Week 4 - Gluconeogenesis Flashcards
Gluconeogensis
How liver and kidney maintain blood glucose in the absence of carbohydrates
After 9 days of starvation… b
brain still uses glucose***
Insulin is used in what phase
What is used in post absorptive phase?
What is used in early staravation?
Absorptive phase
Glucagon (overnight fast)
Cortisol (glucocorticoid hormones… )
Relate this to table
What are most important steps in glycolysis
PFK 1 * most important
Glucokinase
Pyruvate Kinase (PK L)
in liver important, that PKA phosphorylates PKL and inhibits it…
What are the key regulatory steps in Gluconeogenesis?
The reverse of glycolysis and same regulatory steps
Every step is the same but the reverse reaction…
There are different enzymes tho *** the steps are the same…
What tissues require glucose for fuel?
Brain and RBCs
What happens to glucose after eating a meal (FED state)?
What happens during transition into FASTED state?
When glucose from a recent meal is consumed, the liver provides glucose first from glycogenolysis, then from gluconeogenesis.
As hepatic glycogen stores are depleted, gluconeogenesis is the sole source of blood glucose.
What are the sources of carbon for gluconeogenesis?
What is the source of energy?
RBCs always do anaerobic glycolysis, so lactate is produced and then turned back into glucose
Normal starvation response is incerease of free fatty acids in blood - triacylglycerol lypolyis can turn them back into glycerol (the carbon from the fatty acids doesnt end up in glucose tho (just to energy or keytone bodies), the glycerol provides the carbon)
Energy comes form beta oxidation of fatty acids..
How can pyruvate be made from gluconeogenesis precursors?
What is most important?
Alanine is most important
What is another way pyruvate is formed from gluconeogenesis precursors?
Glycerol from triacylglycerol lypolysis
The product can be then used to make fructose 1,6 bis phosphate …
How is pyruvate kinase regulated..
with gluccagon around (fasted state) PK is shut off…
in cytosol. look as diagram
THIS does not apply when glycerol is used - only for alanine and lactate..
Oxaloacetate cannot cross metochondrial barrier.. so it is converted to asp or malate.. (they have transporters)
They they are turned back into oxaloacetate (OAA cytosolic) and turned into PEP phosphoenolpyruvate.. uses GTP
then it can go into gluconeogenesis…
So malate vs Asp depends on NADH/NAD ratio and concentrations in cytosol…
Pyruvate to Oxaloacetate..
Glutamate is amine donor..
mitochondria transpofters
What are two fates of OAA?
Oxaloacetate to PEP via PEPck (phosphoenolpyruvate carboxykinase
What are inhibitoros and activateors of PEPck?
CRE carbohydrate response element
CREB is carbohydrate response element binding protein
The corticoid receptor (when binds cortisol) the receptor goes to nucleus and actually promotes transcription.. (unlike a glucagon receptor that just transduces a signal)
Insulin response unit is inhibatory response to PEP ck
GLuconeogenesis in liver depends on PEP ck and glucocorticoids and also thorugh other transcritption factors: PGC1 (not important)
People with type II (insuin resistant diabetes)
A lot of sugar in blood but insulin isnt shutting gluconeogenesis off so liver is always producing glucose..
Metformin is the threaputic element deactivates TORC2 (phosphorylates it) so it cant
metrofmin is ampk mimic.. so it mimics a low energy state in cell. it prevents transcription of PEP ck and other gluconeogenesis genes and slows production of sugar.. IN LIVER
Futile cycling in gluconeogenesis
parallel anabolic and catabolic pathways.. Interconverting with two substrates using ATP but not having a net change.
SO if gluconeogenesis and glycolysis were happenign at same time, net concentrations wouldnt change but we would be using energy..
SO when glycolysis is active gluconeogenesis is shut off and visa versa
How is futyle cycling prevented?
PKA is inactivated and PDH is inactivated.. So that promotes pyruvate carboxylase reaction (into OAA in TCA skipping pyruvate) and also PEP ck is activated by PKA cortisol..
IN FED STATE EVERYTHING IS REVERSED.
What is PFK 1 rxn in glycolysis?
how is it different in gluconeogenesis?
What is fructose 1,6 bisphosphatase rxn in gluconeogenesis.. what is the glycolysis opposite step?
PFK2 actas as an inhibitor of what?
how to prevent futile cycling of PFK1 step…
fructose 1, 6 bis phosphatase..
Glucose 6 phosphatase step..
How is last step of gluconeogenesis (G6P to glucose) not futally cycled?
kinetics
differenc of Km’s..
What are the different glucose transporters?
What transports used in FASTED state?
Going to go out of liver and into other cells through GLUT 1 and 3 (main transporter for brain and getting glucose across blood brain barrier.. also in muscle tcells, adopose, etcs)
In FED State glut 4 will be used
What are the energetics of gluconeogenesis?
So it take energy to make glucose**
Glucose 6 Phosphatase Deficiency (GSD I)
glycogen storage disease: fasting hypoglycemia, lactic acidosis, enlarged liver
Glucose 6 Phosphatase is used in gluconeogenesis and glygogenolysis… IN LIVER - becuase of this enzyme the liver can regulate whole body blood glucose level.. Muscle cells do not have this enzyme
Fructose 1,6 bisphosphatase deficiency
rare autosomal recessive disorder
episodic fasting hypoglycemia (when liver glycogen is depleted)
cant produce glucose from gluconeogenesis using this emzyme - (what can be used still, alanine, lactate, or glycerol)
Only in gluconeogenesis.
Phosphoenolpyruvate carboxykinase deficiency
extremely rare (or does not exist)
3 or 4 pateints have ever had (or thought) to have this
Could this make surgar from alanine? no
lactate? no
glycerol? yes. that is why
Clinical case..
Hyperglycemic
so ddx : think diabetes..
polyuria and polydypsia are secondary to hyperglycemia.. body trying to flush out glucose from blood..
So first, do an oral glucose tolerance test to rule out diabetes.. give injection of insulin, if blood glucose dosent go down suspect diabetes.
neuro symptoms osmotic balance, water is leaving brain to go into blood.. also polypol pathway in eye (blurred vision)
So drugs dad brough were different. prednisone is a drug agonist of glucocorticoid receptors so it upregulates PEPck and increases gluconeogenesis..
Death becaue of dehydration of nervous tissue….
2nd clinical case.
