M104 T2 L9 Flashcards
What states does the human metabolism oscillate between?
the fed and fasting states
What is the ‘switch’ that determines metabolic changes?
the molar ratio of insulin to glucagon in the blood
When is the FED metabolic state in place?
during meals and for several hours afterwards
What are the FED and fasting metabolic states characterized by?
FED - high insulin and low glucagon (a high insulin/glucagon ratio)
fasting - low insulin and high glucagon (a low insulin/glucagon ratio)
When does the fasting metabolic state kick in?
6-12 hr after a meal
What is the criteria of ‘prolonged fasting’ or starvation?
fasting that lasts in excess of 12 hrs
What is the effect of food intake (FED state)?
stimulates insulin release
insulin inhibits glucagon secretion
this affects metabolism in the liver, muscle and adipose tissue
However, glucose utilization in the brain remains unchanged
What is the effect of high Cs of nutrients on the the insulin:glucagon ratio?
causes it to increase
What happens when there is a high blood glucose?
it enters the liver and is converted to glycogen and TGs
these are secreted as VLDL
some enters TCA cycle
What is glycerol from peripheral tissues converted into?
triacylglycerols
What happens to excess amacs entering from the gut?
they are converted to pyruvate and metabolised via the TCA cycle for energy or converted to triacylglycerols
How does glucose enter muscle tissue?
via the insulin-stimulated Glut 4 transport system
What happens to glucose once it has entered the muscle tissue?
it is converted to glycogen or metabolised via glycolysis and TCA cycle
How do FAs enter muscle tissue?
via chylomicrons (if from the diet) via VLDL (if from the liver) via VLDL. These
What are the two sources of FAs?
the diet
the liver
What happens to FAs once they enter muscle tissue?
they are oxidised via β-oxidation to acetyl CoA to produce ATP to support contraction
How does glucose enter adipose tissue?
via the insulin-dependent Glut 4 transport system
What happens to glucose once it enters adipose tissue?
it is converted into acetyl CoA and PDH via glycolysis
glucose < acetyl CoA and PDH < FAs < triacylglycerol
How do FAs enter adipose tissue?
via VLDL and chylomicrons
What happens to FAs once they enter adipose tissue?
it is converted to triacylglycerol
What happens to glycerol released from TGs?
it is returned to liver for re-use
What is the effect of insulin activity on LPL and HSL
activity?
LDL - is increased
HSL - is reduced
How does the brain take up glucose?
via Glut 1 & 3 transporters
What happens once glucose enters the brain?
it metabolises it oxidatively by glycolysis and the TCA cycle to produce ATP
How does the role of the liver change during fasting?
switches from a glucose-utilizing to a glucose-producing organ
there is a decrease in glycogen synthesis and an increase in glycogenolysis
What happens as plasma glucose falls?
glucose no longer enters liver as Glut 2 transporter has low affinity
What is the effect of a reduced insulin: glucagon ratio?
it activates glycogenolysis and gluconeogenesis (from lactate and alanine) via cAMP production in response to glucagon
What are FAs from lipolysis used for?
to produce E via b-oxidation
What is citrate and acetyl CoA produced from?
from the oxidation of FAs - this activates gluconeogenesis and inhibits glycolysis
What is the effect in reduced insulin levels?
it reduces glucose entry into muscle tissue
glycogenolysis does not occur as there are no glucagon receptors in skeletal muscle to cause activation
When insulin levels are low, what is used as an alternative E source?
muscle and other peripheral tissues switch to FA oxidation as a source of E
this inhibits glycolysis and glucose utilisation
In the early fasting state, what happens to proteins
they are broken down to amacs
the carbon skeletons can be used for E
or exported to the liver in the form of alanine
What is the entry of glucose into adipose tissue via the Glut 4 transport system reduced in response to?
in response to the lowered insulin and metabolism of glucose via glycolysis being severely inhibited
What does the mobilisation of TGs occur in response to?
in response to the reduced insulin:glucagon ratio and activation of the sympathetic NS by release of noradrenaline
What are FAs used for in adipose tissue?
used directly within the tissue to produce energy
the remainder are released into the bloodstream to support glucose-independent E production in muscle and other tissues
What happens to glycerol in adipose tissue?
it cannot be metabolised so it is recycled to the liver to support gluconeogenesis
How does the brain continue to take up glucose in the early fasting state?
bc of the high affinity of Glut1 and Glut3 transport system and independence from insulin
so glucose continues to be metabolised despite the fact that no glucose is provided in the diet
Why does the brain continue to take up glucose in the early fasting state rather than using alternatives?
bc the brain can’t switch to FAs as a source of fuel as free FAs don’t cross the blood brain barrier
What is the metabolism like in the starved state?
Chronic low-insulin, high glucagon state
What happens to hormone levels in the starved state?
the concentration of thyroid hormones decreases, which decreases the metabolic rate
What is the major E source in the starved state?
Free FAs
the production of ketone bodies is an alternative fuel source
How is absorption of the liver affected in the starved state?
no glucose enters liver and glycogen stores are depleted within 24 hours
In the starved state, what is the plasma glucose dependent on?
gluconeogenesis from lactate, glycerol & alanine from fat and protein breakdown
the kidney also becomes an important source of gluconeogenesis
In the starved state, why is the synthesis of urea stimulated?
to cope with increasing amacs entering liver
What processes are inhibited under the starved state?
Glycogen synthesis and glycolysis
What is the role of FAs in the liver under the starved state?
they provide E to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies
What ketone bodies is excess acetyl CoA converted into in gluconeogenesis of the liver?
acetoacetate and β-hydroxybutyrate
What are ketone bodies in the starved state, located in the liver, used for?
they are released for oxidation by other tissues
What happens to muscle glucose in the starved state?
glucose entry is reduced with a fall in insulin
FAs are used instead as the fuel
What happens to ketone bodies in the starved state?
they are taken up by muscle and other peripheral tissues
they are used as a further source of fuel in heart and muscle conserving glucose
What are the effects of the actions of ketone bodies in the starved state?
they reduce proteolysis and decrease muscle wasting
What does muscle tissue use for the E to contract in the starved state?
FA oxidation
What is the first stage of the glucose-fatty acid cycle?
glucagon or adrenaline causes the mobilisation of FAs this increases FA oxidation to acetyl CoA in peripheral tissues
What is the second stage of the glucose-fatty acid cycle, involves acetyl CoA?
Excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1
What is the third stage of the glucose-fatty acid cycle, involves acetyl CoA?
Build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
What is the fourth stage of the glucose-fatty acid cycle, involves acetyl CoA?
Increase in glucose prevents further glucose entry and so conserves glucose
What happens to adipose glucose in the starved state?
glucose entry is reduced with a fall in insulin
FAs from triacylglycerol are used as fuel for all the major tissues
What process is greatly activated in adipose tissue in the starved state and what causes it?
Lipolysis
bc the low insulin:glucagon ratio and blood levels of FAs rise 10-fold
What happens to adipose glycerol in the starved state?
it is exported to the liver to be converted into glucose
What happens to the brain in the starved state?
limited levels of glucose for the brain to use
as the levels of ketone bodies rise in the plasma, FAs can cross the blood brain barrier and enter the brain as a source of E, even though FAs can’t be used by the brain
How are ketone bodies used by the brain in the starved state?
they can’t completely make up for glucose, so the brain still needs to take it up glucose and metabolise via glycolysis
maintaining net glucose synthesis during starvation is essential
What happens to ketone body concentration during fasting or starvation?
it increases
What concentration of plasma ketone bodies is sufficient to allow use by the CNS? When does this occur?
4mM+
occurs after approx. 3 days of starvation
What is glucose sourced by across the different metabolic states?
Fed state - diet
Fasted state - most from the breakdown of liver glycogen, increasing amounts by gluconeogenesis
Starved state - most from gluconeogenesis
What are enzymes involved in glycogenolysis / glycogen synthesis regulated by?
allosteric control
hormonal control
What are examples of hormones responsible for regulating enzymes involved in glycogenolysis / glycogen synthesis?
glucagon, adrenaline, cortisol and insulin
What is hormonal control of enzymes regulated by?
phosphorylation
Where is glucagon released from?
pancreatic α-cells
What is the initiator of glucagon release?
hypoglycaemia
What is the effect of glucagon and adrenaline on glycogenolysis/ gluconeogenesis?
rapid activation
Where is adrenaline and coritsol released from?
adrenal medulla
What is the initiator of adrenaline release?
stress and hypoglycaemia
What is the initiator of coritsol release?
stress
What is the effect of coritsol on glycogenolysis/ gluconeogenesis?
chronic activation
What is the initiator of insulin release?
hyperglycaemia
Where is insulin released from?
pancreatic β-cells
What is the effect of insulin on glycogenolysis/ gluconeogenesis?
inactivation
What triggers insulin release?
increased bgc, promoting glucose oxidation, glycogen synthesis and TG synthesis
What triggers glucagon and adrenaline release?
low bgc
releases glucose from glycogen in the liver to increase it
What is another name for adrenaline?
epinephrine
What happens to adrenaline levels during exercise?
its levels rise greatly during exercise when glycogen breakdown is required to support muscle contraction
How does glucagon (liver) and adrenaline (muscle) activate glycogen breakdown and inhibit synthesis?
by activating cAMP PK with ultimate phosphorylation of phosphorylase and glycogen synthase
Mimicked by increasing Ca2+ during contraction
Insulin activates protein phosphatase to reverse these effects
What are the effects of glucagon (liver) and adrenaline (muscle)?
they activate glycogen breakdown and inhibit synthesis
they increase cAMP production and activate cAMP PK
What is the effect of the activation of cAMP PK?
it phosphorylates glycogen synthase switching it OFF
it phosphorylates phosphorylase kinase leading to activation
Phosphorylase kinase can also phosphorylate glycogen synthase ensuring it is inactive
What two substances does cAMP PK phosphorylate?
glycogen synthase
phosphorylase kinase
What is the effect of phosphorylating glyocgen synthase?
it is switched off - inactivated
What is the effect of phosphorylating phosphorylase kinase?
it is switched on - activated
What are the two forms of phosphorylase kinase?
active “a” form - is phosphorylated
inactive “b” form - is not phosphorylated
What is the role of phosphorylase kinase?
it phosphorylates Phosphorylase, switching it ON
What happens when Phosphorylase is activated?
glycogen degradation occurs
glycogen synthesis is inhibited
What substances activate Phosphorylase kinase?
glucagon
Ca2+ ions (allosterically)
How is Phosphorylase kinase activated by Ca2+ ions?
links muscle contraction with glycogen breakdown ensuring adequate ATP
What is the effect of insulin on protein phosphatase -1?
it activates it, which removes the phosphates from phosphorylase, glycogen synthase and phosphorylase kinase
this switches OFF glycogen breakdown and switches ON glycogen synthesis
How does glucagon stimulate glycogenolysis?
via the 2nd messenger cAMP in the liver
How does adrenaline stimulate glycogenolysis?
the 2nd messenger cAMP and Ca2+ in the liver and muscles
via b-adrenergic receptors and a1-adrenergic
What is the role of LPL in adipose tissue?
it controls lipid uptake into the adipose tissue
its activity is increased by insulin
Does glucagon affect muscle tissue and why?
no becuase muscle cells don’t have glucagon receptors
