Posts Tagged ‘nutrition’

This series of posts is a followup to the project that Dr. Eugene Fine and I described in our campaign at Experiment.com. as follow-up to Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we are carrying out in parallel.

The last post described the two major processes in energy metabolism, (anaerobic) glycolysis and respiration. Pyruvate is the product of glycolysis and has many fates. (Remember pyruvate and pyruvic acid refer to the same chemical). For cells that rely largely on glycolysis, pyruvate is converted to several final products like ethanol, lactic acid and a bunch of other stuff that microorganisms make in the fermentation of glucose. (The unique smell of butter, e.g., is due to acetoin and other condensation products of pyruvate). Rapidly exercising muscles also produce lactic acid.

The sudden interest in the metabolic approach to cancer stems from the work of Otto Warburg whose lab in the 1930’s was a center for the study of metabolism. (Hans Krebs was an Assistant Professor in the lab). Warburg’s landmark observation was that cells from cancer tissue showed a higher ratio of lactate to CO2 than normal cells, that is, the cancerous tissue was metabolizing glucose via glycolysis to a greater degree than normal even though oxygen was present. The Coris (Carl and Gerty of the Cori cycle) demonstrated what is now called the Warburg effect in a whole animal. Ultimately, Warburg refined the result by comparing the ratio of lactate:CO2 in a cannulated artery to that in the vein for a normal forearm muscle. He compared that to the ratio in the forearm of the same patient  that contained a tumor. Warburg claimed that this greater dependence on glycolysis was a general feature of all cancers and for a long time it was assumed that there was a defect in the mitochondrion in cancer cells. These are both exaggerations but aerobic glycolysis appears as a feature of many cancers and defects in mitochondria, where they exist, are more subtle than gross structural damage. The figure shows current understanding of the Warburg Effect.

kdforca_blog_iii_warburg_figure

What about this mechanism makes us think that  ketone bodies are going to be effective against cancer? We need one more step in biochemical background to explain what we think is going on. In normal aerobic cells, pyruvate is converted to the compound acetyl-CoA.  Acetyl-CoA represents another big player in metabolism and functions as the real substrate for aerobic metabolism. If you have taken general chemistry, you will recognize acetyl-CoA as a a derivative of acetic acid.

The reaction acetyl-CoA ➛ 2CO2 is the main transformation from which we get energy. Acetyl-CoA provides the building block for fatty acids and for ketone bodies. Conversely, fatty acids are a fuel for cells because they can be broken down to acetyl-CoA. Under conditions of starvation, or a low-carbohydrate diet, the liver assembles 2 acetyl-CoA’s to ketone bodies (β-hydroxy butyrate and acetoacetyl-CoA). The ketone bodies are transported to other cells where they are disassembled back to acetyl-CoA and are processed in the cell for energy. The liver is a kind of metabolic command center and ketone bodies are a way for the liver to deliver acetyl-CoA to other cells.kdforca_blog-iii_dec_4

Now we are at the point of asking how a cell knows what to do when presented with a choice of fuels? In particular, how does the input from fat dial down glycolysis so that pyruvate, which could be used for something else (in starvation or low-carb, it will be substrate for gluconeogenesis), is not used to make acetyl-CoA.  It turns out that acetylCoA (that is, fat or ketone bodies) regulate their own use by feeding back and directly or indirectly turning off glycolysis (in other words: don’t process pyruvate to acetyl-CoA because we already have a lot). The feedback system is known as the Randle cycle and appears (roughly) as the dotted line in our expanded metabolic scheme.

robin_map_2012-2Where we are going. In our earlier work Dr. Fine and I and our assistant, Anna Miller, found that if we grow cancer cells in culture, acetoacetate (one of the ketone bodies) will inhibit their growth and will reduce the amount of ATP that they can generate. Normal cells, however, are not inhibited by ketone bodies and the cells may even be using them. Our working explanation is that the ketone bodies are inhibiting the cancer cell through the Randle cycle. Now, normal cells can maintain energy, that is compensate for the Randle cycle, by running the TCA cycle (in fact, that is the purpose of the Randle cycle: to switch fuel sources). The cancer cells, however, have some kind of  defect in aerobic metabolism and can’t compensate.  How does this happen? That’s what we’re trying to find out but we have a good guess. (A good guess in science means that when we find out it’s wrong we’ll probably see a better idea). We find that our cancer cells in culture over-express a protein called uncoupling protein-2 (UCP2). We think that’s a player. To be discussed in Part IV.

The  SBU (Swedish Council on Health Technology Assessment) is charged by the Swedish government with assessing health care treatments. Their recent acceptance of low-carbohydrate diets as best for weight loss is one of the signs of big changes in nutrition policy.  I am happy to reveal the next bombshell, this time from the American Diabetes Association (ADA) which will finally recognize the importance of reducing carbohydrate as the primary therapy in type 2 diabetes and as an adjunct in type 1.  Long holding to a very reactionary policy — while there were many disclaimers, the ADA has previously held 45 – 60 % carbohydrate as some kind of standard — the agency has been making slow progress. A member of the writing committee who wishes to remain anonymous has given me a copy of the 2014 nutritional guidelines due to be released next year, an excerpt from which, I reproduce below. (more…)

Paris. The summer of 1848. Mobs filled the streets, building barricades just like in Les Mis. If they’d had cars, they probably would have been set on fire.  In February of that year, the King, Louis-Phillipe, had abdicated in yet another French Revolution.  There was a new government, what is called the Second Republic, but whatever it tried to do, it didn’t make anybody happy and there was more unrest. At the Collège de France, faculty complained that it had “slackened the zeal for research among all of the chemists, and all of their time … is absorbed by politics.”

Horace_Vernet-Barricade_rue_Soufflot

 Figure 1. The Revolution of 1848. Barricades on the Rue Soufflot (Horace Vernet)

Bernard (more…)

Mayor-Bloomberg-The-Littlest-Dictator--99309

My comments in answer to Jonny Bowden’s Huffington Post take on the sugar tax where he suggested that despite it’s flaws, “it’s all we’ve got.” I insisted that It’s not all we’ve got. We have the science and, in one afternoon, Bloomberg could convene a panel of scientists to evaluate presentations by all the players including me who believe that sugar is a smokescreen for not facing the importance of total carbohydrate restriction which you [Jonny Bowden], among others, have explained. Everybody should be heard. What I see is another rush to judgement like the low fat fiasco which we still have with us.

That you “have to do something” comes right out of Senator McGovern’s mouth as in Fat Head. And “deadly white substance that literally creates hormonal havoc and appetite dysregulation … promoting metabolic syndrome, diabetes, obesity and heart disease” is way outside of the bounds of science. I am not the only one to point out that Lustig’s population study represented the return of Ancel Keys.

We go with science or we don’t.

(more…)

In the last post, I had proclaimed a victory for dietary carbohydrate restriction or, more precisely, recognition of its explicit connection with cell signaling. I had anointed the BMC Washington meeting as the historic site for this grand synthesis. It may have been a matter of perception — many researchers in carbohydrate restriction entered the field precisely because it came from the basic biochemistry where the idea was that the key player was the hormone insulin and glucose was the major stimulus for pancreatic secretion of insulin. We had largely ignored the hook-up with cell-biology because of the emphasis on calorie restriction, and it may have only needed getting everybody in the same room to see that the role of insulin in cancer was not separate from its role in carbohydrate restriction. (more…)

Doctor:    Therein the patient

  Must minister to himself.

Macbeth: Throw physic [medicine] to the dogs; I’ll none of it.

— William Shakespeare, Macbeth

The quality of nutrition papers even in the major scientific and medical journals is so variable and the lack of restraint in the popular media is so great that it is hard to see how the general public or even scientists can find out anything at all. Editors and reviewers are the traditional gate-keepers in science but in an area where rigid dogma has reached Galilean proportions, it is questionable that any meaningful judgement was made: it is easy to publish papers that conform to the party line (“Because of the deleterious effects of dietary fructose, we hypothesized that…”) and hard to publish others: when JAMA published George Bray’s “calorie-is-a-calorie” paper and I pointed out that the study more accurately supported the importance of carbohydrate as a controlling variable, the editor declined to publish my letter.  In this, the blogs have performed a valuable service in providing an alternative POV but if the unreliability is a problem in the scientific literature, that problem is multiplied in internet sources. In the end, the consumer may feel that they are pretty much out there on their own. I will try to help.  The following was posted on FatHead’s Facebook page:

 How does one know if a study is ‘flawed’? I see a lot of posts on here that say a lot of major studies are flawed. How? Why? What’s the difference if I am gullible and believe all the flawed studies, or if I (am hopefully not a sucker) believe what the Fat Heads are saying and not to believe the flawed studies — eat bacon.

Where are the true studies that are NOT flawed…. and how do I differentiate? : /

 My comment was that it was a great question and that it would be in the next post so I will try to give some of the principles that reviewers should adhere to.  Here’s a couple of guides to get started. More in future posts:

 1“Healthy” (or “healthful”) is not a scientific term. If a study describes a diet as “healthy,” it is almost guaranteed to be a flawed study.  If we knew which diets were “healthy,” we wouldn’t have an obesity epidemic. A good example is the paper by Appel, et al. (2005). “Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial,” whose conclusion is:

“In the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can further lower blood pressure, improve lipid levels, and reduce estimated cardiovascular risk.”

 It’s hard to know how healthful the original diet, a “carbohydrate-rich diet used in the DASH trials … currently advocated in several scientific reports” really is if removing carbohydrate improved everything.

Generally, understatement  is good.  One of the more famous is from Watson & Cricks’s 1953 paper in which they proposed the DNA double helix structure. They said “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”  A study with the word “healthy” is an infomercial.

2. Look for the pictures (figures).  Presentation in graphic form usually means the author wants to explain things to you, rather than snow you.  This is part of the Golden Rule of Statistics that I mentioned in my blogpost “The Seventh Egg”  which discusses a very flawed study from Harvard on egg consumption. The rule comes from the book PDQ Statistics:

“The important point…is that the onus is on the author to convey to the reader an accurate impression of what the data look like, using graphs or standard measures, before beginning the statistical shenanigans.  Any paper that doesn’t do this should be viewed from the outset with considerable suspicion.”

The Watson-Crick  paper cited above had the diagram of the double-helix  which essentially became the symbol of modern biology.  It was drawn by Odile, Francis’s wife, who is described as being famous for her nudes, only one of which I could find on the internet.

Krauss, et. al. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia.

The absence of a figure may indicate that the authors are not giving you a chance to actually see the results, that is, the experiment may not be flawed but the interpretation may be misleading, intentionally or otherwise.  An important illustration of the principle is a paper published by Krauss. It is worth looking at this paper in detail because the experimental work is very good and the paper directly — or almost directly — confronts a big question in diet studies: when you reduce calories by cutting out carbohydrate, is the effect due simply  to lowering calories or is there a specific effect of carbohydrate restriction.  The problem is important since many studies compare low-carbohydrate and low-fat diets where calories are reduced on both. Because the low-carbohydrate diet generally has the better weight loss and better improvement in HDL and triglycerides, it is said that it was the weight loss that caused the lipid improvements.

So Krauss compared the effects of carbohydrate restriction and weight loss on the collection of lipid markers known collectively as atherogenic dyslipidemia.  The markers of atherogenic dyslipidemia, which are assumed to predispose to cardiovascular disease, include high triglycerides (triacylglycerol), low HDL and high concentrations of the small dense LDL.

Here is how the experiment was set up: subjects first consumed a baseline diet of  54% of energy as carbohydrate, for 1 week. They were then assigned to one of four groups.  Either they continued the baseline diet, or they kept calories constant but reduced carbohydrate by putting fat in its place.  The three lower carbohydrate diets had 39 % or 26 % carbohydrate or 26 % carbohydrate with higher saturated fat.  After 3 weeks on constant calories but reduced carbohydrate, calories were decreased by 1000 kcal/d for 5 week and, finally, energy was stabilized for 4 weeks and the features of atherogenic dyslidemia were measured at week 13.  The protocol is shown in the figure from Krauss’s paper:

The Abstract of the paper describes the outcomes and the authors’ conclusions.

Results: The 26%-carbohydrate, low-saturated-fat diet reduced [atherogenic dylipidemia]. These changes were significantly different from those with the 54%-carbohydrate diet. After subsequent weight loss, the changes in all these variables were significantly greater…(my italics)

 Conclusions: Moderate carbohydrate restriction and weight loss provide equivalent but non-additive approaches to improving atherogenic dyslipidemia. Moreover, beneficial lipid changes resulting from a reduced carbohydrate intake were not significant after weight loss.

Now there is something odd about this.  It is the last line of the conclusion that is really weird. If you lose weight, the effect of carbohydrate is not significant?  As described below, Jeff Volek and I re-analyzed this paper so I have read that line a dozen times and I have no idea what it means.  In fact, the whole abstract is strange.  It will turn out that the lower (26 %) is certainly “significantly different from.. the 54%-carbohydrate diet” but it is not just different but much better. Why would you not say that?  The Abstract is generally written so that it sounds negative about low carbohydrate effects but it is already known from Krauss’s previous work and others that carbohydrate restriction has a beneficial effect on lipids and the improvements in lipid markers occur on low-carbohydrate diets whether weight is lost or not.  The last sentence doesn’t seem to make any sense at all.    For one thing, the experiment wasn’t done that way.  As set up, weight loss came after carbohydrate restriction.  So, let’s look at the data in the paper.  There are few figures in the paper and Table 2 in the paper presents the results in a totally mind-numbing layout.  Confronted with data like this, I sometimes stop reading.  After all, if the author doesn’t want to conform to the Golden Rule of Statistics, if they don’t want to really explain what they accomplished, how much impact is the paper going to have.  In this case, however, it is clear that the experiment was designed correctly and it just seems impossible from previous work that this wouldn’t support the benefits of carbohydrate restriction and the negative tone of the Abstract needs to be explained.  So we all had to slog through those tables.  Let’s just look at the triglycerides since this is one of the more telling attributes of atherogenic dyslpidemia.  Here’s the section from the Table:

Well this looks odd in that the biggest change is in the lowest carb group with high SF but it’s hard to tell what the data look like.  First it is reported as logarithms. You sometime take logs of your data in order to do a statistical determination but that doesn’t change the data and it is better to report the actual value.  In any case, it’s easy enough to take antilogs and we can plot the data.  This is what it looks like:

It’s not hard to see what the data really show: Reducing carbohydrate has an overwhelming effect on triglycerides even without weight loss.  When weight loss is introduced, the high carbohydrate diets still can’t equal the performance of the carbohydrate reduction phase.  (The dotted line in the figure are data from Volek’s earlier work which Krauss forgot to cite).

The statements in the Conclusion from the Abstract are false and totally misrepresent the data.  It is not true as it says “carbohydrate restriction and weight loss provide equivalent…” effects. The carbohydrate-reduction phase is dramatically better than the calorie restriction phase and it is not true that they are “non-additive”  Is this an oversight?  Poor writing?  Well, nobody knows what Krauss’s motivations were but Volek and I plotted all of the data from Krauss’s paper and we published a paper in Nutrition & Metabolism providing an interpretation of Krauss’s work (with pictures).  Our conclusion:

Summary Although some effort is required to disentangle the data and interpretation, the recent publication from Krauss et al. should be recognized as a breakthrough. Their findings… make it clear that the salutary effects of CR on dyslipidemia do not require weight loss, a benefit that is not a feature of strategies based on fat reduction. As such, Krauss et al.  provides one of the strongest arguments to date for CR as a fundamental approach to diet, especially for treating atherogenic dyslipidemia.

An important question in this experiment, however, is whether even in the calorie reduction phase, calories are actually the important variable.  This is a general problem in calorie restriction studies if for no other reason than that there is no identified calorie receptor.  When we published this data, Mike Eades pointed out that in the phase in which Krauss reduced calories, it was done by reducing macronutrients across the board so carbohydrate was also reduced and that might be the actual controlling variable so we plotted the TAG against carbohydrate in each phase (low, medium and high carb (LC, MC, HC) without or with weight loss (+WL) and the results are shown below

This is remarkably good agreement for a nutrition study. When you consider carbohydrates as the independent variable, you can see what’s going on.  Or can you?  After all, by changing the variables you have only made an association between carbohydrate and outcome  of an experiment. So does this imply a causal relation between carbohydrate and triglycerides or not?  It is widely said that observational studies do not imply causality, that observational studies can only provide hypothesis for future testing. It certainly seems like causality is implied here.  It will turn out that a more accurate description is that observational studies do not necessarily imply causality and I will discuss that in the next posts.  The bottom line will be that there is flaw in grand principles like “Random controlled trials are the gold standard.” “Observational studies are only good for generating hypotheses,”  “Metabolic Ward Studies are the gold standard.” Science doesn’t run on such arbitrary rules.

I am currently teaching nutrition and metabolism to first year medical students.  The problem in this subject is the large number of individual reactions which leads students to think of the subject the way somebody described the study of history: just one damned thing after another.  I try to present the big picture and the approach is the systems or “black box”  strategy.  The method is to ask whether we can get some information just by looking at the inputs and outputs to a system even if we don’t know any of the details of what’s going on inside.  In other words, it is a way of organizing limited information.  The method is favored by engineers who are the people most unhappy with the idea that they don’t know anything at all.  First, the big principles.

Metabolism: two goals, two fuels.  

There are two major goals in human energy metabolism: First, to provide energy for life processes in the form of the molecule ATP and second, to provide glucose for those cells that require glucose (particularly brain and central nervous system) and to maintain blood glucose at a relatively constant level: too little is obviously not good but too much is also a problem in that glucose is chemically reactive and can interact with body material, particularly proteins when at high concentrations. Of course, metabolism does many things but these are the two major goals in providing energy.

A second big generalization is that in this process there two kinds of fuels: glucose and acetyl-Coenzyme A (abbreviated acetyl-CoA or sometimes written as acetyl-SCoA; the S, which is meant to show that the compound contains sulfur, is not pronounced).

The black box of life. 

You knew what we do in metabolism even before you started reading this. Putting it into black box terms, you knew: we take in food and we take in oxygen. We excrete CO2 and water.  Somehow this gives us the energy for life as well as the material to build up components of the body.  You don’t have to know too much chemistry to figure out the important conclusion that, inside the black box, living systems use oxidation, just like combustion in a furnace. Lavoisier’s whole animal calorimeter that I described in a previous post was a beautiful real demonstration of this black box.  More technically, this is an oxidation-reduction reaction.  Oxidation, in a biochemical context, means combination with oxygen or loss of hydrogen and reduction means loss of oxygen or gain of hydrogen; we say that the (carbons in the) food gets oxidized and the oxygen gets reduced (to water).  Like the common oxidation reactions you know (combustion in a furnace or an automobile engine), this produces energy which can be used to do work. Some work is mechanical work — moving muscles — but most of the energy is used for chemical: work making body material and keeping biological structures intact and generally keeping things running.  The medium of energy in metabolism is the chemical reaction of synthesis and breakdown of the molecule ATP.  Textbooks frequently refer to ATP as a “high energy molecule” but it is not the compound itself but rather the reaction (synthesis and breakdown (hydrolysis)) that is high energy.  For the moment, we can think of ATP as the “coin of energy exchange in metabolism.”  A heavy-duty thought concept: the challenge for biochemistry historically was to explain how the energy from an oxidation-reduction reaction could be used to carry out the synthesis of ATP which has a different mechanism (phosphate transfer).  The process is called oxidative phosphorylation and was only figured out about fifty years ago.

So again, our two goals in human metabolism: Make energy in the form of ATP and maintain a pretty much constant level of blood glucose for those cells, brain and central nervous system, that require glucose (the brain can’t use fatty acids as a fuel).

Let’s look at energy production first because it is a little easier to understand.  As we look inside the black box, each of the processes uncovered will have its own degree of complexity.  In reading this you have to do what scientists do: hang in there.  Skip over the parts that seem complex and see if you can come back to them later.

The role of redox coenzymes

So, breaking into the black box, the first thing to notice is that the oxidation of food is done in steps, and that there is another player that mediates the process by coupling separate pieces: the food never sees the oxygen.  The intermediaries are called coenzymes or cofactors.  The most important oxidative coenzyme is known as NAD.  It’s always referred to by the acronym, but if you’ve had some organic chemistry and you’re curious, NAD stands for nicotinamide-adenine-dinucleotide; the structure is shown in the figure and the action end of the molecule is indicated. NAD coenzymes are derived from the vitamin niacin.  So   what happens in metabolism is that food is oxidized by NAD+ (the oxidized form of NAD) and the product, NADH (the reduced form) is re-oxidized by molecular oxygen. Although it is still just as we thought (food+oxygen-in, CO2+water-out), the oxygen never sees the food.   Why do we do it this way?  If we did it all in one big blast like an automobile engine, we would have little control over it and we would not be able to capture the energy in a usable chemical form.

It’s easiest to start with glucose, a six-carbon compound. The early steps in metabolism involve a process known as glycolysis (sugar splitting) that ultimately gives you two molecules of a three-carbon compounds known as pyruvic acid. Pyruvic acid is oxidized to a derivative of acetic acid, known as acetyl-CoA. The CoA is short for Coenzyme A, a complicated molecule but, like many coenzymes is always referred to in this way so it is not important to know the detailed structure.  The compound is frequently written acetyl-SCoA to emphasize that it is a thioester (sulfur ester); again, the “S” is not pronounced.

Acetyl-SCoA is the fuel for the major NADH-producing process, known as the Krebs cycle after the major player in its discovery. Without looking into that black box too much the key compound is citric acid, which is, chemically a try-carboxylic acid (TCA) so the Krebs cycle is also called the citric acid cycle or TCA cycle; Krebs called it the TCA cycle so I will generally use that term.  The process whereby NADH is finally re-oxidized by oxygen is known as electron transport.  So, The big black boxes of metabolism:

Where do we get Glucose and Acetyl-CoA?

So far we know: most energy comes from the oxidation of acetyl-CoA and most of the glucose that provides energy does so by first being converted to acetyl-CoA. Where else can we get acetyl-CoA? We’ve taken glucose as synonymous with food but where else can we get glucose from besides the diet?

Looking ahead, the big results that will come out of opening up the black box of metabolism: 1) Acetyl-CoA also comes from fat and to a smaller extent from protein.  2) Glucose can also be formed from protein. 3) Under conditions where there is no dietary glucose (starvation, low carbohydrate diet), glucose will be made from protein or released from stored glycogen, and an alternative fuel ketone bodies will provide acetyl-CoA; ketone bodies are essentially a dimer of acetyl-CoAs and the liver makes and exports ketone bodies to other cells.  Acetyl-CoA and, therefore, glucose can be converted to fat but a major asymmetry that will have profound significance is that 4) glucose cannot be formed from acetyl-CoA.  The significance of the last statement is that: we know all too well that fat can be formed from glucose but, with minor exceptions, 5) glucose cannot be formed from fat. (Chris Masterjohn’s post “We Really Can Make Glucose From Fatty Acids After All!”
indicates the extent to which the exceptions become important but the overriding principle that has the most impact on metabolism is that you cannot make glucose from fat).
So that’s it.  You now have a blackbox view of metabolism.  I will try to open some of the boxes in future posts.

Summary of fuel sources and synthesis and looking ahead.

  1. There are, roughly speaking, two kinds of fuels: glucose and acetyl-CoA.
  2. Carbohydrates and other nutrients, fat (that is, fatty acids) and protein (amino acids) can supply acetyl-CoA.  Glucose is not required for acetyl-CoA and under conditions of low carbohydrate or low total food, fatty acids become the major source of acetyl-CoA.
  3. Not all tissues can use all fuel sources. Brain, CNS and red blood cells, for example cannot use fatty acids. Brain and CNS can use acetyl-CoA but cannot get it from fatty acids.  Red blood cells only use glucose and, to a first approximation, brain and CNS are also dependent on glucose for metabolism.
  4. Under conditions of starvation or carbohydrate restriction, acetyl-CoA can be effectively transported from the liver in the form of  ketone bodies. Ketone bodies, then, are a source of acetyl-CoA that can be used by brain and CNS.  Red blood cells are still dependent on glucose but the brain’s demand for glucose is reduced by the availability of ketone bodies.
  5. There is no dietary requirement for carbohydrate and amino acids can also supply glucose through the process of gluconeogenesis.
  6. Fat as a source of acetyl-CoA also works the other way: acetyl-CoA can be converted to fat.
  7. Whereas glucose can be converted to fat, with a few exceptions, fat cannot be converted to glucose. This will be a key idea behind carbohydrate restriction.
  8. Glucose can also be stored as the polymer glycogen.
  9. Bottom line is the limitation of “you are what you eat.” Metabolism means the interconversion of food and metabolites. Conversely, it will be critical that not everything is interconvertible. In particular, we will emphasize that you can make fat from carbohydrate but, to a large extent,  you cannot make glucose from fat.

Looking ahead on sources of blood glucose:

  1. Glucose from dietary input (referred to as the fed state; in nutrition, as the postprandial period), is depleted after about 8 hours.
  2. Glycogen is a storage/supply source of glucose.  Liver glycogen can supply export glucose to the blood, thereby supplying other tissues.  Muscle glycogen supplies glucose only for the muscle itself.  Glycogen may become largely depleted after 24 hours, depending on the conditions (exercise, for example).
  3. The third source of blood glucose is gluconeogenesis (GNG) which, as the name implies, makes glucose anew from existing metabolites. Depending on the conditions, the source of carbon may be amino acids, lactic acid or glycerol from fat metabolism.  Whereas it is sometimes indicated to be a “last ditch” source of glucose in the textbooks, it goes on all the time. The glucose it synthesizes in GNG may be used to replenish glycogen and only appear in the blood at a later time.