Week 4 - Gluconeogenesis

Question 1

Gluconeogensis

Answer 1

How liver and kidney maintain blood glucose in the absence of carbohydrates

Question 2

After 9 days of starvation… b

brain still uses glucose***

Answer 2

Question 3

Insulin is used in what phase

What is used in post absorptive phase?

What is used in early staravation?

Answer 3

Absorptive phase

Glucagon (overnight fast)

Cortisol (glucocorticoid hormones… )

Relate this to table

Question 4

What are most important steps in glycolysis

Answer 4

PFK 1 * most important

Glucokinase

Pyruvate Kinase (PK L)

in liver important, that PKA phosphorylates PKL and inhibits it…

Question 5

What are the key regulatory steps in Gluconeogenesis?

Answer 5

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…

Question 6

What tissues require glucose for fuel?

Answer 6

Brain and RBCs

Question 7

What happens to glucose after eating a meal (FED state)?

What happens during transition into FASTED state?

Answer 7

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.

Question 8

What are the sources of carbon for gluconeogenesis?

What is the source of energy?

Answer 8

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..

Question 9

How can pyruvate be made from gluconeogenesis precursors?

What is most important?

Answer 9

Alanine is most important

Question 10

What is another way pyruvate is formed from gluconeogenesis precursors?

Answer 10

Glycerol from triacylglycerol lypolysis

The product can be then used to make fructose 1,6 bis phosphate …

Question 11

How is pyruvate kinase regulated..

Answer 11

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…

Question 12

Pyruvate to Oxaloacetate..

Answer 12

Glutamate is amine donor..

Question 13

mitochondria transpofters

Answer 13

Question 14

What are two fates of OAA?

Answer 14

Question 15

Oxaloacetate to PEP via PEPck (phosphoenolpyruvate carboxykinase

Question 16

What are inhibitoros and activateors of PEPck?

Answer 16

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)

Question 17

Insulin response unit is inhibatory response to PEP ck

Question 18

GLuconeogenesis in liver depends on PEP ck and glucocorticoids and also thorugh other transcritption factors: PGC1 (not important)

Answer 18

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

Question 19

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..

Answer 19

SO when glycolysis is active gluconeogenesis is shut off and visa versa

Question 20

How is futyle cycling prevented?

Answer 20

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.

Question 21

What is PFK 1 rxn in glycolysis?

how is it different in gluconeogenesis?

Question 22

What is fructose 1,6 bisphosphatase rxn in gluconeogenesis.. what is the glycolysis opposite step?

Question 23

PFK2 actas as an inhibitor of what?

how to prevent futile cycling of PFK1 step…

Answer 23

fructose 1, 6 bis phosphatase..

Question 24

Glucose 6 phosphatase step..

Question 25

How is last step of gluconeogenesis (G6P to glucose) not futally cycled?

Answer 25

kinetics

differenc of Km’s..

Question 26

What are the different glucose transporters?

Answer 26

Question 27

What transports used in FASTED state?

Answer 27

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

Question 28

What are the energetics of gluconeogenesis?

Answer 28

So it take energy to make glucose**

Question 29

Glucose 6 Phosphatase Deficiency (GSD I)

Answer 29

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

Question 30

Fructose 1,6 bisphosphatase deficiency

Answer 30

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.

Question 31

Phosphoenolpyruvate carboxykinase deficiency

Answer 31

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

Question 32

Clinical case..

Answer 32

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….

Question 33

2nd clinical case.