High vs Low Protein

P. D. Mangan Tweeted a quote from a research paper, Reversal of epigenetic aging and immunosenescent trends in humans by Gregory M. Fahy et al. He stated that  the “Most important sentence in aging reversal study” is the following: “Human longevity seems more consistently linked to insulin sensitivity than to IGF‐1 levels, and the effects of IGF‐1 on human longevity are confounded by its inverse proportionality to insulin sensitivity.” Mangan added that “This line agrees with what I wrote a while back” (How Carbohydrates and Not Protein Promote Aging); and in the comments section of that article, someone pointed to a supporting video by Dr. Benjamin Bikman (‘Insulin vs. Glucagon: The relevance of dietary protein’). Here is the context of the entire paragraph from the discussion section of the research paper:

“In this regard, it must be pointed out that GH and IGF‐1 can also have pro‐aging effects and that most gerontologists therefore favor reducing rather than increasing the levels of these factors (Longo et al., 2015). However, most past studies of aging and GH/IGF‐1 are confounded by the use of mutations that affect the developmental programming of aging, which is not necessarily relevant to nonmutant adults. For example, such mutations in mice alter the normal innervation of the hypothalamus during brain development and prevent the hypothalamic inflammation in the adult (Sadagurski et al., 2015). Hypothalamic inflammation may program adult body‐wide aging in nonmutants (Zhang et al., 2017), but it seems unlikely that lowering IGF‐1 in normal non‐mutant adults can provide the same protection. A second problem with past studies is a general failure to uncouple GH/IGF‐1 signaling from lifelong changes in insulin signaling. Human longevity seems more consistently linked to insulin sensitivity than to IGF‐1 levels, and the effects of IGF‐1 on human longevity are confounded by its inverse proportionality to insulin sensitivity (Vitale, Pellegrino, Vollery, & Hofland, 2019). We therefore believe our approach of increasing GH/IGF‐1 for a limited time in the more natural context of elevated DHEA while maximizing insulin sensitivity is justified, particularly in view of the positive role of GH and IGF‐1 in immune maintenance, the role of immune maintenance in the retardation of aging (Fabris et al., 1988), and our present results.”

In the Twitter thread, Командир Гиперкуба said, “So it is insulin [in]sensitivity than drives ageing rather than IGF‐1/GH. Huge if true.” And GuruAnaerobic added that, “I assume this isn’t IR per se, but IR in the presence of carbohydrate/excess food. IOW, the driver is environment.” Mangan then went onto point out that, “It explains the dichotomy of growth vs longevity, and why calorie restriction increases lifespan.” Mick Keith asked, “So drop carbs and sugar?go paleo style?” And Mangan answered, “There are other aspects to insulin sensitivity, but yes.” All of this cuts to the heart of a major issue in the low-carb community, an issue that I only partly and imperfectly understand. What I do get is this has to do with the conclusions various experts come to about protein, whether higher amounts are fine or intake should be very limited. Some see insulin sensitivity as key while others prioritize IGF-1. The confounding requires careful understanding. In the comments section of Mangan’s above linked article, Rob H. summed it up well:

“Great post, very timely too as I believe this is an issue that seems to be polarising the science-based nutrition space at the moment. Personally I fall down on the same side as you Dennis – as per Ben Bikman’s video which has also been posted here, as well as the views of all the main protein researchers including Stuart Philips, Jose Antonio, Donald Layman, Gabrielle Lyon, Ted Naiman, Chris Masterjohn etc who all believe the science clearly supports a high protein intake eg 1.6 -2.2g/kilo of bodyweight – with no upper limit which has yet been observed. At the same time, I have just been reading the new book by Dr Steven Gundry ‘The Longevity Paradox’. Has anyone read this one yet? Whilst about 90% of the content is fairly solid stuff (although nothing that hasn’t already been written about here) he aggressively supports Longo’s view that we should only consume 0.37g protein/ kilo of bodyweight, eg around 25g of protein/ day for most males. Also that animal protein should be avoided wherever possible. Personally I consume double that amount of protein at each meal! It appears that Longo, Gundry, Dr Ron Rosedale and Dr Mercola are all aligned in a very anti-animal protein stance, but also believe their view is backed by science – although the science quoted in Gundry’s book seems to be largely based on epidemiology. Both sides can’t be right here, so I hope more research is done in this field to shut this debate down – personally I feel that advising ageing males to consume only 25g of protein a day is extremely irresponsible.”

In response, Mangan wrote, “I agree that is irresponsible. Recently Jason Fung and James DiNicolantonio jumped on the anti animal protein bandwagon. My article above is my attempt (successful, I hope) to show why that’s wrong.” Following that, Rob added, “Humans have been consuming animal proteins for most or all of our evolutionary history. And certainly, large quantities of animal protein were consumed at times (as when a kill of a large animal was made). So, I cannot imagine that the “evidence” supporting an anti-animal protein stance can be solid or even science-based. This sounds like a case of certain researchers trying their best to find support for their pre-determined dietary beliefs (vegan proponents do this all the time). I’m not buying it.” It’s very much an ongoing debate.

I have suspicions about the point of confusion that originated this disagreement. Fear of promoting too much growth through protein is basically the old Galenic argument based on humoral physiology. The belief is that too much meat as a stimulating/nurturing substance built up the ‘blood’ with too much heat and dryness which would burn up the body and cause a shortened lifespan. This culturally inherited bias about meat has since been fancied up with scientific language. But ancient philosophy is not the best source for formulating modern scientific theory. Let me bring this back to insulin sensitivity and insulin resistance that appears to play the determining role. Insulin is a hormone and so we must understand this from an endicrinological approach, quite different than Galenic-style fears about meat that was filtered through the Christian theology of the Middle Ages.

Hormones are part of a complex hormonal system going far beyond macronutrients in the diet, although it does appear that the macronutrient profile is a major factor. Harry Serpano, in a discussion with Bart Kay, said that: “In a low insulin state, when you’re heavy meat and fat and your insulin is at 1.3, as Dr. Paul Mangan has actually shown in one of his videos, it’s quite clear; and in what I’m showing in one of the studies, it’s quite clear. It’s so close to basically fasting which is 0.8 — it’s very low. You’re not going to be pushing up these growth pathways like mTOR or IGF-1 in any significant way.” Like with so much else, there is strong evidence that what we need to be worrying about is insulin, specifically on a high-carb diet that causes insulin resistance and metabolic syndrome. That is what is guaranteed to severely decrease longevity.

This question about too much protein recently came up in my own thoughts while reading Dr. Stephen Gundry’s new book, The Longevity Paradox. As mentioned above, he makes a case against too much animal protein. But it sounds like there is more information to be considered in the affect on health, growth, and longevity. In a dialogue with Gundry, Dr. Paul Saladino defended meat consumption (Gundry’s Plant Paradox and Saladino’s Carnivory). What Mangan has added to this debate strengthens this position.

* * *

In one of the above quoted comments, Robert H. mentions that Dr. Joseph Mercola is one of those “aligned in a very anti-animal protein stance, but also believe their view is backed by science.” It’s interesting that I’m just now listening to a discussion between Mercola and Siim Land. They met at a conference and got to talking. Mercola then read Land’s book, Metabolic Autophagy. Land is more in the camp supporting the value of protein. His view is nuanced and the debate isn’t entirely polarized. The role protein plays in health depends on the health outcomes being sought and the health conditions under which protein is being eaten: amounts, regularity of meals, assimilation, etc. It’s about how one’s body is able to use protein and to what end.

Right at the beginning of their talk, Mercola states that he is impressed by Land’s knowledge and persuaded by his view on protein. Land makes the simple point that one doesn’t want to be in autophagy all the time but to cycle between periods of growth and not. Too much protein restriction, especially all the time, is not a good thing. Mercola seems to have come around to this view. So, it’s a shifting debate. There is a lot of research and new studies are coming out all the time. But obviously, context is important in making any statement about protein in the diet. Maybe Saladino will similarly bring Gundry on board with greater protein being a good thing for certain purposes or maybe come to a middle ground. These dialogues are helpful, in particular for an outsider like me who is listening in.

* * *

On a personal note, I’m not sure I take a strong position either way. But I’ve long been persuaded by Siim Land’s view. It feels more moderate and balanced. The opposite side can sound too fear-mongering about protein, not seeming to allow as much differences in contexts and conditions. From a low-carb perspective, one has to replace carbs with something and that means either protein or fat, and one can only consume so much fat. Besides, proteins really are important for anabolism and activating mTOR, for building of the body. Maybe if you’re trying to lose weight or simply maintaining where you’re at with no concern for healing or developing muscle then protein would play less of a role. I don’t know.

Traditional societies don’t seem to worry about protein amounts. When they have access to it, they eat it, at times even to the point of their bellies distending. And when not, they don’t. Those populations with greater access don’t appear to suffer any harm from greater protein intake. Then again, these traditional societies tend to do a lot of strenuous physical activity. They also usually mix it up with regular fasting, intermittent and extended. I’m not sure how optimal protein levels may differ depending on lifestyle. Still, I’d think that the same basic biological truths would apply to all populations. For most people in most situations, increased protein will be helpful at least some of the time and maybe most of the time. Other than fasting, I’m not sure why one needs to worry about it. And with fasting, protein restriction happens naturally.

So, maybe eat protein to satiation. Then throw in some fasting. You’ll probably be fine. There doesn’t seem to be anything to be overly concerned about, based on what evidence I’ve seen so far.

Caloric Confusion

In human biological terms, there is no such thing as a calorie. It’s an abstraction measured by machines, in breaking down matter to determine the energy it contains. That isn’t how the body functions. It’s similar to the view of nutritionism where chemical analyses determines the amounts of specific vitamins and minerals found in any given food. None of this, however, tells us how the body absorbs, processes, and uses them.

Take sugar, for example. It is worse than empty calories. Rather, we are talking about actively toxic calories. It also interferes with nutrient intake and so can contribute to malnourishment. In the 1890s in Britain and by 1940 in the United States, a shockingly high number of recruits and draftees were being rejected because of malnourishment and tooth decay. This had been preceded by decades of rising levels of sugar and carbs in the diet, combined with processed vegetable oils that were replacing saturated fat.

A commonly discussed example of this is how more vitamin C is required on a high-carb diet because glucose competes with it, whereas on a low-carb diet very little vitamin C is needed to avoid scurvy. Sugar is causing harm simultaneously on multiple levels. That it is fattening is bad enough, especially considering all that is involved: dental caries, diabetes, heart disease, fatty liver, depression, etc — no minor set of health consequences and that list could go on much longer. Yet sugar was exonerated while saturated fat was scapegoated, which is rather inconsistent in that saturated fats have never been treated as mere empty calories equal to anything else.

It turns out calories aren’t all equal and on some level everyone probably always knew that was true, but in its simplicity it was an easy way of describing nutrition to the public. The problem is that it is so simplistic as to be fundamentally wrong. It is meaningless to speak of calories-in/calories-out. That doesn’t explain anything. We are still left with the issue of why the body burns some calories while turning others into fat. Recent research has shown that there is a metabolic advantage to low-carb diets in that more calories are burned in ratio to calories consumed. This is particularly true in a ketogenic state where the body efficiently burns fat. Fat easily turns into fat when eaten with carbs, but this is not true to the same degree when carbs are limited.

It is understandable how this all came about. We study what we can perceive and we ignore what we can’t. Scientific researchers early on learned how to measure calories with machines and it was assumed that the body was like a machine, burning a fuel in the way an engine burned coal and released heat. It became not only one model among many but a defining paradigm to explain human behavior and even morality, with the sins of gluttony and sloth taking key roles. Calories-in/calories-out created a perfect moral calculus. If you were fat or whatever, it was your fault. It couldn’t possibly have anything to do with the severely health-destroying food system, demented nutritional advice, and sub-par healthcare.

Other models of dietary health developed such as the endocrinological study of hormones and the hormonal systems, but the calorie model was already established. Besides, most of this other early research was done in Europe, much of it in German. The World Wars scattered the European research communities and their scientific literature mostly remained untranslated. When the US became the new center of nutritional research, English-speaking researchers were largely ignorant of all that previous researchers had already figured out.

Until this past decade or so, this state of affairs has remained that way, more than a century after that early research was done. Only now has the American-dominated nutritional research begun to return to old knowledge long forgotten.

* * *

The Curious History of the Calorie in U.S. Policy:
A Tradition of Unfulfilled Promises
by Deborah I. Levine

The Progressive Era Body Project:
Calorie-Counting and “Disciplining the Stomach” in 1920s America
by Chin Jou

Forget Calories
by James Hamblin

Death of the Calorie
by Peter Wilson

How Do We Gain Weight? – Calories Part I, II, IIIIV, V, VI, VII, VIII, IX, X, & XI
Historic Perspective on Obesity – Hormonal Obesity Part I, II, III, IV, & V
The Myth about Exercise – Exercise Part I, II, III, & IV
by Jason Fung

11 Experts Demolish the “Calories-In-Calories-Out” (CICO) Model of Obesity
9 More Experts Lay Waste to the “Calories-In-Calories-Out” (CICO) Model of Obesity
by Adam Kosloff

* * *

The Case Against Sugar
by Gary Taubes
pp. 23-25

Meanwhile, the latest surge in this epidemic of diabetes in the United States— an 800 percent increase from 1960 to the present day, according to the Centers for Disease Control—coincides with a significant rise in the consumption of sugar. Or, rather, it coincides with a surge in the consumption of sugars, or what the FDA calls “caloric sweeteners—sucrose, from sugarcane or beets, and high-fructose corn syrup, HFCS, a relatively new invention.

After ignoring or downplaying the role of sugars and sweets for a quarter-century, many authorities now argue that these are, indeed, a major cause of obesity and diabetes and that they should be taxed heavily or regulated. The authorities still do so, however, not because they believe sugar causes disease but, rather, because they believe sugar represents “empty calories” that we eat in excess because they taste so good. By this logic, since refined sugar and high-fructose corn syrup don’t contain any protein, vitamins, minerals, antioxidants, or fiber, they either displace other, more nutritious elements of our diet, or simply add extra, unneeded calories to make us fatter. The Department of Agriculture, for instance (in its recent “Dietary Guidelines for Americans”), the World Health Organization, and the American Heart Association, among other organizations, advise a reduction in sugar consumption for these reasons primarily.

The empty-calories argument is particularly convenient for the food industry, which would understandably prefer not to see a key constituent of its products—all too often, the key constituent—damned as toxic. The sugar industry played a key role in the general exoneration of sugar that took place in the 1970s, as I’ll explain later. Health organizations, including the American Diabetes Association and the American Heart Association, have also found the argument convenient, having spent the last fifty years blaming dietary fat for our ills while letting sugar off the hook. […]

This book makes a different argument: that sugars like sucrose and high-fructose corn syrup are fundamental causes of diabetes and obesity, using the same simple concept of causality that we employ when we say smoking cigarettes causes lung cancer. It’s not because we eat too much of these sugars—although that is implied merely by the terms “overconsumption” and “overeating”—but because they have unique physiological, metabolic, and endocrinological (i.e., hormonal) effects in the human body that directly trigger these disorders. This argument is championed most prominently by the University of California, San Francisco, pediatric endocrinologist Robert Lustig. These sugars are not short-term toxins that operate over days and weeks, by this logic, but ones that do their damage over years and decades, and perhaps even from generation to generation. In other words, mothers will pass the problem down to their children, not through how and what they feed them (although that plays a role), but through what they eat themselves and how that changes the environment in the womb in which the children develop.

Individuals who get diabetes—the ones in any population who are apparently susceptible, who are genetically predisposed—would never have been stricken if they (and maybe their mothers and their mothers’ mothers) lived in a world without sugar, or at least in a world with a lot less of it than the one in which we have lived for the past 100 to 150 years. These sugars are what an evolutionary biologist might call the environmental or dietary trigger of the disease: the requisite ingredient that triggers the genetic predisposition and turns an otherwise healthy diet into a harmful one. Add such sugars in sufficient quantity to the diet of any population, no matter what proportion of plants to animals they eat—as Kelly West suggested in 1974 about Native American populations—and the result eventually is an epidemic of diabetes, and obesity as well.

pp. 117-121

The second pillar of modern nutritional wisdom is far more fundamental and ultimately has had far more influence on how the science has developed, and it still dominates thinking on the sugar issue. As such, it has also done far more damage. To the sugar industry, it has been the gift that keeps on giving, the ultimate defense against all arguments and evidence that sugar is uniquely toxic. This is the idea that we get obese or overweight because we take in more calories than we expend or excrete. By this thinking, researchers and public-health authorities think of obesity as a disorder of energy balance,” a concept that has become so ingrained in conventional thinking, so widespread, that arguments to the contrary have typically been treated as quackery, if not a willful disavowal of the laws of physics.

According to this logic of energy balance, of calories-in/calories-out, the only meaningful way in which the foods we consume have an impact on our body weight and body fat is through their energy content—calories. This is the only variable that matters. We grow fatter because we eat too much—we consume more calories than we expend—and this simple truth was, and still is, considered all that’s necessary to explain obesity and its prevalence in populations. This thinking renders effectively irrelevant the radically different impact that different macronutrients—the protein, fat, and carbohydrate content of foods—have on metabolism and on the hormones and enzymes that regulate what our bodies do with these foods: whether they’re burned for fuel, used to rebuild tissues and organs, or stored as fat.

By this energy-balance logic, the close association between obesity, diabetes, and heart disease implies no profound revelations to be gleaned about underlying hormonal or metabolic disturbances, but rather that obesity is driven, and diabetes and heart disease are exacerbated, by some combination of gluttony and sloth. It implies that all these diseases can be prevented, or that our likelihood of contracting them is minimized if individuals—or populations—are willing to eat in moderation and perhaps exercise more, as lean individuals are assumed to do naturally. Despite copious reasons to question this logic and, as we’ll see, an entire European school of clinical research that came to consider it nonsensical, medical and nutrition authorities have tended to treat it as gospel. Obesity is caused by this caloric imbalance, and diabetes, as Joslin said nearly a century ago, is largely the penalty for obesity. Curb the behaviors of gluttony (Shakespeare’s Falstaff was often invoked as a pedagogical example) and sloth (another deadly sin) and all these diseases will once again become exceedingly rare.

This logic also served publicly to exonerate sugar as a suspect in either obesity or diabetes. By specifying energy or caloric content as the instrument through which foods influence body weight, it implies that a calorie of sugar would be no more or less capable of causing obesity, and thus diabetes, than a calorie of broccoli or olive oil or eggs or any other food. By the 1960s, the phrase a calorie is a calorie had become a mantra of the nutrition-and-obesity research community, and it was invoked to make just this argument (as it still is). […]

The energy-balance idea derives ultimately from the simple observation that the obese tend to be hungrier than the lean, and to be less physically active, and that these are two deviations from normal intake and expenditure: gluttony and sloth. It was first proposed as an explanation of obesity in the early years of the twentieth century, when nutrition researchers, as we discussed, were focused on carefully quantifying with their calorimeters the energy content of foods and the energy expended in human activity. At the time, the application of the laws of thermodynamics and particularly the conservation of energy to living creatures—the demonstration that all the calories we consume will either be burned as fuel or be stored or excreted—was considered one of the triumphs of late-nineteenth-century nutrition science. Nutrition and metabolism researchers embraced calories and energy as the currency of their research. When physicians began speculating as to the cause of obesity, they naturally did the same.

The first clinician to take these revelations on thermodynamics and apply them to the very human problem of obesity was the German diabetes specialist Carl von Noorden. In 1907, he proposed that “ the ingestion of a quantity of food greater than that required by the body, leads to an accumulation of fat, and to obesity, should the disproportion be continued over a considerable period.”

Noorden’s ideas were disseminated widely in the United States and took root primarily through the work of Louis Newburgh, a University of Michigan physician who did so based on what he believed to be a fundamental truth: “All obese persons are alike in one fundamental respect—they literally overeat.” Newburgh assumed that overeating was the cause of obesity and so proceeded to blame the disorder on some combination of a “perverted appetite” (excessive energy consumption) and a “lessened outflow of energy” (insufficient expenditure). As for obese patients who remained obese in spite of this understanding, Newburgh suggested they did so because of “various human weaknesses such as overindulgence and ignorance.” (Newburgh himself was exceedingly lean.) Newburgh was resolutely set against the idea that other physical faults could be involved in obesity. By 1939, his biography at the University of Michigan was already crediting him with the discovery that “ the whole problem of weight lies in regulation of the inflow and outflow of calories” and for having “undermined conclusively the generally held theory that obesity is the result of some fundamental fault.”

The question of a fundamental fault could not be dismissed so lightly, however. To do that required dismissing observations of German and Austrian clinical researchers who had come to conclude that obesity could only be reasonably explained by the existence of such a fault—specifically, a defect in the hormones and enzymes that served to control the flow of fat into and out of cells. Newburgh rejected this hormonal explanation, believing he had identified the cause of obesity as self-indulgence.

Gustav von Bergmann, a contemporary of Noorden’s and the leading German authority on internal medicine, * 1 criticized Noorden’s ideas (and implicitly Newburgh’s) as nonsensical. Positive energy balance—more energy in than out—occurred when any system grew, Bergmann pointed out: it accumulated mass. Positive energy balance wasn’t an explanation but, rather, a description, and a tautological one at that: logically equivalent to saying that a room gets crowded because more people enter than leave. * 2 It was a statement that described what happens but not why. It seems just as illogical, wrote Bergmann, to say children grow taller because they eat too much or exercise too little, or they remain short because they’re too physically active. “ That which the body needs to grow it always finds, and that which it needs to become fat, even if it’s ten times as much, the body will save for itself from the annual balance.”

The question that Bergmann was implicitly asking is why excess calories were trapped in fat tissue, rather than expended as energy or used for other necessary biological purposes. Is there something about how the fat tissue is regulated or how fuel metabolism functions, he wondered, that makes it happen?

The purpose of a hypothesis in science is to offer an explanation for what we observe, and, as such, its value is determined by how much it can explain or predict. The idea that obesity is caused by the overconsumption of calories, Bergmann implied, failed to explain anything.

p. 129

These revelations led both directly and indirectly to the notion that diets restricted in carbohydrates—and restricted in sugar most of all—would be uniquely effective in slimming the obese. By the mid-1960s, these carbohydrate-restricted diets, typically high in fat, were becoming fashionable, promoted by physicians, not academics, and occasionally in the form of hugely successful diet books. Academic nutritionists led by Fred Stare and Jean Mayer of Harvard were alarmed by this and denounced these diets as dangerous fads (because of their high fat content, particularly saturated fat), suggesting that the physician-authors were trying to con the obese with the fraudulent argument that they could become lean without doing the hard work of curbing their perverted appetites. It is a medical fact that no normal person can lose weight unless he cuts down on excess calories,” The New York Times would explain in 1965.

This battle played out through the mid-1970s, with the academic nutritionists and obesity researchers on one side, and the physicians-turned-diet-book-authors on the other. The obesity researchers began the 1960s believing that obesity was, indeed, an eating disorder—Newburgh’s “perverted appetite”—and the ongoing revolution in endocrinology, spurred by Yalow and Berson’s invention of the radioimmunoassay, did little to convince them otherwise. Many of the most influential obesity researchers were psychologists, and much of their research was dedicated to studying why the obese failed to restrain their appetites sufficiently—to eat in moderation—and how to induce them to do a better job of it. The nutritionists followed along as they focused on the question of whether dietary fat caused heart disease and perhaps obesity as well, because of its dense calories. (A gram of protein or a gram of carbohydrate has four calories; a gram of fat has almost nine.) In the process, they would continue to reject any implication that sugar had fattening powers beyond its caloric content. That it might be the cause of insulin resistance—after all, something was—would not cross their radar screen for decades.

pp. 199-201

In 1986, with the perceived FDA exoneration of sugar, the public-health authorities and the clinicians and researchers studying obesity and diabetes had come to a consensus that type 2 diabetes was caused by obesity, not sugar, and that obesity itself was caused merely by eating too many calories or exercising away too few. By this logic, the only means by which a macronutrient could influence body weight was its caloric content, and so, calorie for calorie, sugar was no more fattening than any other food, and thus no more likely to promote or exacerbate diabetes. This was what the sugar industry had been arguing and embracing since the 1930s. It was what Fred Stare of Harvard had in mind when he said publicly that he would prefer to get his calories from a martini than from a dessert.

A more nuanced perspective, one nourished by scientific progress, would be that if two foods or macronutrients are metabolized differently—if glucose and fructose, for instance, are metabolized in entirely different organs, as they mostly are—then they are likely to have vastly different effects on the hormones and enzymes that control or regulate the storage of fat in fat cells. One hundred calories of glucose will very likely have an entirely different effect on the human body from one hundred calories of fructose, or fifty calories of each consumed together as sucrose, despite having the same caloric content. It would take a leap of faith to assume otherwise.

Nutritionists had come to assume that a hundred calories of fat had a different effect from a hundred calories of carbohydrate on the accumulation of plaque in coronary arteries; even that a hundred calories of saturated fat would have an entirely different effect from a hundred calories of unsaturated fat. So why not expect that macronutrients would have a different effect on the accumulation of fat in fat tissue, or on the phenomena, whatever they might be, that eventually resulted in diabetes? (Insulin resistance and hyperinsulinemia, as Rosalyn Yalow and Solomon Berson, among others, had suggested in the 1960s, seemed to be a very likely bet.) But obesity and diabetes researchers, as we’ve seen, had come to embrace the mantra that “a calorie is a calorie”; they would repeat it publicly when they were presented with the idea that there was something unique about how the human body metabolizes sugar that sets it apart from other carbohydrates. The long-held view was based on the state of the science in the early years of the twentieth century, and to cling to it required a willful rejection of the decades’ worth of relevant revelations in the medical sciences that had come since.

By the 1980s, biochemists, physiologists, and nutritionists who specialized in the study of sugar or in the fructose component of sugar had come to consistent conclusions about the short-term effects of sugar consumption in human subjects, as well as the details of how sugar is metabolized and how this influences the body as a whole. The glucose we consume—in starch or flour, or as half of a sugar molecule—will be used directly for fuel by muscle cells, the brain, and other tissues, and can be stored in muscles or the liver (as a compound called glycogen), but the fructose component of sugar has a much different fate. Most of it never makes it into the circulation; it is metabolized in the liver. The metabolic pathways through which glucose passes when it is being used for fuel—in both liver and muscle cells—involve a feedback mechanism to redirect it toward storage as glycogen when necessary. This is the case with fructose, too. But the metabolism of fructose in the liver is “unfettered by the cellular controls,” as biochemists later put it, that work to prevent its conversion to fat. One result is the increased production of triglycerides, and thus the abnormally elevated triglyceride levels that were observed in many research subjects, though not all, when they ate sugar-rich diets.

While cardiologists and epidemiologists were debating whether elevated triglycerides actually increased the risk of heart disease (in the process, challenging their own beliefs that cholesterol was key), biochemists had come to accept that sucrose was “the most lipogenic” of carbohydrates—as even Walter Glinsmann, author of the FDA report on sugar, would later acknowledge—and that the liver was the site of this fat synthesis. * 2 The Israeli biochemist Eleazar Shafrir would describe this in the technical terminology as “the remarkable hepatic lipogenic capacity induced by fructose-rich diets.” It was also clear from the short-term trials in humans that this happened to a greater extent in some individuals than others, just as it did in some species of animals and not others. In human studies, subjects who had the highest triglycerides when the trials began tended to have the greatest response to reducing sugar intake, suggesting (but not proving) that the sugar was the reason they had such high triglycerides in the first place. These same individuals also tended to see the greatest drop in cholesterol levels when they were put on low-sugar diets.