Posts Tagged ‘nutrition’

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.

The joke in academic circles is that there are three responses to a new idea. First, “This is wrong,” second, “There’s nothing new in this,” and third, the sub-title of this post. Priority in a scientific discovery is fundamental in science, however, and “we thought of this first” is not always that funny.  Getting “scooped” can have serous practical consequences like jeopardizing your grant renewal and, if nothing else, most of us are motivated by a desire to solve the problem and don’t like the feeling that, by analogy, somebody came along and filled in our crossword puzzle.  In dietary carbohydrate, all three of the responses co-exist.  While an army of dietitians is still claiming that people with diabetes need ever more carbohydrate, in the background the low-fat paradigm crumbles and, somewhat along the lines of the predictions in A Future History of Diabetes , the old guard are coming forward to tell us that they have been recommending low-carb all along.

The latest discoverer of the need to reduce dietary carbohydrate is David Jenkins whose recent paper is entitled “Nuts as a Replacement for Carbohydrates in the Diabetic Diet.” [1] The title is crazy enough, following the tradition of getting away from nutrients, that is, well-defined variables, and replacing it with “food,” that is, mixtures of everything. It is, in fact, not really a low carbohydrate study but the experimental design is not the problem.  It is the background and rationale for the study which recognizes the disintegration of the low-fat diet paradigm but, at the same time, fails to cite any of the low-carbohydrate studies that have been instrumental in showing the need to replace carbohydrates in the diabetic diet. Given forty years of studies showing the benefits of low carbohydrate diets and forty years of unrestrained attacks on the method, it will be interesting to see how Jenkins shows that it is actually the nutritional establishment that invented carbohydrate restriction.

Disputes over priority are well known in the history of science. Newton’s frequently quoted statement that he had seen farther than others because he had “stood on the shoulders of giants” has been interpreted by some historians as a sarcastic comment aimed at Robert Hooke  with whom he had, among other things, a dispute over the priority for the inverse square law (force of gravity varies as the inverse of the square of the distance: F = GmM/g2). Hooke was short and suffered from kyphosis and is assumed not to have shoulders you would profitably stand on.

Even Einstein had trouble.  His dispute with the mathematician David Hilbert about priority for the field equations of general relativity (also about gravity) is still going on, a dispute that I prefer to stay out of. Cited by his biographer, Abraham Pais, Einstein had apparently made up the  verb to nostracize (nostrazieren) which he accused Hilbert of doing. (He meant that Hilbert had made Einstein’s idea community knowledge.  Googling the word gives you only “ostracize” and “Cosa Nostra.”)

It is not the priority dispute, per se — the original low carbohydrate diet is usually attributed to William Banting who published the Letter on Corpulence in 1863, although Brillat-Savarin’s 1825 Physiologie du goût  understood the principle. He said that some people were carbophores and admitted to being one himself.  It is not just priority but that the people who are now embracing carbohydrate restriction were previously unrestrained in their attacks on the dietary approach and were adamant in denying the strategy to their patients.

David Jenkins: “Nuts.”

In trying to find an appropriate answer to the recent bit of balderdash by the redoubtable Hope Warshaw, Tom Naughton recounted the story of the Battle of the Bulge of WWII.  Towards the end of the war, Hitler launched a massive winter attack around the city of Bastogne where, at one point, American Forces were surrounded. When the Germans demanded surrender, the American General, Anthony McAuliffe, sent the one-word reply: “Nuts!”  I always thought it was a euphemism and that he actually went “Vice-presidential” as it was called in the last administration, but it turns to have been a common expression with him and he really did write “nuts” which, of course, had to be explained to the German couriers. (There is a “Nuts” Museum in Bastogne commemorating the battle which the Americans won somewhat as described in the movie Patton).

For installation in the Nutritional Nuts Museum and as an example of the current attempts to co-opt carbohydrate restriction, one can hardly beat Jenkins’s recent paper [1].

Richard:…Who knows not that the gentle duke is dead? ….

King Edward: Who knows not he is dead! Who knows he is?

Queen Elizabeth: All-seeing heaven, what a world is this!

— William Shakespeare, Richard III

The trick is to act as if the point you are making is already established. The Abstract of Jenkins study: “Fat intake, especially monounsaturated fatty acid (MUFA), has been liberalized in diabetic diets to preserve HDL cholesterol and improve glycemic control….” It has? Liberalized by whom?  Although the American Diabetes Association guidelines are traditionally all over the place, few would consider that there is any sense of substantial liberalization on replacing carbohydrate with fat from them or any health agency.

“Replacement of carbohydrate by healthy fat … has been increasingly recognized as a possible therapeutic strategy in the treatment of diabetes [2] as concerns emerge over the impact of refined carbohydrate foods in increasing postprandial glycemia and reducing HDL cholesterol.”  Reference [2] ((1) in the original) actually “emerged” in 2002 and is ambiguous at best: “Carbohydrate and monounsaturated fat together should provide 60–70% of energy intake.” (It is not my style of humor, but the behavioral therapists call this “shoulding on people.”) The paper admits that the evidence “is based on expert consensus”  and contains what might be called the theme song of the American Diabetes Association:

 “Sucrose and sucrose-containing food do not need to be restricted by people with diabetes based on a concern about aggravating hyperglycemia. However, if sucrose is included in the food/meal plan, it should be substituted for other carbohydrate sources or, if added, be adequately covered with insulin or other glucose-lowering medication.” (my italics)

In fact, one emerging piece of evidence is Jenkins 2008 study comparing a diet high in cereal with a low glycemic index diet [3].  The glycemic index is a measure of the actual effect of dietary glucose on blood glucose.  Pioneered by Jenkins and coworkers, a low-GI diet is based on the same rationale as a low-carbohydrate diet, that glycemic and insulin fluctuations pose a metabolic risk but it emphasizes “the type of carbohydrate,” that is, it is a politically correct form of low-carbohydrate diet and as stated in the 2008 study: “We selected a high–cereal fiber diet treatment for its suggested health benefits for the comparison so that the potential value of carbohydrate foods could be emphasized equally for both high–cereal fiber and low–glycemic index interventions.” (my emphasis) The Conclusion of the 24-week study was: “In patients with type 2 diabetes, 6-month treatment with a low–glycemic index diet resulted in moderately lower HbA1c levels compared with a high–cereal fiber diet.”  The figure below shows the results for HbA1c and weight loss and just looking at the figures, the results are certainly modest enough.

By coincidence, on almost the same day, Eric Westman’s group published a study that compared a low glycemic index diet with a true low carbohydrate diet [4].  The studies were comparable in duration and number of subjects and a direct comparison shows the potential of low carbohydrate diets (NOTE: in the figure, the units for the change are those of the individual parameters; an earlier version showed this as % which was an error):

 

Fad_Westman_Jenkins_FigWe thought of this first.

Oddly, neither of these papers are cited in the current study by Jenkins, et al.  In fact, according to the paper, the precedents go way back:

“Recently, there has been renewed interest in reducing carbohydrate content in the diet of diabetic patients. In 1994, on the basis of emerging evidence, the American Diabetes Association first suggested the possibility of exchanging dietary carbohydrate for MUFA in dietary recommendations for type 2 diabetes). Although not all studies have shown beneficial effects of MUFAs in diabetes, general interest has persisted, especially in the context of the Mediterranean diet.”

The ADA discovered low carbohydrate diets ? Did my blogpost see it coming, or what? But wait…

 “low carbohydrate intakes have also been achieved on the Atkins diet by increasing animal fats and proteins. This influential dietary pattern is reflectedin the relatively lower pre-study carbohydrate intakes of ~ 45% in the current study rather than the 50–60% once recommended.

The researchers in this area might not feel that 45 % carbohydrate has much to do with the Atkins diet but, in any case, it appears not to have been “influential” enough to actually get the studies supporting it cited.

Again: “Fat intake, especially monounsaturated fatty acid (MUFA), has been liberalized…” but “… the exact sources have not been clearly defined. Therefore, we assessed the effect of mixed nut consumption as a source of vegetable fat on serum lipids and HbA1c in type 2 diabetes.”  Therefore? Nuts?  That’s going to clearly define the type of MUFA?  Nuts have all kinds of nutrients.  How do we know that it is the MUFA in the nuts?  In fact, the real question is whether any benefit would not be due to the reduction in carbohydrate regardless of what it were replaced with. So what was the benefit? The figure above shows the effect on hemoglobin A1C. As described by the authors:

 “The full-nut dose reduced HbA1c by two-thirds of the reduction recognized as clinically meaningful by the U.S. Food and Drug Administration (.0.3% absolute HbA1c units) in the development of antihyperglycemic drugs…”

 In other words, almost meaningful, and

 “the number of participants who achieved an HbA1c concentration of <7% (19 pre-study participants, down to 13 post-study participants) was significantly greater on the nut treatment than on the muffin treatment (20 pre-study participants, remaining at 20 post-study participants…).”

This is some kind of accomplishment but the figure above shows that, in fact, the results were pretty poor.  The statistics do show that the “full nut dose” was significantly different from the half-nut dose or the muffin.  But is this what you want to know?  After all, nobody has an average change in HbA1c.  What most of us want to know is the betting odds. If I down all those nuts, what’s the chance that I’ll get better.  How many of the people in the full-nut study did better than those in the half-nut study (did the authors not know that this would sound funny?).  You can’t tell for sure because this information is buried in the statistics but the overlap of the error bars, highlighted in pink, suggests that not everybody gained anything — in fact, some may have gotten worse.

What kind of benefit is possible in a dietary intervention for people with diabetes?  Well, the studies discussed above from Jenkins himself and from Westman show that, with a low-GI diet, it is possible to obtain an average reduction of about 4 %, more than ten times greater than with nuts and with a real low-carbohydrate diet much greater.  I have added an inset to the Figure from Jenkins with data from a 2005 study by Yancy, et al. [5].  The red line shows the progress of the mean in Yancy’s studied.  If you had diabetes, would you opt for this approach or go for the full-nut dose?

Bibliography

1. Jenkins DJ, Kendall CW, Banach MS, Srichaikul K, Vidgen E, Mitchell S, Parker T, Nishi S, Bashyam B, de Souza R et al: Nuts as a replacement for carbohydrates in the diabetic diet. Diabetes Care 2011, 34(8):1706-1711.

2. Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeister LA, Hoogwerf B, Mayer-Davis E, Mooradian AD et al: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002, 25(1):148-198.

3. Jenkins DJ, Kendall CW, McKeown-Eyssen G, Josse RG, Silverberg J, Booth GL, Vidgen E, Josse AR, Nguyen TH, Corrigan S et al: Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes: a randomized trial. JAMA 2008, 300(23):2742-2753.

4. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR: The Effect of a Low-Carbohydrate, Ketogenic Diet Versus a Low-Glycemic Index Diet on Glycemic Control in Type 2 Diabetes Mellitus. Nutr Metab (Lond) 2008, 5(36).

5. Yancy WS, Jr., Foy M, Chalecki AM, Vernon MC, Westman EC: A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond) 2005, 2:34.

Baseball is like church. Many attend. Few understand.

— Leo Durocher.

The movie Moneyball provides an affirmative answer to an important question in literature and drama: can you present a scene and bring out the character of a subject that is boring while, at the same time, not make the presentation boring?  The movie, and  Michael Lewis’sbook that it is based on, are about baseball and statistics!  For fans, baseball is not boring so much as incredibly slow, providing a soothing effect like fishing, interspersed with an occasional big catch. The movie stars Brad Pitt as Billy Beane, the General Manager of the Oakland Athletics baseball team in the 1990s.  A remarkably talented high school athlete, Billy Beane, for unknown reasons, was never able to play out his potential as an MLB player but, in the end, he had a decisive effect on the game at the managerial level. The question is how the A’s, with one-third of the budget of the Yankees, could have been in the play-offs three years in a row and, in 2001, could win 102 games.  The movie is more or less faithful to the book and both are as much about organizations and psychology as about sports. The story was “an example of how an unscientific culture responds, or fails to respond, to the scientific method” and the science is substantially statistical.

In America, baseball is a metaphor for just about everything. Probably because it is an experience of childhood and adolescence, lessons learned from baseball stay with us. Baby-boomers who grew up in Brooklyn were taught by Bobby Thompson’s 1951 home-run, as by nothing later, that life isn’t fair. The talking heads in Ken Burns’s Baseball who found profound meaning in the sport are good examples. Former New York Governor Mario Cuomo’s comments were quite philosophical although he did add the observation that getting hit in the head with a pitched ball led him to go into politics.

One aspect of baseball that is surprising, especially when you consider the money involved, is the extent to which strategy and scouting practices have generally ignored hard scientific data in favor of tradition and lore. Moneyball tells us about group think, self-deception and adherence to habit in the face of science. For those of us who a trying to make sense of the field of nutrition, where people’s lives are at stake and where numerous professionals who must know better insist on dogma — low fat, no red meat — in the face of contradictory evidence, baseball provides some excellent analogies.

The real stars of the story are the statistics and the computer or, more precisely, the statistics and computer guys: Bill James an amateur analyzer of baseball statistics and Paul DePodesta, assistant General Manager of the A’s who provided information about the real nature of the game and how to use this information. James self-published a photocopied book called 1977 baseball abstract: featuring 18 categories of statistical information you just can’t find anywhere else. The book was not just about statistics but was in fact a critique of traditional statistics pointing out, for example, that the concept of an “error;” was antiquated, deriving from the early days of gloveless fielders and un-groomed playing fields of the 1850s. In modern baseball, “you have to do something right to get an error; even if the ball is hit right at you, and you were standing in the right place to begin with.” Evolving rapidly, the Abstracts became a fixture of baseball life and are currently the premium (and expensive) way to obtain baseball information.

It is the emphasis on statistics that made people doubt that Moneyball could be made into a movie and is probably why they stopped shooting the first time around a couple of years ago. Also, although Paul DePodesta (above) is handsome and athletic, Hollywood felt that they should cast him as an overweight geek type played by Jonah Hill. All of the characters in the film have the names of the real people except for DePodesta “for legal reasons,” he says. Paul must have no sense of humor.

The important analogy with nutrition research and the continuing thread in this blog, is that it is about the real meaning of statistics. Lewis recognized that the thing that James thought was wrong with the statistics was that they

“made sense only as numbers, not as a language. Language, not numbers, is what interested him. Words, and the meaning they were designed to convey. ‘When the numbers acquire the significance of language,’ he later wrote, ‘they acquire the power to do all the things which language can do: to become fiction and drama and poetry … . And it is not just baseball that these numbers through a fractured mirror, describe. It is character. It is psychology, it is history, it is power and it is grace, glory, consistency….’”

By analogy, it is the tedious comparison of quintiles from the Harvard School of Public Health proving that white rice will give you diabetes but brown rice won’t or red meat is bad but white meat is not, odds ratio = 1.32. It is the bloodless, mindless idea that if the computer says so, it must be true, regardless of what common sense tells you. What Bill James and Paul DePodesta brought to the problem was understanding that the computer will only give you a meaningful answer if you ask the right question; asking what behaviors accumulated runs and won ball games, not which physical characteristics — runs fast, looks muscular — that seem to go with being a ball player… the direct analog of “you are what you eat,” or the relative importance of lowering you cholesterol vs whether you actually live or die.

As early as the seventies, the computer had crunched baseball stats and come up with clear recommendations for strategy. The one I remember, since it was consistent with my own intuition, was that a sacrifice bunt was a poor play; sometimes it worked but you were much better off, statistically, having every batter simply try to get a hit. I remember my amazement at how little effect the computer results had on the frequency of sacrifice bunts in the game. Did science not count? What player or manager did not care whether you actually won or lost a baseball game. The themes that are played out in Moneyball, is that tradition dies hard and we don’t like to change our mind even for our own benefit. We invent ways to justify our stubbornness and we focus on superficial indicators rather than real performance and sometimes we are just not real smart.

Among the old ideas, still current, was that the batting average is the main indicator of a batter’s strength. The batting average is computed by considering that a base-on-balls is not an official at bat whereas a moments thought tells you that the ability to avoid bad pitches is an essential part of the batter’s skill. Early on, even before he was hired by Billy Beane, Paul DePodesta had run the statistics from every twentieth century baseball team. There were only two offensive statistics that were important for a winning team percentage: on-base percentage (which included walks) and slugging percentage. “Everything else was far less important.” These numbers are now part of baseball although I am not enough of a fan to know the extent to which they are still secondary to the batting average.

One of the early examples of the conflict between tradition and science was the scouts refusal to follow up on the computer’s recommendation to look at a fat, college kid named Kevin Youkilis who would soon have the second highest on-base percentage after Barry Bonds. “To Paul, he’d become Euclis: the Greek god of walks.”

The big question in nutrition is how the cholesterol-diet-heart paradigm can persist in the face of the consistent failures of experimental and clinical trials to provide support. The story of these failures and the usurpation of the general field by idealogues has been told many times. Gary Taubes’s Good Calories, Bad Calories is the most compelling and, as I pointed out in a previous post, there seems to have been only one rebuttal, Steinberg’s Cholesterol Wars. The Skeptics vs. the Preponderance of Evidence. At least within the past ten year, a small group have tried to introduce new ideas, in particular that it is excessive consumption of dietary carbohydrate, not dietary fat, that is the metabolic component of the problems in obesity, diabetes and heart disease and have provided extensive, if generally un-referenced, experimental support. An analogous group tried to influence baseball in the years before Billy Beane. Larry Lucchino, an executive of the San Diego Padres described the group in baseball as being perceived as something of a cult and therefore easily dismissed. “There was a profusion of new knowledge and it was ignored.” As described in Moneyball “you didn’t have to look at big-league baseball very closely to see its fierce unwillingness to rethink any it was as if it had been inoculated against outside ideas.”

“Grady Fuson, the A’s soon to be former head of scouting, had taken a high school pitcher named Jeremy Bonderman and the kid had a 94 mile-per-hour fastball, a clean delivery, and a body that looked as if it had been created to wear a baseball uniform. He was, in short, precisely the kind of pitcher Billy thought he had trained the scouting department to avoid…. Taking a high school pitcher in the first round — and spending 1.2 million bucks to sign — that was exactly this sort of thing that happened when you let scouts have their way. It defied the odds; it defied reason. Reason, even science, was what Billy Beane was intent on bringing to baseball.”

The analogy is to the deeply ingrained nutritional tradition, the continued insistence on cholesterol and dietary fat that are assumed to have evolved in human history in order to cause heart disease. The analogy is the persistence of the lipophobes, in the face of scientific results showing, at every turn, that these were bad ideas, that, in fact, dietary saturated fat does not cause heart disease. It leads, in the end, to things like Steinberg’s description of the Multiple risk factor intervention trial. (MRFIT; It’s better not to be too clever on acronyms lest the study really bombs out): “Mortality from CHD was 17.9 deaths per 1,000 in the [intervention] group and 19.3 per 1,000 in the [control] group, a statistically nonsignificant difference of 7.1%”). Steinberg’s take on MRFIT:

“The study failed to show a significant decrease in coronary heart disease and is often cited as a negative study that challenges the validity of the lipid hypothesis. However, the difference in cholesterol level between the controls and those on the lipid lowering die was only about 2 per cent. This was clearly not a meaningful test of the lipid hypothesis.”

In other words, cholesterol is more important than outcome or at least a “diet designed to lower cholesterol levels, along with advice to stop smoking and advice on exercise” may still be a good thing.

Similarly, the Framingham study which found a strong association between cholesterol and heart disease found no effect of dietary fat, saturated fat or cholesterol on cardiovascular disease.  Again, a marker for risk is more important than whether you get sick.  “Scouts” who continued to look for superficial signs and ignore seemingly counter-intuitive conclusions from the computer still hold sway on the nutritional team.

“Grady had no way of knowing how much Billy disapproved of Grady’s most deeply ingrained attitude — that Billy had come to believe that baseball scouting was at roughly the same stage of development in the twenty-first century as professional medicine had been in the eighteenth.”

Professional medicine? Maybe not the best example.

What is going on here? Physicians, like all of us, are subject to many reinforcers but for humans power and control are usually predominant and, in medicine, that plays out most clearly in curing the patient. Defeating disease shines through even the most cynical analysis of physician’s motivations. And who doesn’t play baseball to win. “The game itself is a ruthless competition. Unless you’re very good, you don’t survive in it.”

Moneyball describes a “stark contrast between the field of play and the uneasy space just off it, where the executives in the Scouts make their livings.” For the latter, read the expert panels of the American Heat Association and the Dietary Guidelines committee, the Robert Eckels who don’t even want to study low carbohydrate diets (unless it can be done in their own laboratory with NIH money). In this

“space just off the field of play there really is no level of incompetence that won’t be tolerated. There are many reasons for this, but the big one is that baseball has structured itself less as a business and as a social club. The club includes not only the people who manage the team but also in a kind of women’s auxiliary many of the writers and commentators to follow and purport to explain. The club is selective, but the criteria for admission and retention and it is there many ways to embarrass the club, but being bad at your job isn’t one of them. The greatest offense a club member can commit is not ineptitude but disloyalty.”

The vast NIH-USDA-AHA social club does not tolerate dissent. And the media, WebMD, Heart.org and all the networks from ABCNews to Huffington Post will be there to support the club. The Huffington Post, who will be down on the President of the United States in a moment, will toe the mark when it comes to a low carbohydrate story.

The lessons from money ball are primarily in providing yet another precedent for human error, stubbornness and, possibly even stupidity, even in an area where the stakes are high. In other words, the nutrition mess is not in our imagination. The positive message is that there is, as they say in political science, validator satisfaction. Science must win out. The current threat is that the nutritional establishment is, as I describe it, slouching toward low-carb, doing small experiments, and easing into a position where they will say that they never were opposed to the therapeutic value of carbohydrate restriction. A threat because they will try to get their friends funded to repeat, poorly, studies that have already been done well. But that is another story, part of the strange story of Medicineball.

“Doctors prefer large studies that are bad to small studies that are good.”

— anon.

The paper by Foster and coworkers entitled Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet, published in 2010, had a surprisingly limited impact, especially given the effect of their first paper in 2003 on a one-year study.  I have described the first low carbohydrate revolution as taking place around that time and, if Gary Taubes’s article in the New York Times Magazine was the analog of Thomas Paine’s Common Sense, Foster’s 2003 paper was the shot hear ’round the world.

The paper showed that the widely accepted idea that the Atkins diet, admittedly good for weight loss, was a risk for cardiovascular disease, was not true.  The 2003 Abstract said “The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease.” The publication generated an explosive popularity of the Atkins diet, ironic in that Foster had said publicly that he undertook the study in order to “once and for all,” get rid of the Atkins diet.  The 2010 paper by extending the study to 2 years would seem to be very newsworthy.  So what was wrong?  Why is the new paper more or less forgotten?  Two things.  First, the paper was highly biased and its methods were so obviously flawed — obvious even to the popular press — that it may have been a bit much even for the media. It remains to be seen whether it will really be cited but I will suggest here that it is a classic in misleading research and in the foolishness of intention-to-treat (ITT).

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The study of metabolic pathways provides an insight into chemical reactions and the way they function in living systems but, in the end, even a biochemistry professor still has to answer the question  “What should I eat.”  Adam Cambell, an editor at Men’s Health magazine once asked me: “You’ve just had a meal that conforms to your idea of good nutrition and satisfying portions of food but you’re still hungry.  What should you do?”

“Think of a perfectly-cooked juicy steak or perfectly-prepared fish, or some similar high protein food that you usually like,” I suggested.  “If that sounds good, you’re hungry and you should eat something.  If it doesn’t sound good, you’re not hungry.  You may want desert.  You may want something feeling good in your mouth, but you’re not hungry.” What I meant, of course, is that foods that are high in protein, and lower in carbohydrate, tend to be more filling. This satiating effect of protein is well-known in the biochemical literature and is one of the advantages of diets that restrict carbohydrates and keep protein high.  The fact that protein is satisfying also means that it provides its own control over intake and, for that reason, “concerns” about high protein intake that you hear from nutritional expert are not usually a real problem.  In the obesity epidemic where there was a large increase in carbohydrate consumption and a general decline in fat consumption, protein stayed about the same.  When nutritionists carry out experiments in which people can eat freely, they generally do not change their protein consumption.  In fact, it now seems likely that most people are not getting enough protein.  Recent studies show that people benefit from replacing carbohydrate in their diet with protein, the benefit is in better weight control, in an improved ratio to lean body mass compared to fat and in better control of blood insulin and glucose.  I will describe some of the features of this problem with references to papers in the scientific literature that are either open access or have been made publicly available and public and do not require a subscription.

Nutritionists who study protein think that we need modification of official recommendations for protein consumption.  Donald Layman at the University of Illinois has reviewed some of the important research on this question and he came up with several important points:

•    Protein is a critical part of the adult diet. Beyond physical growth which is only important for a brief period in your life, there is a continuing need to repair and remodel muscle and bone

•    Protein needs for adults relate to body weight not, as you sometimes see, as a per cent of total calories. So, if you are reducing calories, protein needs to stay high and may be a higher percentage of total calories. In choosing a diet, you should establish the grams of protein first.

•    The amount of protein at each meal can be important.  Research indicates that an ideal is 30 g of protein per meal although this may not be practical for everybody. It is recommended that breakfast be high in protein.

•    Most adults benefit from protein intakes above the minimum RDA (recommended daily allotment) and this is especially true for an aging population with increased risks of poor health.  The RDA represents a minimum daily intake for active healthy adults but most people will benefit from replacing at lest some carbohydrate in the diet with protein.

The full story on protein recommendations can be found at Nutrition & Metabolism (no subscription required.

A look at the science

Proteins are generally more complicated molecules than fat or carbohydrate.  Like starch, they are polymers (think chain of beads).  Most starches are homopolymers (all the beads are the same, glucose in this case), but protein molecules are made of 20 different kinds of beads (amino acids).  About half are interchangeable or can be made from other nutrients and are said to be non-essential.  The other half are required in the diet and are said to be essential amino acids, or, for some reason, the more modern term is indispensable.  Now your body is continually breaking down and re-synthesizing its own proteins, the most obvious function of dietary protein is supplying amino acids to replenish body proteins so high quality dietary proteins will be those that supply all the essential amino acids.  Meat, fish and eggs are high quality proteins but combinations of vegetables can also supply the full complement of amino acids.  Many web sites and other sources will give you information about how vegetables can be combined to supply amino acids, but there is another aspect of protein nutrition that should be considered.  Amino acids, like carbohydrate are not just sources of cell material but may have a signaling function.  Remember that it is not just that glucose supplies energy but that it stimulates the release of insulin which further controls metabolism.  Amino acids also perform this function and stimulate insulin release and trigger other physiologic processes, in particular, synthesis of new body protein and provide control over blood glucose.  One essential amino acid in particular, leucine, is of greatest importance in this role.  In comparative studies, diets that are high in leucine improve the ratio of lean body mass to fat. Whey and other milk proteins are particularly high in leucine; red meat is also a good source.

The benefit in substituting protein for carbohydrate is greatest for people with diabetes.  The studies from the laboratories of Mary Gannon and Frank Nuttall are pretty remarkable and I show you a picture of the actual results from their experiments.  They studied the effect of reducing dietary carbohydrate on responses of people with diabetes.  The figure shows that after 5 weeks on a diet with 20 % available glucose (circles in the figure), the response to meals is drastically improved compared to the response if the traditional diet is continued (triangles).  As the diet proceeded, hemoglobin A1c was also reduced.  Gannon and Nuttall have also showed that diets with slightly higher glucose may be effective but the response depends on how much glucose is in the diet.  A very important feature of the studies of this study is that the diets were designed so that patients maintained their weight, in other words, benefit accrued even though no weight was lost.  Given how hard it is to lose weight, this has to be considered a real plus for the higher protein, lower carbohydrate diet.  You can see the whole study, again, without subscription here.

Is there a danger of too much protein?

How many times have you read an article in the media, or even in the medical literature, warning you about the dangers of high protein diets for your kidneys, or for kidney stones, or whatever.   Probably quite a few.  Are they for real?  To answer that question, think of how often you have read an article in the media describing somebody who actually had kidney problems or stones due to a high protein diet? That number is zero or close (there’s always a case study someplace with an isolated patient).

To understand the danger in a high protein diet for people with normal kidneys, consider the following conversation I had with an expert on kidney disease when I was the editor of Nutrition & Metabolism.

RF: I received a manuscript today that rather strongly and categorically says that there is no danger in high protein diets for people with normal kidneys.

Nephrologist: That’s right.

RF: It is?  Can we document that?

N: How do you document that there are no people with three eyes.  We have looked very hard for it and we never found it.

So, what’s wrong.  Mostly what’s wrong is that we never got around to agreeing on what high protein is.  Diets that encourage you to replace carbohydrate with protein are only trying to counteract the high carbohydrate message. Few people actually eat huge amounts of protein.  As discussed above, protein tends to be more satisfying than carbohydrate and what might be considered high protein is pretty average.

In other words, there is common sense.  A healthy high protein diet is currently estimated to have a daily intake of about 1 to 4 g of protein for every kg (2.2 lbs) of body weight while the USDA recommendation is only 0.8 g/kg).  So, if you weigh 175 lbs., an optimal level of protein will be at least 80.  The diet shown below is actually quite a bit higher. Is this really unusual?  In fact, if you ate 3 eggs or even bigger portion of  brisket, do you think something terrible will happen.  Is this dangerous?  To say that normal eating, even with occasional over-indulgence, is dangerous requires real proof and that’s what’s always been missing.

Finally, it is likely that for people with diabetes, there is great danger to kidneys from continued high blood sugar and most physicians would say that this risk is real while any risk from high protein is conjecture.

The bottom line: Substituting protein for carbohydrate in the diet improves blood glucose and insulin control.  As part of a weight loss diet, higher protein preserves lean mass compared to higher carbohydrate diets but the benefits of higher protein, lower carbohydrate diets provide benefit even in the absence of weight loss.