Monday, September 30, 2013

The Carbohydrate Monster Under your Bed Part 2

Insulin Resistance, Gary Taubes, Carbohydrates make you fat, Low Carbohydrate Diet, Low Carbohydrate Weight loss, South Beach Diet, low Carb Weight regain, Cellular Respiration, beta Oxidation, De Novo Lipogenesis, paleo
"Remember that fear always lurks behind perfectionism. Confronting your fears and allowing yourself the right to be human can, paradoxically, make you a far happier and more productive person."

Dr. David M. Burns

In part 1 of this series we discussed the basic carbohydrates we consume, the functions of the pancreas (insulin secretion, glucagon, amylin, Incretins) and the Liver's job in regulating blood sugar. In this section we are going to look where the glucose goes and how it used in various parts of your body. Far too often people mis interpret the main function of glucose and's not to make us fat and sick but to instead nourish and provide much needed energy as the biochemistry below will clearly demonstrate and hopefully change a individuals mind set from carbohydrates = fat carbohydrates = power, strength, health and vitality.

-->  The Fate of Glucose in the body

Where exactly does all of this glucose from the carbohydrates we ingest end up???  That is an excellent question because there are many places in the body where glucose can "end up" if you catch my drift. Glucose typically has two can either be stored or burned. In the first part of this section, We will discuss the burning of glucose...

The burning of Glucose is through a process more commonly known as cellular respiration. Remember that we as humans can not use glucose as fuel directly, we use ATP for our energy needs and this is why cellular respiration is essential for life. I touched on this briefly in the section regarding the Beta Cells where I described the actions involved in the secretion of insulin and part of that sequence involved what? yes, cellular respiration. ( go back and review if need be)

 There are three parts to cellular respiration but the basic formula is as follows:

C6H12O6 + 6O2 ----> 6CO2 + 6H2O + Energy/ATP/Heat or...

 Glucose + Oxygen = Carbon dioxide + Water + Energy ~ 36 ATP (some books will say 38 ATP)

This process occurs through 4 steps ( I said 3 steps in the above but I am going to discuss the prep step so 3 and a half I guess):

1) Glycolysis
1.5) The "Prep Step",
2) Krebs/TCA/Citric cycle
3) Finally the electron transport chain:

First glucose will enter the cell membrane through something called a glucose transporter protein. Glucose transporters come in many different forms and help to facilitate the transport of glucose through the concentration gradient. Once inside the cytoplasm, the glucose enters into something called...
1) Glycolysis is anaerobic(does not require oxygen) and occurs in the cytoplasm...that is outside of the mitochondria. For all intensive purposes of simplicity I will just discuss the inputs and outputs in each step:

Glucose + 2 ADP + 2 Pi + 2 NAD --> 2 Pyruvate + 2 ATP + 2 NADH + heat
Input: Glucose
Output: 2ATP(net), 2NADH, 2 Pyruvate, Lactate**

** Lactate can be produced from this reaction as there are three end products from pyruvate processing and we will discuss this in a later section.

From this series of reactions , as seen to the right, we have produced two ATP so that leaves us with 34 more ATP left to produce. In the diagram in the right we also see that reactions actually require ATP to produce more ATP which is why I said "net" ATP produced and not total as there was actually 4 ATP produced in total. The NADH will come in handy later but for now just remember that it is there waiting to be utilized. What we want to turn our attention to now is the pyruvate which will enter into the next step...

2) The Prep Step or preparation of pyruvate is the first step when the pyruvate enters the mitochondria.

2 Pyruvate + 2 NAD + 2CoA --> 2 Acetyl CoA + 2 CO2 + 2 NADH + heat
Input: 2 Pyruvate
Output: 2 Acetyl CoA*, 2 CO2, 2 NADH

*Acetyl CoA is one of the most important molecules involved in metabolism

In this reaction we have produced 2 more NADH along with 2 Carbon dioxide molecules. Our total number of NADH produced rises to 4 (2 from glycolysis and 2 from Prep step) Next the Acetyl CoA will move to the TCA Cycle

Prep step and TCA cycle
3) Krebs/TCA cycle: This is also referred to as the citrate cycle because once acetyl CoA enters the Kreb cycle it is first turned into citrate by oxaloecetate.

2 AcetylCoA + 6 NAD + 2 FAD + 2 ADP + 2Pi --> 4 CO2 + 6 NADH + 2 FADH2 + 2 ATP + 2 CoA + heat

Input: 2 AcetylCoA
Output: 4 Co2, 6 NADH 2 FADH2, 2 ATP

NADH count before TCA cycle: 4
NADH count after TCA Cycle : 4 + 6 = 10

So far we have produced 10 NADH, 6 CO2, 4 ATP and we have only used glucose. We still have yet to use oxygen and we are still missing 32 ATP and water. 

4) Electron Transport Chain

10 NADH + 2 FADH2 + 32 ADP + 34 Pi + 6 O2--> 32 ATP + 10 NAD + 2 FAD + heat

Input: 10 NADH, 2 FADH2, and 6O2
Output: 32 ATP and Water

This is the part of cellular respiration where the NADH and FADH come in to play because NADH and FADH are high electron carriers. In the ETC, electrons are passed along from one molecule to another and energy is given off to make ATP. This done by the electron carriers taking the before mentioned high energy electrons to the folds of the inner compartment of the mitochondria. The enzymes then take these high energy enzymes and then pass them down the transport line. As the electron is passed, H+ ions are pumped out to the outer compartment of the mitochondria from the NADH. The H+ ions then move back into the inner compartment through ATP synthase channel protein that will then catalyze the ADP reaction to create ATP. This is driven through a process known as chemiosmosis.

What about the water and Oxygen? ah yes I did not forget... oxygen is used in the electron transport chain to assist the electron movement and the by product of the reaction being water. So the math should add up in the end but as I mentioned in the first equation some books will say 38 ATP while others will say 36 ATP, both of which still work out in my opinion.

In addition to glucose, our bodies can also oxidize Fatty acids to produce ATP through a process known as Beta Oxidation. I know the point of this discussion is the fate of glucose but Beta oxidation will become extremely relevant shortly so it will need to be discussed and I felt it appropriate to mix it into this oxidation section. Protein can also be used as well to produce ATP but it's not normally a dominate substrate so we will put aside that discussion point for now. (Ethanol can be used too but no one is consuming a high ethanol diet unless you are an alcoholic in which case you probably not reading this...)

Beta Oxidation: is very similar to glucose oxidation so review the above reactions if you are still confused about cellular respiration.

--> Just like Glucose and its Glucose transport proteins, Fatty acids also have transport proteins that are called Fatty Acid Transport Proteins (FATP) and they assist fatty acids into the cell. Once inside the cell, a Co-A is added onto the Fatty acid by fatty acid CO-A Synthase, forming long chain Acetyl Co-A

--> CPT1 then converts the Acetyl Co-A to acetyl Carnitine which then allows the fatty acid to transverse the mitochondrial membrane via CAT in exchange for carnitine

--> Inside the membrane CPT2 converts Acetyl Carnitine back to Long chain Acetyl CO-A

Let's stop here and understand why this step is so important.

One aspect we will get into later but is important now is that fatty acids are toxic to our cells in certain amounts. Which is why are bodies will store this excess in lipid droplets and create more/expand the adipose tissue. Protection from ourselves. The first way it protects us is by making sure that fatty acids do not enter Beta Oxidation in excess. This is regulated through the Carnitine shuttle. Think about it... why would convert Acetyl Co-a to acetyl carnitine just to covert it back to Acetyl Co-a? seems inefficient right? give up?

The answer: this is rate limiting step to protect us

Selective transport is one way to make sure you only send fatty acids to mitochondria when they are needed for beta oxidation.

--> The Fatty acid then enters the Beta Oxidation Pathway which results in one Acetyl Co-a for each cycle of Fatty acid Oxidation

--> The Acetyl CO-A then enters the TCA cycle producing NADH and FADH

--> which then finally enters through the electron transport chain to produce ATP.

Be aware that even though beta-oxidation produces more ATP then Glycolysis it involves taking in more oxygen.

As we can see from the above, the oxidation of fats, proteins and glucose are very similar and have the common element of producing Acetyl Co-A in their catabolism (This similarity will be mentioned many times in later sections so remember this as well). Additionally, what we need to remember is that not all of these substrates can be used at the same rate or time for our energy needs. Meaning that...

 When we eat a high carbohydrate meal -> Fat oxidation will go down and Carbohydrate oxidation will increase for a brief period of time and conversely if we eat a high Fat Meal - > Our bodies will use fat for fuel, not necessarily increasing total fat oxidation as much as carbohydrates do with their substrate, and carbohydrates oxidation will decrease (17).  Our bodies can use either substrate as a fuel source for cellular respiration and adjust according to what we are feeding them... This is a universally accepted fact amongst the scientific community. Remember this as it will come into play in a later section...

Lets now turn our attention towards the storage sites for Glucose as glycogen or Triglcycerides through processes known as Glycogenesis and lipid synthesis

1) Glycogenesis

The main site for Glucose storage is as Glycogen in the muscle and liver, with the kidney and intestines adding minor storage sites. 10% of the weight of the liver is glycogen which then makes the liver the highest specific content of any body tissue for glycogen storage. While the muscle has a much lower amount of glycogen per unit mass of tissue, The total mass of muscle is much greater than the liver. Thus the total muscle glycogen stored is about twice as much as the liver.  (We have already discussed the Liver in the above section so we just focus on the muscles in this subsection. ) Also note that not all the muscle in our body can store glycogen, many of them require a steady stream of glucose in order to meet their energy needs.
--> Similar to Liver Glycogenesis. The Glucose will enter the cell via Glut-4 in the muscle (both fast twitch and slow twitch) in which the Glucose will enter into what? yes that is right glycolysis. In this phase, Glucose is Phosphorylated to Glucose-6 Phosphate via hexokinase

--> G-6-P is then isomerized to Glucose 1-phosphate

--> G-1-P then reacts with UTP to create UDP which basically takes away the water to yield glycogen. To put it more simply, glycogen synthase works to convert excess glucose one by one into a polymeric chain for storage as glycogen. Some of the glucose in this reaction will be oxidized directly to ATP (2 ATP for each glucose moiety that goes through anaerobic glycolysis), pyruvate, and CO2 but the majority is stored for later use.

When we start exercising we generally will release our glycogen stores in our muscles for energy because our workload has increased. When this happens our bodies will first split the Glycogen in the muscle with an enzyme called glycogen phosphorylase to bring it back to Glucose-1-Phosphate (note that this process does not require ATP) and then to G-6 P which can then enter glycolysis to be oxidized to pyruvate(lactate and CO2 as well) and produce ATP (3 ATP).
Glycogen muscle stores can vary in individuals due to the amount of muscle any one person can have. Essentially, the more muscle you have, the more glycogen you require to perform intense exercise:

"The energy demands of exercise dictate that carbohydrate is the preferred fuel for exercise intensities
above 65 percent of VO2 max —the levels at which most athletes train and compete. Fat oxidation cannot supply adenosine triphosphate (ATP) rapidly enough to support such high-intensity exercise."- (18)

"Muscle glycogen and blood glucose provide about half of the energy for moderate intensity exercise (65) percent of VO2 max) and two-thirds of the energy for high-intensity exercise (85 percent of VO2
max). It is impossible to meet the ATP requirements for high-intensity, high-power output exercise when these carbohydrate fuels are depleted (Coyle, 1995). The utilization of muscle glycogen is most rapid during the early stages of exercise and is exponentially related to exercise intensity (Hargreaves, 2006; Jacobs and Sherman, 1999)." - 

"There is a strong relationship between the pre-exercise muscle glycogen content and the length of time that exercise can be performed at 75 percent of V02 max. The greater the athlete’s pre-exercise glycogen content, the greater the endurance potential (Burke, 2006). Bergstrom and associates compared the exercise time to exhaustion at 75 percent of VO2 max after three days of three diets varying in carbohydrate content (Bergstrom, et al.,1967)." - 

2) Lipid Synthesis or more commonly known as Lipogenesis

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As the name implies, Lipogenesis refers to the biosynthesis of lipids not the increase in adipose tissue. Adipogenesis is the actual growth of adipocytes, please don't confuse the two or use them interchangeably for two reasons:

-- Lipogenesis does not necessarily lead to adipogenesis. meaning just because we make new fat does not mean it will increase adipocyte growth. The new fat can be used for other processl depending on the state of the organism and it's current needs.

-- Adipogenesis can occur even without the activation of substantial lipogenesis

"Lipogenesis encompasses the processes of fatty acid synthesis and subsequent triglyceride synthesis, and takes place in both liver and adipose tissue (Figure 1). Lipogenesis should not be confused with adipogenesis, which refers to the differentiation of pre-adipocytes into mature fat cells."(19)

 De novo lipogenesis indicates the synthesis of new lipids/Fatty Acids from various non fat precursors, mainly glucose but also from amino acids and ethanol. Basically, any substrate that produces Acetyl Co-A during its Catabolism is susceptible to be converted to fatty acids in the intermediary metabolism. (Remember from the above how after glucose goes through glycolysis the pyruvate is converted to Acetyl Co-A to enter the Kreb's cycle, see picture to the right.) So how exactly does this process take place?

Ever time we eat a carbohydrate meal some amount of Fatty Acid Synthesis will take place in the cytoplasm (outside the mitochondria) as cells will take the carbon from the sugar and make into the carbon of the fatty acid.( see image to the right). In order for fatty acids to be made we require 4 main ingredients

-- AcCoA
-- CO2
-- ATP.

--> First,  Glucose will enter glycolysis and be converted to pyruvate which will then enter into the mitochondria and into the prep step to make Acetyl Co-a once acetyl CoA enters the Kreb cycle it is first turned into citrate by oxaloecetate and then generates ATPs, NADH Etc

--> once the kreb's cycle has pumped out a substantial amount of ATP and NADH, the top enzyme Isocitrate Dehydrogenase will be inhibited and thus the citrate will be shuttled out of the mitochondria back out into the cytoplasm via the citrate shuttle

--> Once in the cytoplasm, the Citrate is then made into Acetyl CoA where Insulin stimulates the enzyme Acetyl carboxylase which also requires CO2 and ATP to attach carbon onto the Acetyl - CoA to produce Malonyl CoA

--> Then with the help of NADPH and Fatty acid synthase, the Malonyl CoA is synthesized into the end product Fatty Acid Palmitate which is the only Fatty acid which humans make from scratch, we can synthesize other fatty acids but not from scratch like the Fatty acid Palmitate (16:0)

De novo Lipogenesis takes place in the Liver and adipose tissue and there is even some evidence that a small amount takes place in the muscle (20). While the liver is seen as the main site of lipogenesis, there is still much uncertainty as to the amount of lipogenesis occurring between the adipose tissue and liver. It is because of this that many research methods have been used to study lipogenesis and have yielded conflicting results in certain respects. Regardless of the source of de novo lipogenesis whether it be liver, adipose, or muscle, many researchers have found that this is a quantitatively minor pathway for glucose disposal (21, 22232425262728)   See the Exploring The De Novo Lipogenesis Pathway Section as well.

On that same note, Protein is also very difficult to convert to fatty acids even in over feeding situations. (201,202)

This concludes Part 2, Things to gather from this section:
  • Glucose can and will be used a fuel not just stored as Fat
  • Glucose must first go through the kreb's cycle to produce ATP before it enters into "substantial" new fat making
  • Basically, any substrate that produces Acetyl Co-A during its Catabolism is susceptible to be converted to fatty acids in the intermediary metabolism
  • Our Cells can obtain fuel from many sources and will adjust given the circumstance. 
"The TCA cycle (tricarboxylic acid cycle [Krebs]) accounts for over two thirds of the ATP generated from fuel oxidation. The pathways for oxidation of fatty acids, glucose, amino acids, acetate, and ketone bodies all generate acetyl CoA, which is the substrate for the TCA cycle."

Part 3 will discuss more of the aspects involved in De novo Lipogenesis and the Biochemistry involved with the movement of fatty acids in and out of the adipose tissue.

For Part 3 Click Here

To start from the beginning click Here