Diabetes causing Acidosis?

[justadream]

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“Diabetics who are acidotic due to the metabolism of proteins and fats instead of glucose will have an increased ventilation rate to remove CO2 and increase pH”



Why does metabolism involving fats and proteins (instead of glucose) lead to increased CO2 levels?

 

[sillyjoe]

“Diabetics who are acidotic due to the metabolism of proteins and fats instead of glucose will have an increased ventilation rate to remove CO2 and increase pH”



Why does metabolism involving fats and proteins (instead of glucose) lead to increased CO2 levels?

The digestion of fats and proteins can lead to ketone body formation which are weakly acidic. There protons dissociate at physiological pH, lowering the pH of the blood and causing acidosis.

 

[justadream]

@sillyjoe

Oh that makes sense!

So I think I remember reading that Ketone Bodies are formed when there is excess acetyl-coA.

Where does that excess Acetyl-CoA come from? Beta Oxidation? Amino Acid Catabolism?

I assume it is not from glycolysis making pyruvate ===> acetyl coA
(since diabetics wouldn't be able to take in glucose for glycolysis in the first place)

 

[sillyjoe]

@sillyjoe

Oh that makes sense!

So I think I remember reading that Ketone Bodies are formed when there is excess acetyl-coA.

Where does that excess Acetyl-CoA come from? Beta Oxidation? Amino Acid Catabolism?

I assume it is not from glycolysis making pyruvate ===> acetyl coA
(since diabetics wouldn't be able to take in glucose for glycolysis in the first place)

Both protein breakdown and lipid breakdown yields acetyl CoA. Certain proteins can enter gluconeogenesis. The others are broken down into acetyl CoA, which cannot go into the TCA cycle through gluconeogenesis because it needs the carbon backbone of oxalaoacetate to continue the Kreb cycle. Consequently, you get ketone body formation. Lipids are also broken down into acetyl CoA through beta oxidation.

 

[justadream]

@sillyjoe

"The others are broken down into acetyl CoA, which cannot go into the TCA cycle through gluconeogenesis because it needs the carbon backbone of oxalaoacetate to continue the Kreb cycle."

So the acetyl Coa from the breakdown of certain proteins cannot do the TCA cycle because of a lack of Oxa?

I thought Oxa was always regenerated in the TCA. And why is it that these Acetyl Coa molecules (from the protein breakdown) don't have an Oxa to use while Acetyl Coa from sugars do?

 

[sillyjoe]

I had a professor teach it as a piggy back ride as shown in the diagram below. This is a crucial concept to understanding how the TCA cycle works and why acetyl CoA cannot just go through the TCA cycle if we don't have the carbon backbone of oxaloacetate which is made from pyruvate (like acetyl CoA):

So as you can see, the acetate (acetyl CoA) will join the 4 carbon oxaloacetate to create a 6 carbon molecule (citrate). This 6 carbon molecule, citrate, will then lose 2 carbons as CO2 through the reaction to yield a 4 carbon molecule that is then converted back to oxaloacetate in the last 3 steps of the TCA cycle. The overall reaction leads to the oxidation of acetyl CoA to two carbon dioxide molecules plus capture of the energy from oxidation.

So let me ask you, where does the original oxaloacetate come from that initially condenses with acetyl CoA? It turns out that oxaloacetate is made from pyruvate (glycolysis end product). Without glucose, you cannot make pyruvate, and you cannot make oxaloacetate from pyruvate to join acetyl CoA to form citrate. You need that carbon backbone from glucose.

Finally, pyruvate dehydrogenase that turns pyruvate into acetyl CoA is irreversible so it cannot go through gluconeogenesis (reverse of glycolysis) to make glucose.

 

[justadream]

@sillyjoe

Great diagram!

2 Follow-Up questions:

1) So glycolysis indirectly produces exactly enough Oxa (from pyruvate) for itself and no extra?

2) At the end, the Oxa is free again. Why can't it be reused (like by acetyl coA from a protein?)?

 

[sillyjoe]

@sillyjoe

Great diagram!

2 Follow-Up questions:

1) So glycolysis indirectly produces exactly enough Oxa (from pyruvate) for itself and no extra?

2) At the end, the Oxa is free again. Why can't it be reused (like by acetyl coA from a protein?)?

No, you cannot look at these things in isolation like that.

First off, the pyruvate dehydrogenase enzyme complex is completely irreversible i.e. it's product, acetyl CoA cannot go through gluconeogenesis. It is committing pyruvate to going through the TCA cycle or lipid synthesis.

Almost all of the intermediates/products in glycolysis and the TCA cycle can go on to make tons of other important molecules in our body and vice versa. It is not that your body is making exactly enough to meet demands. It is just that there is an overall problem in the scenario outlined above, and that is that oxaloacetate has to come from somewhere. It can be regenerated, but there is no NET increase in it.

If your body needs glucose and is breaking down lipids/proteins in order to meet it's energy needs you would think that you can just add acetyl CoA to the TCA cycle to make oxaloacetate (which is gluconeogenic) right? NO! Because there is no net increase in oxaloacetate from the TCA cycle.

Let's say you tried. Your body is suddenly low on glucose and your glycogen stores have depleted. It is switching to lipids and proteins for energy. We now have acetyl CoA and we go through the TCA cycle, which remember needs an oxaloacetate to combine with an acetyl CoA to make citrate. Now, we go all the way around the cycle to make oxaloacetate. Great! We can go into gluconeogenesis now because we have oxaloacetate. But if we do, we completely remove oxaloacetate from the TCA cycle and the TCA cycle will stop because there is NO NET INCREASE in oxaloacetate from the TCA cycle. You put 1 in you get 1 out.

The only way you can do the above scenario is if you can replenish the oxaloacetate with other products from glycolysis, which is how oxaloacetate is made in the first place. But guess what? If you have enough glucose to replenish oxaloacetate you wouldn't have needed to switch to protein and lipid catabolism!

 

[justadream]

@sillyjoe

So if you don't eat any sugar for a while, what does the body do? Does the supply of Oxa diminish from normal protein recycling?

"If your body needs glucose and is breaking down lipids/proteins in order to meet it's energy needs you would think that you can just add acetyl CoA to the TCA cycle to make oxaloacetate right? NO!"
Are you referring to artificially adding in Oxa (like injecting it)?

 

[sillyjoe]

@sillyjoe

So if you don't eat any sugar for a while, what does the body do? Does the supply of Oxa diminish from normal protein recycling?

If you are starving your body will start breaking down lipids and proteins for energy until you die.

Are you referring to artificially adding in Oxa (like injecting it)?

No. I am referring to the fact that when you switch to a lipid/protein catabolism you make acetyl CoA. That's what I meant by adding acetyl CoA to the TCA cycle.

 

[justadream]

@sillyjoe

Going back to (you may have answered this before but just want to confirm):

"The others are broken down into acetyl CoA, which cannot go into the TCA cycle through gluconeogenesis because it needs the carbon backbone of oxalaoacetate to continue the Kreb cycle."

Okay so I get that the amount of Oxa you have (which is not increased in the TCA - you get 1 and then you use 1 in each cycle) is limited. But there is still some Oxa that does exist. So some of the acetyl-coA derived from non-sugar sources should still be able to enter TCA right?

 

[sillyjoe]

@sillyjoe

Going back to (you may have answered this before but just want to confirm):

"The others are broken down into acetyl CoA, which cannot go into the TCA cycle through gluconeogenesis because it needs the carbon backbone of oxalaoacetate to continue the Kreb cycle."

Okay so I get that the amount of Oxa you have (which is not increased in the TCA - you get 1 and then you use 1 in each cycle) is limited. But there is still some Oxa that does exist. So some of the acetyl-coA derived from non-sugar sources should still be able to enter TCA right?

Right, but we are talking over long term states in the body. We were originally discussing why acetyl CoA cannot go into the TCA cycle and goes on to make ketone bodies for energy. Your body has a basal level of lipid catabolism. However, when you are in a starved state (note: not transiently low in glucose), you will have an increase in ketone body formation because the ratio of protein/lipid : glucose catabolism increases. As a result you have an excess of acetyl CoA and not enough oxaloacetate (or said another way, not enough glucose) to keep the TCA cycle running. As a result, you get ketone body formation.

 

[sillyjoe]

And just to take it a step further to come in full circle. When a diabetics cannot get glucose into their cells they are in a sense in a "starved" state. This is why you get mainly lipid and some protein breakdown that leads to ketone body formation.

 

[justadream]

@sillyjoe

Got it. Thanks so much!

How much of Beta-oxidation and Amino Acid Catabolism do you think we should know for MCAT?

Do you think knowing the products (e.g., Amino Acids can be made into glucose and Acetyl-CoA, fats also can be made into glucose and Acetyl-CoA) is too simplistic?

 

[Czarcasm]

@sillyjoe @justadream

Really great post guys. Just thought I'd throw in this picture and text from my biology book for some additional clarity:

And a relevant picture from EK:

All this makes sense when you bare in mind that the cells of people with diabetes are essentially starving due to lack or insulin (DB T1) or insulin-resistance (DB T2). Glucose is not able to be stored in the Liver, so a lot of usable glucose is lost through excretion. So as an alternative energy source, fat reserves are broken down from adipose tissue and mobilized through the blood to the liver. In the liver, glycerol can be converted to PGAL and enter the later part of glycolysis and converted to pyruvate, which then can enter TCA, etc. Also in the liver, the fatty acids undergo beta-oxidation to produce acetyl-CoA, which can enter citric acid cycle directly. These two sources provide energy to the liver, but doesn't resolve the issue for the rest of the bodies cells. To resolve this, the liver transport acetyl-CoA in the modified form of ketone bodies, which the body cells can utilize and degrade for energy. The problem with this form of energy, as indicated above and by the passage, is that in high amounts, they result in blood acididty, which is catastrophic for many proteins and other biological systems which function at normal blood pH of 7.3. Receptors within the body detect high levels of H+ and signal the hypothalamus to trigger an effective response. Because of the dynamic equilibrium between H+ and CO2, the person will begin to expire more CO2 (which ultimately shifts the equilibrium to produce CO2 lost, and thereby consume excess H+). The accumulation of H+ is so rapid though, that this isn't a viable long term solution.

I highly highly highly recommend you read this to understand the big picture. Will really clear things up: http://dtc.ucsf.edu/types-of-diabet...e-body-processes-sugar/the-liver-blood-sugar/

 

[Czarcasm]

@sillyjoe

Got it. Thanks so much!

How much of Beta-oxidation and Amino Acid Catabolism do you think we should know for MCAT?

Do you think knowing the products (e.g., Amino Acids can be made into glucose and Acetyl-CoA, fats also can be made into glucose and Acetyl-CoA) is too simplistic?

Honestly, this information is a little bid advanced, but just being familiar with the above processes and knowing they exist will help immensely. Typically, this information would be explained in a passage though. All the information required for the MCAT Biology section is convered in general biology classes. The information above is typically explained in biochemistry 2, a class not required for the MCAT.