Posts Tagged ‘diet’

Our 2015 paper, Low-carbohydrate diets as the first approach in the treatment of diabetes. Review and evidence-base, summarized the clinical experience and the research results of the 26 authors. Meant to be a kind of manifesto on theory and practice, the first version of the manuscript was submitted to a couple of major journals under the title “The 15 Theses on…” harking back to Martin Luther’s 95 Theses. A critique of Church practices, particularly indulgences — for a few bucks, we get you or your loved ones out of purgatory — the Theses were supposed to have been nailed by Luther to the door of a church in Wittenberg. Our MS was rejected by BMJ and New England Journal although, like the original 95, it did not seem particularly radical — The American Diabetes Association (ADA) acknowledges that dietary carbohydrate is the major source of high blood glucose and most of our points of evidence were based on pretty solid fact.  Anyway, somebody suggested that we were, in effect, trying to nail our low-carbohydrate paper to the door of the ADA and, in the end, we changed the name to “evidence base” and it was ultimately published.

Until recently, I had not noticed the extensive parallels of the current low-carbohydrate revolution with the Protestant Reformation. The recent imperious and rather savage actions of professional organizations, notably two in Australia, the DAA (Dietitian’s Association of Australia) and AHPRA (Australian Health Practitioner Regulation Agency) in clamping down on their own members for deviation from orthodoxy brought out the similarities. Unlike Luther, who felt that the church really needed his help in getting abuses straightened out, Jennifer Elliott, a dietitian with an established practice of 30 years and Gary Fettke an orthopedic surgeon, thought that they were just doing their job and that, however, non-standard, the low-carbohydrate diets that they recommended for people with diabetes, was far from heresy. Because of the ties between government health agencies, Jennifer ultimately lost her job and Gary is under the bizarre order not to recommend diets to his patients because, as an orthopedic surgeon, there is “nothing associated with your medical training or education that makes you an expert or authority in the field of nutrition, diabetes or cancer.” (Those of us who are actively trying to upgrade the medical curriculum would question which part of the medical profession has such expertise or authority). Dr. Fettke’s training does, however, allow him to perform amputations which have diabetes as its greatest cause, second only to accidents. In any case, offering low-carbohydrate diets to patients has long been perceived as a threat by establishment medicine.  While their claims to control the epidemics of obesity and diabetes has been at the level of offering reduction of time in purgatory, the medical establishment has largely responded to criticism by delaying or preventing publication and refusing to fund research. The direct attacks on practitioners is new. There are several instances but the Australian cases distinctly represent desperation.

diet_luther_worms_vonwerner_1877crop

Luther at the Diet of Worms.

History of religion remains one of the gaps in my undergraduate liberal education and I was unfamiliar with the dramatic events surrounding Luther’s mission. The sixteenth century was a brutish time and I should have guessed how violent and oppressive would have been the response of the Catholic Church to Luther’s suggestions for improvement. After all, if you insisted on the word of the Bible rather than the word of priests, indeed, if you wanted direct access to a Bible in your own language rather than in Latin, then everybody could be their own savior. Being burnt at the stake was standard punishment for such heresy. We all know about Galileo’s brutal treatment and his being forced to recant his heliocentric theories, although at some point, he supposedly muttered, under his breath, “eppur se muove.” (It (the earth) does move anyway). That was almost a century after Luther’s protest and the danger was even greater in 1521. Luther, however, was a madman and refused to recant. Ultimately, he faced a trial at the Diet of Worms. (Contrary to popular opinion, “Diet” is an English word and means assembly; the German is Reichstag; Worms is in Germany, about 60 kilometres from Frankfurt-am-Main, and is pronounced “Vorms,” to rhyme with “norms,” but the joke is widely made, even by Shakespeare: see end of this post). At The Diet, Luther got off because a unanimous vote was required for conviction. He had an inside man, Frederick the Wise, the elector (as local political leaders were known) in his province.  Frederick seems to have thought that Luther was good for tourism (and probably helped get the Church off his back). Of course,“not guilty,” doesn’t mean innocent and, as for sex-offenders in our day, you could get killed in the street anyway and the authorities would understand. Frederick had him “kidnapped,” disguised him as an aristocrat with the alias Junker Jörg and he went to the mattresses in a Castle in Wartburg for a year until it all blew over. Lucas Cranach the Elder painted a portrait of Jörg, possibly to let followers know that Luther was still alive.

575707-1449742854         Junker Jörg aka Martin Luther.

Heresy down under

So what had the Australian health professionals done to arouse the wrath of the “Church”? Not much. Jennifer Elliott has more than 30 years of experience and is the author of the excellent book, Baby Boomers, Bellies & Blood Sugars  which is distinguished by its straight-forward practical approach and does not seem to tweak anybody’s beard. In fact, she was not really accused of any specific thing although the message was clear: low-carbohydrate high fat (LCHF) diets are forbidden. Trying to help out, I sent an email message to Claire Hewat, head of DAA. I attached the twelve-points of evidence paper and I explained our position. I pointed out that “Ms. Elliott seems quite upset and genuinely puzzled since carbohydrate restriction has been a treatment for diabetes more or less forever, certainly going back to Elliott Joslin (early twentieth century physician and authority on diabetes).”

hewat_claire11474634995-300x224        Claire Hewat, head of DAA.

I mentioned an interview with a reporter from the New York Times who could not understand the resistance to an established, successful and ultimately obvious therapy, — you don’t give carbohydrates to people with a disease of carbohydrate intolerance — and I made the case that the burden of proof should be on anyone who didn’t approve. I suggested a discussion, “perhaps an online webinar, in which all sides present their case. I and/or my colleagues would be glad to participate.” Claire’s answer was that I was “obviously not in possession of all the facts in this matter, nor can I apprise you of them as this is part of a confidential complaints process …nor is DAA afraid of debate but this is not the place for it.”

Not to digress too much, I loved the idea that I did not have the facts right but the facts were not available because they were confidential. It reminded me of watching a scene in one of the old Basil Rathbone Sherlock Holmes movies. Holmes is playing the violin and his arch-enemy, Professor Morality suddenly appears in the doorway:

Moriarity: “Holmes, I’ve come to….Well, I am sure that you can deduce why I’ve come.”

Holmes: “Yes. And I’m sure you can deduce my answer.”

Moriarity: “So that’s final?”

Holmes: “I’m afraid so.”

Most distressing remains the fact that DAA constitutes a professional dietitians’ organization which should, as in Macbeth, “against his murderer shut the door, / Not bear the knife myself.” (Is this a DAAger I see before me?)

The details of Jennifer’s case are buried in evasive legal double-talk but were obviously caused by her recommending low-carbohydrate diets to her patients with diabetes. Claire Hewat’s defense against the obvious lack of due process was that Jennifer was invited to appear before an inquiry, obviously set up along the lines of the Diet of Worm, but she refused to appear. In fact, it would have been worse than the Diet in that there were no formal charges and even Luther was afforded legal representation. There would certainly be no defenders, as Luther had in Frederick, the Wise. Most important, recanting was not an option — if it wasn’t about anything real, there was nothing to recant. (Like Luther, she probably would not have felt able to recant anyway). Jennifer declined to attend telling Claire that it appeared to be “an invitation to a beheading.” The net effect is that she lost her job and and legal recourse would likely be exorbitant.

The words

In the reformation, heresy might have meant simply owning a Bible in your native language, or really owning any Bible at all. The Church held onto the Latin versions which you did not get to see directly. Somewhat like governmental nutritional guidelines, it was not in your native language, and required an “expert” priest to tell you what’s what. The first English translation was accomplished by John Wycliffe. During the English Reformation, several people were actually executed for owning a Wycliffe Bible. I found it somewhat analogous to the persistent hatred of Dr. Atkins so long after his death, that, at some point, the Church in England had Wycliffe’s body exhumed and burnt at the stake.

Ultimately, Luther succeeded because of Gutenberg and the invention of movable type. Now you did not have to make copies by hand. Now Luther could get the word out. And he wrote the word. During his period of lying low in Wartburg, he translated the Bible into German.  And he published it. It was a big hit although the German population recognized that they had been swindled — financially as well as theologically — and history records a Peasant’s Revolt put down with great brutality. This is where we really are in the establishment’s determination to repress LCHF diets. And everybody recognizes the analog of Gutenberg’s press.

Unser Gutenberg  and the Fettke case

Our Gutenberg is, of course, the internet where technical and scientific writings, once the province of specialists, can now be viewed by many and where they can be discussed widely. Publishers of many journals try to maintain pay-walls in keeping with somebody’s observation that publishers’ function used to be to make new information available while now they work to make information unavailable.  (Many simultaneously cash in on open access which charges the authors outrageous fees). Whether the availability of scientific facts is out-weighed by proliferation of alternative facts is open to question but, on balance, we have a view, not only of the science, but of the inner workings of the health agencies that might otherwise be visible to only a few. And that’s how we have extensive access to the Fettke case and an associated Diet convened by the Australian Senate.

As reported by Marika Sboros, Fettke “cannot tell patients not to eat sugar. Why not? Because the country’s medical regulatory body, Australian Health Practitioners Regulatory Authority (AHPRA), says so….It has been investigating Fettke for more than two years now. That was after the first anonymous complaint from a DAA dietitian in 2014. Earlier this year,  AHPRA told Fettke to stop talking about nutrition until it had decided on a suitable sanction.” and — I’m not making this up — “informed Fettke that it was investigating him for ‘inappropriately reversing (a patient’s) type 2 diabetes…’”

Dr. Gary Fettke testified at an Australian Senate Inquiry on November 1. and just “by coincidence,” a few hours later, AHPRA’s 2 1/2 year investigation came to an end and Fettke was told that he would be constrained from giving nutritional advice.  In the end, this did not sit well with the Senate which undertook further hearing interrogating Martin Fletcher, the CEO of APHRA.

“Haven’t you got better things to do?”

You can see Martin Fletcher trying to defend AHPRA’s actions.  on Youtube. At 31:25, one of the Senators asked “…if a health practitionerr is advising a patient to go on a … sensible, medically-accepted diet program, why would you risk-assess that and have all guns blazing? Haven’t you got better things to do?”

One of life’s great disappointments is that when you finally corner the bad guys, they turn out to be pathetic like Saddam Hussein. They don’t break down on the stand as in the old Perry Mason episodes. It is sad but it is also hard to feel much sympathy.

diet_aphra_fletcher-1and2

Martin Fletcher, CEO of AHPRA trying to juggle the truth at the Senate hearing.

“Bread thou art…”

It was a trip to Rome, intended to deepen his faith, that ultimately contributed to Luther’s transformation. What he saw was corruption on a grand scale. The thing that really freaked him out was that the corruption and vice were coupled with a cynical disregard for religious practice: a priest going through the motions of giving the elements in the sacrament  muttered to himself “Bread thou art, and bread thou shalt remain; wine thou art, and wine thou shalt remain.”

That becomes the most distressing feature of this analogy. The quotation above, “There is nothing associated with your medical training or education that makes you an expert or authority in the field of nutrition, diabetes or cancer,” was in a letter to Dr. Fettke that continued “Even if, in the future, your views on the benefits of the LCHF lifestyle become the accepted best medical practice, this does not change the fundamental fact that you are not suitably trained or educated as a medical practitioner to be providing advice or recommendations on this topic as a medical practitioner.”

This statement that treating disease is less important than loyalty to political power stands as the greatest exposition of the need for Reformation in Medicine.

Appendix. Shakespeare on the Diet of Worms.

Hamlet has been charged by his father’s Ghost with avenging the father’s murder by Claudius, the current king. Hamlet has put on an “antic disposition” to hide his motives. At one point, mistaking him for the King, Hamlet kills Polonius, a pompous court official, who is hiding behind a wall-hanging. The king hears about it and is pissed and wants to know where the body is (Act 4,Scene 3):

CLAUDIUS: Where’s Polonius?

HAMLET: At supper.

CLAUDIUS: At supper where?

HAMLET: Not where he eats, but where he is eaten. A certain convocation of politic worms are e’en [now] at him. Your worm is your only emperor for diet. We fat all creatures else to fat us, and we fat ourselves for maggots. Your fat king and your lean beggar is but variable service—two dishes, but to one table. That’s the end.

CLAUDIUS: Alas, alas!

HAMLET: A man may fish with the worm that hath eat of a king, and eat of the fish that hath fed of that worm.

CLAUDIUS: What dost thou mean by this?

HAMLET: Nothing but to show you how a king may go a progress through the guts of a beggar.

CLAUDIUS: Where is Polonius?

HAMLET: In heaven. Send hither to see. If your messenger find him not there, seek him i’ th’ other place yourself. But if indeed you find him not within this month, you shall nose him as you go up the stairs into the lobby.

CLAUDIUS (to attendants) Go seek him there.

(Exeunt some attendants)

HAMLET: He will stay till ye come.

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.

Dr. Eugene Fine and I will described the problem as laid out in our campaign at Experiment.com. The campaign intends to follow-up 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.We got good feedback and some good questions and we want to continue the scientific interaction and keep the community intact that was started on the “lab notes” at Experiment. We will recapitulate some of the points made during the  campaign and you can “ask the researchers” in comments.

“What makes you think ketone bodies will help?”

We and others have carried out experiments that show the effects of ketone bodies on cancer cells in culture, as diet for patients with advanced cancer or as adjuncts to other modalities. Most direct experimental studies, however, must be considered preliminary and it is reasonable to ask why we thought ketone bodies might help.

The evidence supporting carbohydrate restriction, or specifically ketogenic diets in cancer remains largely indirect and speculative. Our recent perspective  summarized some of the relevant evolutionary and mechanistic factors: the central theme rests with the role of the glucose-insulin axis in promoting growth and proliferation, the predominant characteristic of cancer sells. So it has been observed for some time that patients with diabetes have higher risk of cancer. Epidemiological and other kinds of studies are generally consistent with the idea although different cancers are more or less closely associated with diabetes. Drugs employed as diabetes therapy, particularly metformin, have been found to have beneficial effects in cancer as well. Metformin reduces the risk of developing cancer although the effects on mortality are not clear cut. We made the case, in our critical review that dietary carbohydrate restriction is the first line of treatment for type 2 diabetes and the best adjunct for pharmacology in type 1 diabetes.

cancer-diabetes

The association between cancer and diabetes in combination with the benefits of carbohydrate restriction in diabetes constitute one big connection. In dietary approaches, however, it is total caloric reduction that has received the most attention and, in fact, experiments show that if implemented as stated, calorie restriction represents a reliable approach to prevention and treatment of cancer, particularly in animal models. It is unknown how much of the effect is due to de facto reduction in particular macronutrients but when tested, carbohydrate reduction as the means of reducing calories prove most effective. We cited an important study by Tannenbaum. He found, in 1945 (!) that a carcinogen-induced sarcoma in mice was repressed by reduction in total calories but if  reduced by specifically lowering the carbohydrate intake, there was an enhanced response.

tannenbaum_low-carb_cr

Impressive cancer prevention with calorie restriction in animal models has been repeated many times. Oddly, the protocol is most often presented as caloric restriction.  Odd in that this appears in sophisticated scientific papers where the downstream effects of the stimulation may pinpoint twenty molecular components and where the molecular targets of the “nutrients” are characterized and may specifically be the insulin receptor and the related IGF-1 (insulin-like growth factor -1) receptor. (Insulin is probably most important in that it stimulates IGF-1 activity by reducing the levels of the associated binding proteins). In these studies, where total caloric reduction is the independent variable, the involvement of insulin and the insulin-dependent downstream pathways have been shown to be involved.

It is now appreciated that the Warburg effect, the apparent reliance of tumors on glucose for fuel, is a key observation that has been insufficiently explored. The effect provides motivation and clues for exploring the metabolic approach to cancer. Warburg thought that all cancers showed this phenotype which is not true but a large number do; of significance is that one that does not, prostate cancer, is the outlier in the figure above on relation to diabetes. The next post will start from some basic biochemistry and explain why (and how) we think that the Warburg effect points to the potential value of ketogenic diets.

 

 

One of my favorite legal terms, collateral estoppel, refers to procedures to prevent re-litigation of issues that have already been settled in court. From the same root as stopper, that is, cork, it prevents harassment and wasting of the court’s time. The context is the recent flap over a poster presented by Kevin Hall which has started re-trying the case of whether all diets have the same metabolic efficiency, a question which, in my view, has been adjudicated several times. I put it this way because frequently I have made an analogy between evidence-based-medicine (EBM) and evidence as presented in a court of law. My main point has been that, in the legal system, there are rules of evidence and there is a judge who decides on admissibility. You can’t just say, as in EBM, that your stuff constitutes evidence.  My conclusion is usually that EBM is one of the self-congratulatory procedures that allows people to say anything that they want without having to defend their position. EBM represents one of the many corruptions of research procedure now under attack by critics (perpetrators ?) as in the recent editorial by Richard Horton, editor of The Lancet. One thing that I  criticize medical nutrition for is its inability to be estopped from funding and endlessly re-investigating whether saturated fat causes heart disease, whether high protein diets hurt your kidneys, and whether a calorie is a calorie. It seems that the issue is more or less settled — there are dozens of examples of variable energy expenditure in the literature. It would be reasonable to move on by investigating the factors that control energy balance, to provide information on the mechanisms that predict great variability and, most important, the mechanisms that make it so small in biological systems — most of the time, a calorie is a calorie, at least roughly. Funding and performing ever more expensive experiments to decide whether you can lose more or less weight on one diet or another, as if we had never done a test before, is not helpful.

Several bloggers discussed Hall’s study which claims that either a calorie is a calorie or it is not depending on whether, as described by Mike Eades, you look at the poster itself or at a video of Kevin Hall explaining what it is about. Mike’s blog is excellent but beyond the sense of déja-vu, the whole thing reminded me of the old joke about the Polish mafia. They make you an offer that you can’t understand.  So, because this is how I got into this business, I will try to explain how I see the problem of energy balance and why we might want this trial estopped.

I have taught nutrition and metabolism for many years but I got into nutrition research because the laws of thermodynamics were, and still are, invoked frequently in the discussion. Like most chemists, I wouldn’t claim to be a real expert but I like the subject and I teach the subject at some level. I could at least see that nobody in nutrition knew what they were talking about. I tried to show that the application of thermodynamics, if done correctly, more or less predicts that different diets will have different efficiencies (from the standpoint of storage, that is, weight gained per calorie consumed).

But you don’t really need thermodynamics to see this. Prof. Wendy Pogozelski at SUNY Geneseo pointed out that if you think about oxidative metabolic uncouplers, that is all you need to know. “Coupling,” in energy metabolism, refers to the sequence of reactions by which the energy from the oxidation of food is converted to ATP, that is, into useful biologic energy. The problem in energy metabolism is that the fuel, as in many “combustion engines,” is processed by oxidation — you put in oxygen and get out CO2 and water . The output, on the other hand  is a phosphorylation reaction — generation of ATP from ADP, its low energy form. The problem is how to couple these two different kins of reactions. It turns out that the mitochondrial membrane couples the two processes (together called oxidative phosphorylation). A “high energy” state is established across the membrane by oxidation and this energy is used to make ATP. Uncouplers are small molecules or proteins that disengage the oxidation of substrate (food) from ATP synthesis allowing energy to be wasted or channeled into other mechanisms, generation of reactive oxygen species, for example.

BLOG_car_analogy_May_16The car analogy of metabolic inhibitors. Figure from my lectures. Energy is generated in the TCA cycle and electron transport chain (ETC). The clutch plays the role of the membrane proton gradient, transmitting energy to the wheels which produce forward motion (phosphorylation of ADP). Uncouplers allow oxidation to continue — the TCA cycle is “racing” but to no effect. Other inhibitors (called oxidative phosphorylation inhibitors) include oligomycin which blocks the ATP synthase, analogous to a block under the wheels: no phosphorylation, no utilization of the gradient; no utilization, no gradient formation; no gradient, no oxidation. The engine “stalls.”

In teaching metabolism, I usually use the analogy of an automobile where the clutch connects the engine to the drive train . The German word for clutch is Kupplung and when you put a car in neutral your car is uncoupled, can process many calories of gasoline ‘in,’ but has zero efficiency, so that none of the ‘out’ does the useful work of turning the wheels. Biological systems can be uncoupled by external compounds — the classic is 2, 4-dinitrophenol which, if you are familiar with mitochondrial metabolism, is a proton ionophore, that is, destroys the proton gradient that couples oxidation to ADP-phophorylation.  There are natural uncouplers, the uncoupling proteins, of which there are five, named UCP-1 through UCP-5. Considered a family because of the homology to UCP-1, a known uncoupler, it has turned out that at least two others clearly have uncoupling activity. The take-home message is that whatever the calories in, the useful calories out (for fat storage or whatever) depends on the presence of added or naturally occurring uncouplers as well.

This is one of many examples of the mechanisms whereby metabolic calories-out per calorie-in could be variable.  The implication is that when somebody reports metabolic advantage (or disadvantage), there is no reason to disbelieve it. Conversely, this is one of the mechanisms that can reduce variability.

In fact, homeostatic mechanisms  are usually observed. You don’t have to have a metabolic chamber to know that your intake is variable day-to-day but your weight may be quite stable. The explanation is not in the physics which, again,  predicts variation, but rather in the biological system which is always connected in feedback so as to resist change. However strong the homeostasis (maintenance of steady-state), conversely, everybody has the experience of being in a situation where it doesn’t happen. “I don’t understand. I went on this cruise and I really pigged out on lobster and steak but I didn’t gain any weight.”  (It is not excluded, but nobody ever says that about the pancake breakfast). In other words, biochemistry and daily experience tells us that black swans are to be expected and, given that the system is set up for variability, the real question is why there are so many white swans.

So it is physically predicted that a calorie is not a calorie. When it has been demonstrated, in animal models where there is control of the food intake, or in humans, where there are frequently big differences that cannot reasonably be accounted for by the error in food records, there is no reason to doubt the effect. And, of course, a black swan is an individual. Kevin Hall’s study, as in much of the medical literature, reported group statistics and we don’t know if there were a few winners in with the group. The work has not been reviewed or published but, either way, I think it is likely to waste the court’s time.

 

It was in July of 2012 that I suddenly realized that we had won, at least scientifically. It was now clear that we had a consistent set of scientific ideas that supported the importance of insulin signaling in basic biochemistry and cell biology and that there was a continuum with the role of dietary carbohydrate restriction in obesity, diabetes or for general health.  The practical considerations, how much to eat of this, how much to eat of that, were still problematical but now we had the kernel of a scientific principle. In fact, it was not so much that we had the answer as that we had the right question.  In science, the question is frequently more important than the answer.  Of course, winning wasn’t the original idea. When my colleagues and I got into this, about ten years ago, coming from basic biochemistry, we hadn’t anticipated that it would be such a battle, that there would be so much resistance to what we thought was normal scientific practice.

(more…)

The following question was posted on Facebook:

I had thought that free fatty acids were triglycerides. But I am reading a study that measured both. Can someone enlighten me on free fatty acids? … please.

 I think I can help.  The good news is that, contrary to the college myth, organic chemistry is easy — it is freshman chemistry that is hard because it has more physics and mathematics.  Now, jumping into lipid metabolism is a little bit of starting in the middle of things but the reason organic chemistry is easy is that it has only a few assumptions and basic principles and the basic theory, at least, is logical and you can get pretty far deducing things from simple principles, so with a few basic ideas we may have a shot. I have two YouTube videos that are short, relatively easy and might be a background.  The take home message from the videos, the one big idea in organic, is that organic compounds have two parts: A hydrocarbon backbone and a non-hydrocarbon part that contains the chemically reactive part of the molecule, the functional groups. The assumption is that all compounds with the same functional group have similar chemistry.  So, for example, all carboxylic acids have the carboxyl (-COOH) functional group. In many ways, even a simple acid like acetic acid has chemical properties that are similar to a complicated acid, like the fatty acids.  You may need the YouTube to appreciate this: chemistry is about structure, that is, it is visual.

Bottom line on fatty acids and Triglycerides

All dietary and body fats and oils are triglycerides (TG) or, more correctly, triacylglycerols (TAG).  The term “acyl” (pr. A-sill) is the adjective form of acid (i.e. There are three acids).

Fats have a roughly E-shaped structure. The arms of the E are the fatty acids and there are three of them. The fatty acids provide the real fuel in fats.  The three fatty acids are attached to the compound glycerol which is the vertical stroke of the E.  The chemical bond that attaches the fatty acid  to the glycerol is called an ester bond.  You only need to know the term ester because when the fatty acids are found alone, especially in blood, they are referred to either as free fatty acids (FFA) or, because they are no longer attached to the glycerol by the ester bonds, as non-esterified fatty acids (NEFA): FFA and NEFA are the same thing.

Metabolism: the fatty acid-TAG cycle.

The digestion of fat in the intestine involves the progressive removal of the fatty acids from the first and last position of the glycerol.  The process is called lipolysis and the enzyme that catalyzes the reaction is called a lipase. What remains is called 2-monoacylglycerol, or 2-MAG  (fatty acid still attached at the center carbon of glycerol) and  2-MAG and the free fatty acids from digestion are absorbed into the intestinal cells.  Within these cells they are re-formed into TAG which is exported together with cholesterol and other components in particles called chylomicrons.  Chylomicrons, in turn, represent one type of complex structure known as lipoproteins. The lipoproteins transport lipids and some of these are familiar, e.g., LDL (low density lipoprotein), HDL. Triglycerides in the blood are carried in these particles. So this is probably the triglycerides you read about.

These are the transporters of lipids.  TAG, in particular is brought into cells by another lipase (lipoprotein lipase or LPL) on the cell surface that removes the fatty acids.  In other words, to be absorbed the TAG is broken down into fatty acids again.  Once absorbed, the fatty acids can be oxidized for fuel or, once again can be re-synthesized, step-wise: → MAG → diacylglycerol (DAG)  → TAG.  Here’s the summary figure:

Bottom line:

Fat (TAG) is continually broken down and re-synthesized.  The breakdown process is called lipolysis and the lipolysis-synthesis cycle goes on in different places in the body but notably in fat cells.  An interesting thing about fat cells is the way they carry out the cycle. Lipolysis is a simple process but synthesis is complicated.  Speaking in energy terms, it is easy to break down nutrients. It requires energy to put them back together.  To make TAG, either the glycerol or the fatty acid has to be “activated”: so the actual reactive form is a molecule called fatty acyl-coenzyme A or fatty acyl-CoA (pr. Co-A).

Biochemical reactions almost never run by themselves even if energetically favorable but are rather controlled by catalysts, that is, enzymes.  The enzyme that catalyzes the first step in the reaction, a transferase, will not work with glycerol itself.  The enzyme requires a particular form of glycerol, glycerol-phosphate.  The special characteristic of the fat cell is that the required glycerol-phosphate cannot be made directly from glycerol as it can, for example, in the liver which also has an active fatty acid-TAG cycle.  In order to make glycerol phosphate, fat cells require glucose. In the absence of glucose, as in starvation or a low carbohydrate diet, fat synthesis is repressed.  At the same time the enzyme that catalyzes breakdown, hormone-sensitive lipase, is enhanced because it is turned on by glucagon and turned offby insulin (these are the hormones in the term “hormone-sensitive lipase”).  This was the original rationalization for the apparent advantage in a low-carbohydrate diet: without carbohydrate the adipocyte would not be able to supply glycerol-phosphate and the fatty acid-TAG cycle would go largely in one direction: breakdown to produce fatty acids and this is undoubtedly one of the major effects.

It turns out, however, that the fat cells protect stores of energy in fat by other methods. We now understand that cells run a process called glyceroneogenesis which is a truncated form of gluconeogenesis, the process whereby glucose is synthesized from other nutrients, mostly protein, that is, the process supplies an intermediate in the synthesis of glucose and this can be converted to glycerol-phosphate. Generally, especially if the diet is hypocaloric, the net effect is to break down fat and supply fatty acids as a fuel for other cells.  Fatty acids circulate in the blood bound to a protein called albumin. Under conditions where there is higher carbohydrate, however, and the fatty acids are not being used for fuel, they can stimulate insulin resistance. So, fatty acids in the blood are a good thing if you are breaking down fat to supply energy.  They are not so good if you are over-consuming energy or carbohydrates because, in the presence of insulin, they can lead to insulin resistance.

Summary: triglycerides are made of three fatty acids.  There is a continual fatty acid-TAG cycle that goes on all the time in different cells.  Triglycerides in the blood are carried in lipoprotein particles, chylomicrons, LDL, HDL.  Fatty acids in the blood are carried by the protein albumin.

In 1985 an NIH Consensus Conference was able to “establish beyond any reasonable doubt the close relationship between elevated blood cholesterol levels (as measured in serum or plasma) and coronary heart disease” (JAMA 1985, 253:2080-2086).

I have been making an analogy between scientific behavior and the activities of the legal system and following that idea, the wording of the conference conclusion suggests a criminal indictment. Since the time of the NIH conference, however, data on the role of cholesterol fractions, the so-called “good (HDL)” and “bad (LDL)” cholesterols and, most recently, the apparent differences in the atherogenicity of different LDL sub-fractions would seem to have provided some reasonable doubt. What has actually happened is that the nutrition establishment, the lipophobes as Michael Pollan calls them, has extended the indictment to include dietary fat, especially saturated fat at least as accessories on the grounds that, as the Illinois Criminal Code put it “before or during the commission of an offense, and with the intent to promote or facilitate such commission, … solicits, aids, abets, agrees or attempts to aid… in the planning or commission of the offense. . . ..”

A major strategy in the indictment of saturated fat has been guilt by association.  The American Heart Association (AHA), which had long recommended margarine (the major source of trans-fats), has gone all out in condemning saturated fatty acids by linking them with trans-fats.  The AHA website has a truly deranged cartoon film of the evil brothers: “They’re a charming pair, Sat and Trans.  But that doesn’t mean they make good friends.  Read on to learn how they clog arteries and break hearts — and how to limit your time with them by avoiding the foods they’re in.”. While the risk of trans-fats is probably exaggerated — they are a small part of the diet — they have no benefit and nobody wants to defend them; dietary saturated fat, however, is a normal part of the diet, is made in your body and is less important in providing saturated fatty acids in the blood, than dietary carbohydrate.  Guilt by association is a tricky business in courts of law — just having a roommate who sells marijuana can get you into a good deal of trouble — but it takes more than somebody saying that you and the perpetrator make a charming pair.

The failure of the diet-cholesterol-heart hypothesis in clinical trials as been documented by numerous scientific articles and especially in popular books that document the original scientific sources. It is unknown what the reaction of the public is to these books.  However, amazingly, there is only one book I know of that takes the side of the lipophobes and that is Daniel Steinberg’s Cholesterol Wars. The Skeptics vs. the Preponderance of Evidence. A serious book with careful if slightly biased documentation and an uncommon willingness to answer the critics,  it is worth reading.  I will try to discuss it in detail in this and future posts.  First, the title indicates a step down from criminal prosecution.  “Preponderance of the evidence” is the standard for conviction in a civil court and is obviously a far weaker criterion.  One has to wonder why it is that the skeptics have the preponderance of the popular publications — if the scientific evidence is there and health agencies are so determined that the public know about this, why are there so few —  maybe only this one — rebutting the critics.

The Skeptics vs. the Preponderance of Evidence

In any case, what is Steinberg’s case?  The indictment on page 1 is somewhat different than one would have thought.

“….the [lipid] hypothesis relates to blood lipids not dietary lipids as the putative directly causative factor. Although diet, especially dietary lipid is an important determinant of blood lipid levels, many other factors play important roles. Moreover, there is a great deal of variability in response of individuals to dietary manipulations. Thus, it is essential to distinguish between the indirect “diet-heart” connection and the direct “blood lipid — hard” connection failure to make this distinction has been a frequent source of confusion. (his italics)”

What?  Are we really supposed to believe that diet is an incidental part of the lipid hypothesis?  Are we supposed to believe that our cholesterol is just a question of the variability of our response to diet.  Has the message really been that diet is not critical and that heart-disease is just the luck of the draw (until we start taking statins)?  This is certainly the source of confusion in my mind.  Of course by page 5, we are confronted with this:

“In 1966, Paul Leren published his classic five-year study of 412 patients who had had a prior myocardial infarction. He showed that substitution of polyunsaturated fat and saturated fat-rich butter-cream-venison diet favored by the Norwegians reduced their blood cholesterol by about 17 per cent and kept it down.  The number of secondary current events in the treated group was reduced by about one-third and the result was significant at the p < 0.03 level.”

In a future post, I will describe Paul Leren’s classic five-year study which, by 1970, had a follow-up to eleven years and the results will turn out not to be as compelling as described by Steinberg.  For the moment, it is worth considering that, given the strong message, from the AHA, from the American Diabetes Association, from the NIH Guidelines for Americans, the criterion really should be beyond a reasonable doubt. There shouldn’t be even a single failure like the Framingham Study or the Women’s Health Initiative. In fact, the preponderance of the evidence when you add them all up, isn’t there.