MCAD deficiency

[Phloston]

What's the mechanism of the decreased glucose in MCAD deficiency?

We'd get decreased acetyl-CoA, but that's normally used to make ketones or is merely processed through the TCA cycle.

I wouldn't think glucose should be particularly affected, unless the lack of monoacyl glycerol produced (because beta-oxidation is impaired) is significant enough such that gluconeogenesis, based on this substrate alone, decreases.

Could anyone please explain? Thanks,

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[Jack is Back]

What's the mechanism of the decreased glucose in MCAD deficiency?

We'd get decreased acetyl-CoA, but that's normally used to make ketones or is merely processed through the TCA cycle.

I wouldn't think glucose should be particularly affected, unless the lack of monoacyl glycerol produced (because beta-oxidation is impaired) is significant enough such that gluconeogenesis, based on this substrate alone, decreases.

Could anyone please explain? Thanks,

You wouldn't think glucose would be affected?

Then basically you're saying that FA aren't ever used for energy throughout the day... if this were true then glucose wouldn't be affected. But since we do break down fat for energy and you're eliminating that, then obviously the body will use something else... note that it typically says hypoketotic hypoglycemic (there's a reason for the first word there).

Acetyl CoA is used both to make ketones/TCA... depends on the tissue right (brain/muscle aren't making ketone bodies).

If your question is, why don't AA or other glucogenic substrates just supply all the glucose, I think you're over thinking it. FFA and ketones are a huge source of energy and an efficient source. You can't simply lose half of your team and then think you're going to be fine because someone else on the team supplies some energy. You're thinking that gluconeogenesis should just be able to run on overdrive after knocking out your entire system of using fat for energy? Think about the body... fat and adipocytes play a huge role, so much so that when we study biochemical pathways we look at liver/muscle/adipocyte/brain/etc. It's a cornerstone to providing energy, not a nice option to use here and there.

 

[Phloston]

I'm asking if the drop in glucose occurs specifically because monoacyl-glycerol (the only glucogenic component of FAs) levels ebb, or if there's another mechanism, because the acetyl-CoA and ketone catabolites don't feed into the gluconeogenic pathways, so their lessened production shouldn't matter.

 

[Jack is Back]

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[Belleza156]

What's the mechanism of the decreased glucose in MCAD deficiency?

We'd get decreased acetyl-CoA, but that's normally used to make ketones or is merely processed through the TCA cycle.

I wouldn't think glucose should be particularly affected, unless the lack of monoacyl glycerol produced (because beta-oxidation is impaired) is significant enough such that gluconeogenesis, based on this substrate alone, decreases.

Could anyone please explain? Thanks,

As far as I understand the problem with the acyl-CoA dehydrogenase deficiencies are when there is prolonged fasting, but not in between meals if they are spaced out correctly.
So any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. End result being severe hypoglycemia and hypoketonuria.

So after we used up all our glucose and try to create more through gluconeogenesis, we can't because gluconeogenesis depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. End result being that gluconeogenesis can't compensate for the continued consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.

 

[Aclamity]

Acetyl-coA is used as an energy source for gluconeogenesis. No acetyl-CoA --> no gluconeogenesis --> no glucose. That's how I reasoned it out at least.

 

[phoenix89]

Acetyl-coA is used as an energy source for gluconeogenesis. No acetyl-CoA --> no gluconeogenesis --> no glucose. That's how I reasoned it out at least.

Acetyl CoA is an an obligate enzyme activator for Pyruvate Carboxylase, which is one of the key enzymes in GNG. Decreased Acetyl CoA = no activation of Pyruv Carboxylase = dec Gluconeogenesis.

Just another way of looking at it.

I got this from the Uworld Qbank answer discussions where they discussed how N-Acetyl Glutamate is an Obligate Activator of the Urea Cycle, similar to how Acetyl Coa is an Obligate Activator of GNG. These are the only two Obligate Enzyme Substrates relevant to the USMLE (a/c to the Kaplan videos)

 

[Phloston]

Acetyl CoA is an an obligate enzyme activator for Pyruvate Carboxylase, which is one of the key enzymes in GNG. Decreased Acetyl CoA = no activation of Pyruv Carboxylase = dec Gluconeogenesis.

Just another way of looking at it.

I got this from the Uworld Qbank answer discussions where they discussed how N-Acetyl Glutamate is an Obligate Activator of the Urea Cycle, similar to how Acetyl Coa is an Obligate Activator of GNG. These are the only two Obligate Enzyme Substrates relevant to the USMLE (a/c to the Kaplan videos)

That's it!!

You're brilliant, pheonix.

I had been looking for a mechanism. Thanks for that.

 

[Jack is Back]

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[Phloston]

You sound like someone who shouldn't be a doctor.

 

[alternatego]

great thread phloston

 

[nopo18]

Don't understand why people feel the need to make personal attacks. That's fine if Phlos annoys you, but just don't read his stuff. Ive learned from quite a few of his posts myself.

 

[Jack is Back]

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[Dallas]

lol Jack is Black is butthurt because he couldnt explain the question, nice way to compensate for your shortcomings.

BTW Nice thread phloston, and thanks phoenix for the answer, yes it is mentioned under gluconeogenesis but phoenix explains it in such a way that I would never had gotten that integration from reading FA alone so suck it jack is black. Haters can hate outside of this thread.

 

[alternatego]

lol Jack is Black is butthurt because he couldnt explain the question, nice way to compensate for your shortcomings.

BTW Nice thread phloston, and thanks phoenix for the answer, yes it is mentioned under gluconeogenesis but phoenix explains it in such a way that I would never had gotten that integration from reading FA alone so suck it jack is black. Haters can hate outside of this thread.

OMG a flaming/trolling Mahatma Ghandi!!! I thought I would never see something like that in my life!

 

[Dallas]

OMG a flaming/trolling Mahatma Ghandi!!! I thought I would never see something like that in my life!

 

[Jack is Back]

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[Dallas]

Lol. Stupidity abounds! FA didn't explain it well?! Acetyl coa activates gluconeo...

That's as simple and as good ad FA gets.

I see that reading comprehension isnt your strongest quality so I'll try to express myself clearly.


I never said I FA doesnt explain it well. It just doesnt do a good job integrating it like Phoenix did for us. Phoenix said that Ace-CoA and N-acetyl Glu are the two Obligate enzyme activators you need to know for step 1, thats something FA did NOT explain.

Capiche?

 

[Jack is Back]

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[Phloston]

I had actually encountered a practice question in USMLE Rx asking about the activator of the first step of gluconeogenesis. You need to know the first step is the pyruvate carboxylase reaction, and you've gotta know that acetyl-CoA regulates it. The integration here is taking that detail and saying that the decreased acetyl-CoA secondary to MCAD or carnitine deficiency would therefore disfavor glucose formation. This is why reading FA cover-to-cover is more of a memorization vs integration process. During/after my second pass (and I read very slowly, making sure I repeat everything aloud multiple times before turning a page), I was aware that I had made significant strides in terms of memorizing raw data/information, but questions are the key for true integration. In other words, FA enables the initial drastic score increase, but questions put it all together for the final 20-30 points. It's not that we couldn't sit all day and figure this stuff out, but on the exam, when we're rushed for time, it has to be in the preconscious as rapid recall. There won't be much time to think. And when there is, it needs to be on the genuine wtf-questions (such as if we get a plasmid and knock out multiple loci...).

 

[Jack is Back]

I had actually encountered a practice question in USMLE Rx asking about the activator of the first step of gluconeogenesis. You need to know the first step is the pyruvate carboxylase reaction, and you've gotta know that acetyl-CoA regulates it. The integration here is taking that detail and saying that the decreased acetyl-CoA secondary to MCAD or carnitine deficiency would therefore disfavor glucose formation. This is why reading FA cover-to-cover is more of a memorization vs integration process. During/after my second pass (and I read very slowly, making sure I repeat everything aloud multiple times before turning a page), I was aware that I had made significant strides in terms of memorizing raw data/information, but questions are the key for true integration. In other words, FA enables the initial drastic score increase, but questions put it all together for the final 20-30 points. It's not that we couldn't sit all day and figure this stuff out, but on the exam, when we're rushed for time, it has to be in the preconscious as rapid recall. There won't be much time to think. And when there is, it needs to be on the genuine wtf-questions (such as if we get a plasmid and knock out multiple loci...).

Good luck on the test. I think this discussion is beyond productive and I will exit.