von gierke's question

[Aclamity]

What's the rationale behind having Von Gierke's patients avoid fructose and galactose? Got a UWSA2 question where they infused a VG patient with fructose and he got excessive lactic acidosis.

Anyone know the mechanism behind this? What's the mech behind the lactic acidosis in VG in general? My guess was that lactate from muscles/RBCs was just building up due to inhibition of gluconeogenesis (i.e. stalling of the Cori Cycle). I just don't know how galactose and fructose can exacerbate it... maybe they're just adding more intermediates that further backs up the cycle??

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[beeitchness]

Galactose converts to glucose 1 phosphate, then to glucose 6 phosphate. Needs glucose 6 phosphatase to become glucose again and be sent out into the blood. G6P thus accumulates in liver.

Fructose becomes DHAP and glyceraldehyde, then eventually glucose 6 phosphate. Conversion to glucose requires glucose 6 phosphatase. This accumulates G6P in the liver.

Lactate is formed by RBC, muscle and sent to the liver to undergo Cori Cycle to become glucose again. This cannot occur when glucose 6 phosphatase is deficient, and the lactate simply builds up.
If fructose/galactose was given, it worsens lactic acidosis - more G6P build up in liver stops more lactate from attempting gluconeogenesis - therefore more lactate that spills out into the blood

 

[teenmachinery1]

anything that can lead to an increase in glucose-6 phosphate should be avoided. Fructose is only two steps away, fructose to fructose 6 phosphate via hexokinase and then isomerized to glucose-6-phosphate. Galactose to galactose 1 phosphate via galactokinase then to glucose 1 phosphate then to glucose 6 phosphate.

 

[Staradmiral]

What's the rationale behind having Von Gierke's patients avoid fructose and galactose? Got a UWSA2 question where they infused a VG patient with fructose and he got excessive lactic acidosis.

Anyone know the mechanism behind this? What's the mech behind the lactic acidosis in VG in general? My guess was that lactate from muscles/RBCs was just building up due to inhibition of gluconeogenesis (i.e. stalling of the Cori Cycle). I just don't know how galactose and fructose can exacerbate it... maybe they're just adding more intermediates that further backs up the cycle??

You need to review your carbohydrate biochemistry. You don't seem to understand the problem in Von Gierke's disease. Glucose 6 phosphatase is mutated so glucose cannot be secreted by the liver, thus all glucuse is shunted downward through glycolysis causing lactic acidosis, ketone bodies. Any sugar such as fructose and galactose which produces glycolysis intermediates will feed the shunt and exasperate the disease. You need to first understand the basic biochemistry pathways before memorize all the glycogen storage diseases.

 

[Aclamity]

You need to review your carbohydrate biochemistry. You don't seem to understand the problem in Von Gierke's disease. Glucose 6 phosphatase is mutated so glucose cannot be secreted by the liver, thus all glucuse is shunted downward through glycolysis causing lactic acidosis, ketone bodies. Any sugar such as fructose and galactose which produces glycolysis intermediates will feed the shunt and exasperate the disease. You need to first understand the basic biochemistry pathways before memorize all the glycogen storage diseases.

dude, I think YOU need to review your biochem. People with Von Gierke's are in a constant state of hypoglycemia (read: excess glucagon + epi + cortisol). There's no way in hell they'd be shunting things through glycolysis; F-2,6-BP is likely to be almost non-existent in their cells and insulin levels are probably close to zero. Draw it out if you have trouble understanding.

 

[Phloston]

You need to review your carbohydrate biochemistry. You don't seem to understand the problem in Von Gierke's disease. Glucose 6 phosphatase is mutated so glucose cannot be secreted by the liver, thus all glucuse is shunted downward through glycolysis causing lactic acidosis, ketone bodies. Any sugar such as fructose and galactose which produces glycolysis intermediates will feed the shunt and exasperate the disease. You need to first understand the basic biochemistry pathways before memorize all the glycogen storage diseases.

dude, I think YOU need to review your biochem. People with Von Gierke's are in a constant state of hypoglycemia (read: excess glucagon + epi + cortisol). There's no way in hell they'd be shunting things through glycolysis; F-2,6-BP is likely to be almost non-existent in their cells and insulin levels are probably close to zero. Draw it out if you have trouble understanding.

Aclamity raises a good point that F-2,6-BP would be very low, however, that's only relevant with respect to the shunting to galactose intermediates through glycolysis, since galactose ultimately would lead to G6P, which is upstream of PFK-1. Keep in mind that fructose will ultimately result in 2 x G3P, which is already downstream of the PFK-1 (which would normally be upregulated by F-2,6-BP), so in Von Gierke's, fructose could absolutely cause increased lactic acidosis, whereas galactose wouldn't.

My guess for avoiding galactose/fructose would be for the sake of not depleting inorganic phosphate, since there would be the accumulation of phosphate-trapping glycolytic intermediates, not only because glucose cannot be formed from G6P, but also because the NADH/NAD+ ratio would be elevated, so even if these intermediates were shunted to acetyl-CoA, oxaloacetate is likely to be depleted since the increased NADH/NAD+ has it shunted to malate, so acetyl-CoA is forced through ketogenesis, exacerbating the acidosis.

 

[Aclamity]

Aclamity raises a good point that F-2,6-BP would be very low, however, that's only relevant with respect to the shunting to galactose intermediates through glycolysis, since galactose ultimately would lead to G6P, which is upstream of PFK-1. Keep in mind that fructose will ultimately result in 2 x G3P, which is already downstream of the PFK-1 (which would normally be upregulated by F-2,6-BP), so in Von Gierke's, fructose could absolutely cause increased lactic acidosis, whereas galactose wouldn't.

My guess for avoiding galactose/fructose would be for the sake of not depleting inorganic phosphate, since there would be the accumulation of phosphate-trapping glycolytic intermediates, not only because glucose cannot be formed from G6P, but also because the NADH/NAD+ ratio would be elevated, so even if these intermediates were shunted to acetyl-CoA, oxaloacetate is likely to be depleted since the increased NADH/NAD+ has it shunted to malate, so acetyl-CoA is forced through ketogenesis, exacerbating the acidosis.

Well, even though fructose jumps into the glycolysis pathway downstream from PFK-1 the high glucagon/low insulin state will probably also inhibit pyruvate kinase (the other major regulated step in the pathway), in which case pyruvate would never even be formed. So I'm not so sure that even fructose can lead to lactic acidosis.

Your point about the phosphate, though, is a good one. I can definitely see that as being a reason not to infuse fructose/galactose

 

[gayle]

does ketone bodies are elevated or decreased in von girkes disease?

 

[sylhet]

You need to review your carbohydrate biochemistry. You don't seem to understand the problem in Von Gierke's disease. Glucose 6 phosphatase is mutated so glucose cannot be secreted by the liver, thus all glucuse is shunted downward through glycolysis causing lactic acidosis, ketone bodies. Any sugar such as fructose and galactose which produces glycolysis intermediates will feed the shunt and exasperate the disease. You need to first understand the basic biochemistry pathways before memorize all the glycogen storage diseases.

things are always not so easy. moral of the story. end.

 

[Jonari]

Well, even though fructose jumps into the glycolysis pathway downstream from PFK-1 the high glucagon/low insulin state will probably also inhibit pyruvate kinase (the other major regulated step in the pathway), in which case pyruvate would never even be formed. So I'm not so sure that even fructose can lead to lactic acidosis.

Your point about the phosphate, though, is a good one. I can definitely see that as being a reason not to infuse fructose/galactose

Aclamity, what was the right answer for the question?

 

[Aclamity]

things are always not so easy. moral of the story. end.

Haha re-reading that post really struck a nerve. Just want StarAdmiral to know I utterly demolished the biochem section on the real deal, so he can take his no-good biochem advice elsewhere. yea I hold grudges. but honestly, I hope he came to his senses and buckled down to study; he was a little too overconfident about his faulty biochem logic.

Aclamity, what was the right answer for the question?

Posts 2 and 3 nailed it.

 

[ShawnW59]

Guys. I had this same question and I hope this will help. Feel free to correct me if I am wrong!

We all have FA, and the first page on all FA's regardless of year will show the complete metabolism flow chart which shows that:

1) glycogen + galactose will eventually be converted into Glucose-1-P and later into Glucose-6-Phosphate which will become glucose if Glucose-6-phosphatase is present OR continue on in the glycolysis cycle

2) fructose will enter the glycolysis a bit different, skipping the PFK-1 regulating enzyme but for the sake of this conversation the point is it joins the previous 2 sugars along the pathway ending in pyruvate

Here is where I had my question, in Von Gierke's, or aka a patient in a hypoglycemic, the goal is to increase blood glucose levels to 'feed' the organs and the tissue in need of them for sustaining life and ATP production when sufficient. Why won't fructose or galactose just enter TCA upon entering our system, and instead becomes lactic acid instead?

I later recalled that it is the free fatty acid catabolism that is causing the lactic acidosis, because that's what causes hyperlipidemia in VG's secondary to hypoglycemia in the first place. The increase of free fatty acid will cause hyperlipidemia all because of the effort to increase blood glucose through transporting this resource to the liver.

The main breakthrough came when the simple fact that the babies with Von Gierke's are simply in a very serious starvation state, the severe hypoglycemia will cause all functions to direct towards gluconeogenesis and fatty acid catabolism will have the purpose of producing ketone bodies and the halting of TCA cycle due to all the OAA shunting into gluconeogenesis.

Because of the halting of TCA cycle all the products entering gluconeogenesis will eventually end up back down to pyruvate due to the lack of the final step enzyme, g-6-phosphatase, and shunted into lactic acid causing lactic acidosis and eventually the fight for excretion will cause decreased uric acid excretion.

I hope I didn't get it too twisted. Thanks.

 

[notbobtrustme]

holy **** so glad to be done with this bull**** lol