlled?
Allosteric control
Hormonal control
List the hormones involved in the hormonal control of glycogenolysis and gluconeogenesis
Glucagon
Adrenaline
Cortisol
Insulin
When are glucagon and epinephrine (adrenaline) released?
The hormones glucagon and epinephrine (adrenaline) are released in response to low blood glucose, thus releasing glucose from glycogen in the liver to increase blood glucose
Epinephrine is also part of the “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
How is glycogen metabolism controlled by adrenaline?
Adrenaline stimulates glycogenolysis in muscle via b-adrenergic receptors and cAMP formation, but in liver uses a1-adrenergic receptors and Ca2+ and diacylglycerol as second messengers
Describe the regulation of glycogen metabolism
Occurs via both allosteric and covalent modification (phosphorylation) of the enzymes
During exercise glycogen breakdown is stimulated to provide energy for muscle contraction while glycogen synthesis is inhibited
Epinephrine (Adrenaline) 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 a high blood glucose, whereas it simultaneously switches off glycogen breakdown in both liver and muscle.
