Sunday, September 15, 2013

The Carbohydrate Monster Under your Bed Part 1

Gary Taubes, Good Caloires, Bad Calories, Why do we get Fat, Low Carb Diet, Paleo, Carbohydrates make fat, Insulin carbohydrate theory, Blood Sugar control
"Fear doesn't exist anywhere except in the mind." - Dale Carnegie

 Fear is defined as a distressing emotion that is brought on by an impending danger, evil or pain whether or not the threat is real or imaginary. The imaginary fear being the most trifling in this instance because we are not even sure if this so called "threat" exists in the first place. For example: When I was a child, I watched the movie Halloween (one of my favorite movies to this day) and from that point onward I could never go to sleep on Halloween night again for the next several years in fear of Michael Myers coming to kill me. As I grew older, I realized something... it was just a movie and there was nothing to be afraid of. The monster under my bed, or in this case the serial killer out to get me, was nothing more than a figment of my imagination but at the time, this movie sure had me convinced that this threat was real. I bring this up because the mental fear doesn't just apply to serial killers and monsters; there is a very real fear of carbohydrates that also exists in the minds of tens if not hundreds of thousands of Americans that, in my opinion, is completely unwarranted.

Of all the nutrition myths that exist in the health community and message boards, the theory behind carbohydrates consumption leading to weight gain has to be the most debated topic amongst the common folk. There exists a lot of confusion on the Internet, as one health blog says A while another Blog says B and yet the biggest body of evidence from nutrition experts says C. So the big question becomes: Who do we believe? I personally have always found that those individuals presenting unbiased information in the most logical and rational manner usually get my vote of confidence. So, my goal with this post is to do the same...I'm just going to attempt to clear up some of the confusion surrounding this topic( carbohydrate ingestion and weight) by weighing as much evidence as possible to bring about a more rational perspective beyond just the black and white argument that is regurgitated far too often in a grossly misrepresented and overly simplistic fashion.

Essentially, the argument in it's most simplest of form that I have seen floating around the internet and heard recited by individuals in causal conversations which I am attempting to refute with this series of posts goes something...(gasp for air) like this:

Eat Carbohydrates --> Spike Blood Sugar --> Sugar Gets Stored as Fat and then you look like this:

Everybody got it?

...and the reason for this logic is pushed forward by numerous authors and health "experts" for the following reasons:

--> It is well known that the release of insulin from the pancreases leads to suppression of fatty acids in the adipose i.e body fat and an increase in fat uptake.

--> Because of this, it has been hypothesized that elevated insulin causes obesity because of it's ability to promote fat storage and stop its release.  This is a very simple connect the dots game.

--> It then leads to the logic that because carbohydrates cause an insulin spike, they are the most fattening in any amount. It doesn't matter how much, fat, protein or calories you eat as long as you stay away from carbohydrates period. Get it?

There are other claims that will be discussed as well like:

--> Carbohydrates cause cravings due to the intial spike and rapid fall in insulin
--> Blood sugar Spikes are bad
--> Carbohydrates get directly stored as fat
--> Carbohydrates caused the obesity epidemic
--> Carbohydrates are not essential like fat and protein

Pay attention as we review the basics first, I might not outright refute the above in a nice neat paragraph as this is an extremely multi-faceted issue with years of research behind it and will require thorough explanation.

The Basics of Carbohydrates

Carbohydrate -- C6 (Carbon) H12O6 (Water)

The primary role of carbohydrates in the body is to provide energy to the cells through numerous metabolic pathways.

-- Carbohydrates serve as an energy source for many living organisms and as structural elements in energy production. --

While it is not "essential" to consume carbohydrates because your liver can synthesis glucose from various sources, that will not be the main focal point of this discussion as this will be discussed in a latter section.

To start with: There are three main Carbohydrate classes listed below that I will now describe in further detail in terms of what they are, how they are metabolized, and where they are found in our food supply.

1. Monosaccharides
2. Oligosaccharides
3. Polysaccharides

1) Monosaccharides meaning "mono" one and "saccharide" being sugar. The most common monosaccharides in the diet being:

+ Glucose:

 Glucose is found in many foods (fruits, vegetables, starches, milk etc) and it is primarily associated with blood sugar because when diabetics are measuring their blood sugar, they are actually measuring their blood glucose levels. Almost all dietary carbohydrates will be converted to glucose through numerous metabolic pathways and our bodies go to great lengths to keep our blood glucose levels in constant homeostasis. 


 I do not want to go into too much detail on this particular sugar in this post as I have previously written an article on this topic. This sugar is commonly found in fruits and sweeteners like HFCS, Table Sugar, Honey etc

 This sugar being that from dairy sugars and it is mainly found in milk and other dairy products. Just like Fructose, this sugar must also be metabolized in the liver through several metabolic pathways (1)

2) Oligosaccharides meaning "Several" and refers to any carbohydrate chain between 2-10 molecules long. It is basically a bunch of monosaccharides bonded together but there are only 2-10 of them in a chain. The main Oligosaccharides found in our diet are Disaccharide ( meaning two sugars) and below I have listed the most commonly consumed ones:

+ Sucrose = Glucose + Fructose:
This is commonly found in fruits, vegetables, and caloric sweeteners.
+ Lactose = Glucose + Galactose
This is commonly found in dairy products

+ Maltose = Glucose + Glucose
This is found most notably in premium malt beverages i.e Beer

3) Polysaccharides meaning "many" sugars are sugars which can range anywhere from hundreds to thousands of sugars bonded together. In the human diet these are what are more commonly known as starches like potatoes, beans, grains, and along with certain vegetables and fruits. Starches contain both amylose and amylopectin and the amounts of these two sugars in different starchy foods will vary.

Starch: Plants store glucose as the polysaccharide starch. The cereal grains (wheat, rice, corn, oats, barley) as well as tubers such as potatoes are rich in starch. Starch can be separated into two fractions--amylose and amylopectin. Natural starches are mixtures of amylose (10-20%) and amylopectin (80-90%). -(1)

Amylose forms a colloidal dispersion in hot water whereas amylopectin is completely insoluble. The structure of amylose consists of long polymer chains of glucose units connected by an alpha acetal linkage. All of the monomer units are alpha -D-glucose, and all the alpha acetal links connect C # 1 of one glucose to C # 4 of the next glucose. -(1)

One unique aspect of starch being that the digestion of starches first takes place in the mouth and then it is further broken down in the stomach. For example: try putting a saltine cracker on your tongue and notice how it breakdowns rather rapidly while a piece of beef jerky will not demonstrate the same effect.

Technically speaking, Glycogen is a polysaccharide and we commonly refer to it as the storage form of glucose in humans. Although we do not consume glycogen in our diet from the food we eat it, it is still of great importance and we will discuss its role in a later section.

Figure 3.1 from Advanced Nutrition 5th edition

Understanding the Organs that Regulate Blood Sugar

When we eat carbohydrates(or even food in general) many actions takes place in our body. I will try to discuss as many of these actions as possible but be aware that I may not discuss some concepts as this series of posts would run too long.

 We already know what blood sugar is right? It's basically the amount of glucose we have circulating in our blood and the amount of glucose will change through out the day. Blood sugar usually being the highest after we eat and the lowest upon waking in the morning. Typically, doctors will measure our fasting blood sugar and if it is over 110 mg/dsl then they will let us know that we are in pre-diabetic range or if we take a Oral Glucose Tolerance test and it is over 140 mg/dsl they might use that as a marker as well (I will discuss why this can be problematic assessment method in a latter section)

So how much actual Glucose is 80 MG/DL (milligrams per deciliter) ? Well lets do the Math. 80 mg/dl x 10 dl/L (L=Liter) = 800 mg/L then multiple by 1/1000 g/mg (grams per milligrams) = .8 G/L, there is approx 5 liters of blood circulating through out the human body so we would then multiple by 5 liters and we get 4.0 Grams which equivalent to 1 teaspoon of sugar

Either way, the point of these examples is to demonstrate that blood sugar control is an important homeostatic mechanism and there are few systems in the body that are as tightly controlled as blood sugar because if we have too much blood sugar in the system it can cause damage and too little will lead to our demise. We want to keep our blood sugar in a optimal range and that range will vary from person to person. So what is/are the mechanism/mechanisms that control our blood sugar???

From a technical standpoint there are many mechanisms that can alter our blood sugar levels, However ,Please excuse my over simplicity here, the two main organs regulating blood sugar are the liver and the pancreas. Both of which will be discussed in this section:

The Pancreas

The Pancreas is located deep in the center of the abdomen and is surrounded by numerous important structures and blood vessels. The pancreas acts in two separate ways (endocrine and exocrine) although please note that it is the coordination of these different components in the organ that allow for a harmonious regulatory feedback system for digestion and hormone secretion.

+ The Exocrine Pancreas: Our Pancreas secretes approx 500 to 800 ml isosmotic Pancreatic juice which consists of Acinar and duct secretions. The Acinar cells synthesize enzymes such as amylase (starch digestion), Proteases (protein digestion),  and Lipase (Fat digestion). In addition to the enzymes,  bicarbonate is combined with water to create the final pancreatic juices which is then released in to the duodenum to assist in digestion. (99% of the pancreatic mass is concerned with exocrine function)

 + The Endocrine Pancreas: A very small cluster of cells called the islets of Lanerghans make up the remaining 1% of the mass of the pancreas. There are over 1 million islets of Langerhans in a normal adult pancreas and they vary greatly in size. The Islets contain roughly 3000 to 4000 cells of five major types:

--1) Alpha Cells secrete Glucagon and are located around the outside of the islet ( remember this for later)
--2) Beta Cells make up 70% of the Islet mass and secrete Insulin, C peptide, and Amylin. They are located in the middle of the Islet ( see picture to the right)
--3) Delta Cells secrete Somatostatin and are located throughout the islet
--4) Epsilon Cells secrete Ghrelin
--5) PP cells secrete PP

The cells that get the most attention being what? Yes that is correct, the Beta Cells are going to get the attention here because they produce what? insulin!! the most hated protein hormone of the last couple decades.

-- Glucagon --

 Before we discuss how and why Insulin is secreted, I would first like to discuss the role of glucagon. So what is glucagon? Glucagon is a protein hormone containing 29 amino acids that are secreted by the Alpha cells and starts off as Pro-Glucagon and then eventually leaves the Alpha cells as Mature Glucagon. Glucagon acts mainly on the liver via receptor sites on the hepatocytes. Essentially Glucagon has the exact opposite effect of insulin; It increases Gluconeogenesis, Glycogenolysis  and Ketogenesis to keep our blood sugar from dropping too low and creating hypoglycemia.

"Studies to elucidate the physiological role of glucagon in humans have been advanced by the availability of somatostatin. Isolated deficiency of glucagon produced by suppression of glucagon and replacement of insulin in post absorptive man produce a marked decline in net hepatic glucose production (18) to about 30% of normal and it is not corrected by the glycogenolytic action of catecholamines that rise in response to hypoglycemia (7). Therefore, basal amounts of glucagon are essential for the maintenance of normoglycemia and a physiological role for glucagon is to prevent hypoglycemia." (38)

During prolonged fasting glucagon acts by increasing the hepatic uptake of gluconeogenic precursors i.e glycerol, amino acids, lactate etc. once liver glycogen has been depleted. In the starvation state the gluconeogenesis drive produces enough glucose for the brain to use but it is at the expense of the rest of the proteins in the human body. Normally this will only continue for about a week in a normal physiological scenario in which case the body will then switch to running on ketone bodies thereby sparing valuable proteins. The production of ketones coming from free fatty acids which is initiated by an increase in what? yes glucagon.

Glucagon's role in maintaining homeostasis is crucially dependent on the simultaneously occurring changes in insulin levels because they are constantly working together to keep blood sugar at a constant level. (see Image to the right)

So what do we do when our blood sugar is low and we need stop the release of glucagon and loss of glycogen stores? That's right, we eat something and when we eat, we secrete a protein hormone from the Beta Cells called....drum roll please...Insulin!

 -- Insulin --

Insulin starts off in the Beta cells as Pre-Pro Insulin from translation, then it turns into pro insulin and the final product ends up as mature Insulin ( parts A +B) and c peptide(Part C). The Ratio is normally 1:1, that is one mature insulin to one C peptide ( this will come in handy later) The mature insulin is then stored in the Beta Cells secretory vesicles until it is needed. Technically, amylin is also secreted but we will discuss that in a different section.

This will come in handy later
So the grand question then becomes, how does our pancreas (more specifically our beta cells)  know that our blood sugar is rising?? As we eat, glucose is transported into the circulatory system and travels through the blood to the Beta Cells where Glucose transporters (remember these Gluts as these will come into play in a later section), in this case Glut- 2, assists the glucose though the gradient channel into the cell to a lower concentration. Now, you would think that when Glucose enters the Beta Cell it would automatically release Insulin right? Well not necessarily, there are some steps in between that we need to discuss.

- > First, Glucose Enters the Beta Cells Via Glut 2

- > Glucose is phosphorylated to Glucose-6 Phosphate via an enzyme called Glucokinase

- > Glucose - 6 Phosphate will then be taken into glycolysis where it will be turned into Pyruvic Acid (and some lactate)

- > Pyruvic acid will move into the mitochondria where it will go through the TCA cycle and the electron transport chain

- > that energy is then used to convert ADP to...can you guess?? yes ATP! So as the concentration of ATP goes up, the concentration of ADP will go down in the cell.(2) so far so good...

Now before we go any farther we need to discuss some other aspects of the Beta Cells. There are special types of channels located in the cell membranes of Beta cells...The two we will discuss are the Potassium and Calcium channel. Normally the Potassium channels are open and the cells are constantly losing potassium (Positive ions) and the loss of positive ions develops intracellular negativity. A resting Beta Cell usually hovers around - 70 mv however as ATP increase from the increase in Glucose entering the cell, the ATP will bind with the potassium channel and will close it. Positive Ions will begin to build up( remember Potassium is a positive ion) and the negativity of the cell will decrease to roughly -50 mv as the cell loses some of its negative polarity. This is where the Calcium channels come in. When the polarity of the cell was at -70 mv the calcium channel was closed but as the cell loses negative polarity, the Calcium channels will open. As intra-cellular calcium concentrations go up, it will stimulate the secretory vesicles (i.e insulin) and moves them toward the cell membrane thus producing Insulin(2) and don't forget c-peptide and amylin. (see the picture to the upper left)

What about other macro nutrients?  Does protein stimulate Insulin secretion? Ah an excellent question and here is the answer:

Different proteins can stimulate insulin through many different pathways, some relying on glucose, sodium, other amino acids, etc to assist in the of stimulation insulin while others have not been studied enough to know for sure what mechanisms exactly trigger insulin secretion. The most well studied proteins being L-Glutamine, L-alanine, L-Leucine(3), Arginine, and L-Glutamate to a lesser degree .

"Only a relatively small number of amino acids promote or synergistically enhance insulin release from pancreatic B-cells (13,14). The mechanisms by which amino acids enhance insulin secretion are varied. The cationically charged amino acid, L-arginine, does so by direct depolarization of the plasma membrane at neutral pH but only in the presence of glucose, whereas other amino acids, which are co-transported with Na+, can also depolarize the cell membrane as a consequence of Na+ transport and thus induce insulin secretion by activating voltage-dependent calcium channels. Metabolism, resulting in partial oxida- tion, e.g., L-alanine (3), may initially increase the cellular content of ATP, leading to closure of the ATP-sensitive K (KATP) channel, depolarization of the plasma membrane, activation of the voltage-activated Ca2+ channel, Ca2+ influx, and insulin exocytosis. Additional mitochondrial signals may be generated that affect insulin secretion (15,16). A summary of potential regulatory mechanisms with respect to amino acid–stimulated insulin secretion is illustrated in Fig. 1." -(4)
These proteins can act by either depolarizing the membrane, Increasing the amount of ATP produced via the TCA cycle directly or increasing pyruvic acid and Acetyl COA. However, The most important point to remember here is that protein can stimulate insulin release(5, 6, 7, 8) and sometimes even more so than some carbohydrates(9) as we will discuss in a later section.

-- Amylin --

While most of us have generally heard of the two above hormones in our health research ( insulin and Glucagon) a lesser known hormone, i.e Amylin, also plays a role in glucose and metabolic regulation.

Amylin is a 37 amino-acid peptide produced by the beta cells and responds to many of the same stimuli as insulin. Amylin has many actions which are mostly exerted in the regulation of fuel metabolism by halting glycogen and stimulating glycogenolysis and glycolysis.

Just remeber for now that Amylin is a very important peptide that plays an essential role in the formation of type 2 Diabetes. I will go into further detail in a latter section on this topic.

--Incretins --

The last substances I would like to discuss that can also increase the secretion of insulin are the gatro intestinal peptide Hormones, two examples being Glucagon Like Peptide-1 (or GLP -1 for short) and glucose-dependent insulinotropic peptide. These hormones are released from the epithelial cells of the Gastor intestinal tract and are part of a group of gastro intestinal hormones called incretins. Incretins have been known to increase insulin response based on meal size and macro nutrient proportion, as well as increase satiety, decrease hunger and slow gastric emptying. (10) 

"The incretin effect” designates the amplification of insulin secretion elicited by hormones secreted from the gastrointestinal tract. In the most strict sense, it is quantified by comparing insulin responses to oral and intravenous glucose administration, where the intravenous infusion is adjusted so as to result in the same (isoglycemic) peripheral (preferably arterialized) plasma glucose concentrations (177, 237). In healthy subjects, oral administration causes a two- to threefold larger insulin response compared with the intravenous route. It is, however, important to realize that the effect varies with the size of the glucose challenge, being small with, e.g., 25 g and very large with 100 g of glucose (208). In these dose-response experiments, the plasma glucose excursions were identical despite the increasing glucose loads." -(11)

"...The increase in insulin secretion is mainly due to the actions of insulinotropic gut hormones (177, 178). The same gut hormones are also released by mixed meals, and given that their postprandial concentrations in plasma are similar and that the elevations in glucose concentrations are also similar, it is generally assumed that the incretin hormones are playing a similarly important role for the meal-induced insulin secretion." (11)

To give an example: a very interesting paper I just read, talks about the effect that dairy foods have on incretins... Take a look:

Name: Glycemia and insulinemia in healthy subjects after lactose equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins

"Milk products deviate from other carbohydrate containing foods in that they produce high insulin responses, despite their low GI." (12) 

"Interestingly, there is epidemiologic evidence suggesting that overweight subjects with a high intake of milk and dairy products are at a lower risk of developing diseases related to the insulin resistance syndrome.". (13) (14)*
* Link to original text

Yes, you are reading that correctly, despite diary products relatively low place on the Glycemic index it can create a high insulin response. It has even been reported that people consuming a fair amount of dairy are at lower risk for developing IR.... But why? Well that is multi faceted answer so I will just focus on the incretin effect in this paper and circle back to the dairy delema in a later part of this series of posts

"Instead of being related to amino acids per se, the insulinotropic effect of milk proteins might be related to bioactive peptides either present in the milk or formed during digestion in the small intestine. A possible pathway in the case of peptides may include the activation of the incretin system (24). Previous studies showed a protein-stimulated insulin response in type 2 diabetic patients (40) and healthy subjects (41) that did not parallel the rise in amino acids in the circulation, which suggests the involvement of the incretin hormones in protein-stimulated insulin release." (13) 

"Conversely, Schmid et al (22) concluded that gut factors are only of minor importance and that amino acids are the major insulin secretagogue in the absence of carbohydrates. Whereas the GLP-1 responses to all of the test meals were similar in the current study, whey induced a particularly elevated GIP response."(13)

While incretins can increase insulin, it appears from the above that they are not a significant source for stimulating insulin release and may play a more important role in other systems in the body, ( effects on ghrelin, leptin etc)

For a more in depth analysis please view the following: Insulin Synthesis and Secretion Part 1 and Insulin Synthesis and Secretion Part 2 (The guy has a funny accent but he makes the material very easy to understand IMO)

 To summarize the information so far: we now know that effects of Insulin, Amylin, and Glucagon are secreted/inhibited in response to a meal. The substance that can effect the mechanisms by which these hormones are secreted/inhibited can vary widely from glucose and amino acids to GLP-1 and other Incretins located in the gastrointestinal tract.

The next organ we need to discuss plays just as big of a part in blood sugar regulation as the pancreas...can you guess what it is?

The Liver

The liver is the largest organ inside your body and is located in the upper right hand side of the abdomen behind the ribs. There are over 300 billion specialized cells in the liver that are connected together by a complex system of Bile ducts and blood vessels. 

Amazingly enough even if part of the liver is removed or even if 75% of it is diseased, it can actually grow back. The liver is not only one of the most resilient organs but it is also one of the most vital parts of your body when it comes to blood sugar regulation. Although, for one reason or another it gets overlooked in the insulin resistance puzzle but we will get to that later. From a technical standpoint, the liver has over 500 functions but here is quick summary of the most important functions:

- Stores Iron, Sugars, and Vitamins to help give your body energy
- Controls production and removal of cholesterol
- Clears your blood of drugs, waste products, and other toxins
- Makes clotting factors to stop excessive bleeding
- Produces immune factors to help battle infections
- Releases Bile to assist in digestion and absorption of nutrients

 The functions were are going to focus on in this post are going to pertain to blood sugar only. Now remember from the above that the pancreas is basically unresponsive to insulin and is primarily responsive to blood glucose concentrations. In contrast, the liver is responsive to insulin and in addition the liver is also one of the main storage sites of glucose in the body. 

 Glucose is able to transverse membranes by what? That's right Glucose transport proteins like we discussed with the pancreas These Glut Carriers in the liver are what we call bidirectional carriers allowing glucose to move in and out of the cells. (see picture to the right) When blood sugar is high, the liver accelerates the uptake of glucose into the liver for storage. The liver will take up roughly 1/3 of the absorbed glucose after carbohydrate absorption to manufacture Glycogen. This is done by the following mechanisms:

--> Glucose is Phosphorylated to Glucose -6 Phosphate via Glucokinase. The liver has a High Km for Glucokinase and this ( plus some other factors) explains why more G-6-P is transported and retained in the liver with increased glucose availability. This is one reason why there is much more substrate control in the liver than in the muscle and adipose tissue.

--> Moving forward; once we arrive at G-6-P, it is isomerized to Glucose -1 Phosphate by phosphoglucomutase

--> G-1-P reacts with UTP to create UDPGLc

--> Glycogen synthase catalyzes the formation of a glycoside bond between C1 of the activated glucose of UDPGlc and C4 of a terminal glucose residue of glycogen, liberating uridine diphosphate (UDP)(15)

--> The final step is done by a branching enzyme to assist in the transfer of a 1-4 chain to a neighboring chain to form a 1-6 linkage. Glycogen being the final product.

When blood sugar is low, the liver accelerates glucose production to stabilize blood sugar and one way this can be accomplished is by the breakdown of the hepatic glycogen stores. There are two hormones that can stimulate the breakdown of hepatic glycogen...those being Glucagon (which is stimulated by the alpha cells of the pancreas) and epinephrine i.e adrenaline (this hormone is secreted during exercise by the adrenal glands) but the process to liberate glycogen is not the reverse action of glycogen is a separate pathway. Through a process called Glycogen phosphorylase along with some De-branching enzymes, Glycogen can be completely broken back down to G-1-Phosphate. Luckily the reaction catalyzed by phosphoglucomutase is reversible thus bringing us back to G-6-P. In the Liver, but not in the muscle, there is a specific enzyme called Glucose-6-phosphatase, that hydrolyzes glucose G-6-P back to glucose. Glucose is then exported via Glut-2 and finally leading to an increase in the blood glucose concentration. This is what makes the liver special compared to the other storage places for glucose. In short, the liver is the only organ that can replace blood sugar used by other organs.

Blood sugar regulation, Paleo blood sugar, paleo carbohydrates, Paleo sugar, Insulin Spike, Insulin fat storage, Fat head, insulin resistance
Reverse Glycolysis
In addition to the breakdown of hepatic glycogen stores, the liver can produce glucose from precursors of pyruvate, for example: lactate via process known as gluconeogenesis. Gluconeogenesis can take place in two places in the body, the Liver and the Kidneys with the majority(90%) coming from the Liver. Gluconeogenesis uses many of the same reactions as glycolysis but in a somewhat reverse order.  (see Picture to the right, it is not completely identical) As stated before, Any precursor which can be converted to pyruvate can eventually be converted to glucose via gluconeogenesis. These precursors include but are not limited to all amino acids (expect for Leucine and Lysine), Lactate, Alanine, propionate, a-ketoglutarate, oxaloacetate, glycerol, etc coming from either parts of the brain, muscle tissue (cori cycle), adipose tissue, and/or red blood cells. (see picture below).However, be aware that the production of glucose from these precursors is a very energy expensive process:


Input: 2 pyruvate + 4 ATP + 2 GTP +2 NADH

Output: glucose + 4 ADP + 2 GDP + 2 NAD+  6 Pi


Input: Glucose + 2 NAD+  2 ADP + 2 P

Output: 2 pyruvic acid + 2 ATP + 2 NADH + 2 H+

Energy Cost = 6 high energy bonds used per glucose synthesized in gluconeogenesis, four more than produced in glycolysis.

Putting it all together: Upon waking we are in a fasted state and glucagon levels are high in a normal physiological scenario...why is this? Remember that when we have not eaten in awhile (i.e the fasted state) we have increased production of glucose via gluconeogenesis and glycogen breakdown. So remember that when Glucagon is released from the pancreas it communicates with the liver to breakdown glycogen and increase gluconeogenesis in order to increase blood glucose to stabilize blood sugar. But then we eat our first meal(which for practical purposes is a mixture of fats, carbs, and protein) and upon ingestion we have the increase of insulin and blood glucose, decrease of glucagon, and increase of incretins. At the same time the liver stops breaking down glycogen and instead takes in blood glucose to store glycogen to once again keep blood glucose stable. This will become important in the next discussion points...

"Other than Alzheimer’s disease, type II diabetes is the most prevalent in modern society with currently 346 million diabetic people world-wide, and the World Health Organization (WHO) predicts that the number of deaths that result from this disease will double between 2005 and 2030 (19)" -(16)

For Part 2 Click here