Dr. Jekyll dieted and became Mr. Hyde

One of the most fascinating topics for an independent health researcher is the dichotomy between short- and long-term responses in successful dieters. In the short term, dieters that manage to lose a significant amount of fat mass, tend to feel quite well. Many report that their energy levels go through the roof.

A significant loss of fat mass could be considered one of 30 lbs, or 13.6 kg. This is the threshold for weight loss used in the National Weight Control Registry. Ideally you want to lose body fat, not lean mass, both of which contribute to weight loss.

So, in the short term, significant body fat loss feels pretty good for the dieters. In the long term, however, successful dieters tend to experience the symptoms of chronic stress. This should be no surprise because some of the same hormones that induce a sense of elation and high energy are the ones associated with chronic stress. These are generally referred to as “stress hormones”, of which the most prominent seem to be cortisol, epinephrine (adrenaline), and norepinephrine (noradrenaline).

Stress hormones display acute elevations during intense exercise as well ().

This is all consistent with evolution, and with the idea that our hominid ancestors would not go hungry for too long, at least not on a regular basis. High energy levels, combined with hunger, would make them succeed at hunting-gathering activities, leading to a period of feast before a certain threshold of sustained caloric restriction (with or without full fasting) would be reached. This would translate into a regular and cyclical hunger-feast process, with certain caloric costs having to be met for successful hunting-gathering.

After a certain period of time under sustained caloric restriction, it would probably be adaptive among our ancestors to experience significant mental and physical discomfort. That would compel our hominid ancestors to more urgently engaged in hunting-gathering activities.

And here is a big difference between those ancestors and modern urbanites: our ancestors would actually be working towards getting food for a feast, not restraining themselves from eating what they have easily available at home or from a grocery store nearby. There are major psychological differences here. Dieting, in the sense of not eating when food is easily available, is as unnatural as obesity, if not more.

So what are some of the mechanisms by which the body dials up stress, leading to the resulting mental and physical discomfort? Here is one that seems to play a key role: hypoglycemia.

Of the different types of hypoglycemia, there is one that is quite interesting in this type of context, because it refers to hypoglycemia in response to intake of any food item that raises insulin levels; that is, food that contains protein and/or carbohydrates. More specifically, we are referring here to reactive hypoglycemia, of the same general type as that experienced by those on their way to type II diabetes.

But reactive hypoglycemia in successful dieters is often different from that of prediabetics, as it is caused by something that would sound surprising to many: successful dieters appear to become too insulin sensitive for their own good!

There is ongoing debate as to what is considered a blood glucose level that is low enough to characterize hypoglycemia. Several factors influence that, including measurement method and age. One important factor related to measurement method is this: commercial fingerstick glucose meters tend to grossly underestimate low glucose levels (e.g., 50 mg/dl shows as 30 mg/dl).

Having said that, glucose levels below 60 mg/dl are generally considered low.

Luyckx and Lefebvre selected 47 cases of reactive hypoglycemia for a study, from a total of 663 standard four-hour oral glucose tolerance tests (OGTT). They classified these 47 cases as follows, with the number of cases in each class within parentheses: obesity (11), obesity with chemical diabetes (9), postgastrectomy syndrome (3), chemical diabetes without obesity (1), renal glycosuria (7), and isolated reactive hypoglycemia (16).

Postgastrectomy is the period following a gastrectomy, which is removal of part of one’s stomach. The modern term for this stomach amputation procedure is “bariatric surgery”; admittedly a broader term, which many people say they would do as if they were referring to a walk in the park!

In the cases of isolated reactive hypoglycemia, the individuals had normal weight, normal glucose tolerance, and no glycosuria (excretion of glucose in the urine). As you can see in the paragraph above, this, isolated reactive hypoglycemia, was the category with the largest number of individuals. The figure below illustrates what happened in these cases.



The cases in question are represented in the left part of the graph with dashed lines (the full lines are for normal controls). There a reasonably normal insulin response, lower in fact in terms of area under the curve (AUC) than for the controls, leads to an abnormal reduction in blood glucose levels. They are 9 out of 16, the majority of the isolated reactive hypoglycemia cases. In those 9 individuals, insulin became “more potent”, so to speak.

Reactive hypoglycemia is frequently associated with obesity, in which case it is also associated with hyperinsulinemia, and caused by an exaggerated insulin response. About 40 percent of the reactive hypoglycemia cases in the study were classified as happening in obese individuals.

This study suggests that, if you are not obese, and you are diagnosed with reactive hypoglycemia following an OGTT, chances are that the diagnosis is due to high insulin sensitivity – as opposed to low insulin sensitivity, coupled with hyperinsulinemia. A follow-up test should focus on insulin levels, to see if they are elevated; i.e., to try to detect hyperinsulinemia.

I have been blogging here long enough to hear from people who have gone the full fat2fit2fat cycle, sometimes more than once. They start dieting, go from obese to lean, feel good at first but then miserable, drop the diet, become obese or almost obese again, then start dieting again …

Quite a few are folks who do things like ditching industrial foods, regularly eating organ meats, and doing resistance exercise. How can you go wrong doing all of these, generally healthy, things? Well, they all increase your insulin sensitivity. If you don’t build in plateaus to slow down your progress, you may not give your body enough time to adapt.

You may become too lean, too fast, for your own good. The more successful the diet, the bigger is the risk. No wonder the paleo diet is being targeted lately as a “bad” diet. How can you go wrong on a diet of whole foods; “real” whole foods, not “whole wheat”? Well, here is how you can go wrong. The diet, if not managed properly, may be too successful for your own good; too much of a good thing can be a problem, you know!

See the graph below, from a previous post on a related topic (). I intend to discuss a method to identify the point at which weight loss should stop, in a future post. This method builds on the calculation of a simple index, which is unique to each individual. Let me just say now that I suspect that, with exceptions, frequently people are hurting their health by trying to have six pack abs.



But what does all this have to do with stress hormones? The connection is this. Hypoglycemia is only “felt”, as something unpleasant, due to the body’s frequent acute stress hormone response to it. Elevated levels of stress hormones also increase blood glucose levels, countering hypoglycemia. Our body’s priority is preventing hypoglycemia, not hyperglycemia ().

And here is an interesting pattern, based on anecdotal evidence from HCE () users. It seems that folks who have abnormally high insulin sensitivity, also have medium-to-high HbA1c (a measure of glycation) and fasting blood glucose levels. By medium-to-high HbA1c levels I mean 5.7 to even as high as 6.2.

Since cortisol is elevated, one would expect higher fasting blood glucose levels – the “dawn phenomenon”. But higher HbA1c, how? I am not sure, but I believe that HbA1c will be found in the future to be something a bit more complicated than what it is believed to be: a measure of average blood glucose over a period of time. I am not talking here about cases of anemia.

One indication of this complicated nature of the HbA1c is the fact that blood glucose levels in birds are high yet HbA1c levels are low, and birds live much longer than mammals of comparable size (). Some birds have extremely high glucose levels, even carnivorous birds who consume no or very small amounts of carbohydrate (e.g. hawks), with fairly low HbA1c levels.

The title of this post is inspired in the classic short novel “Strange Case of Dr. Jekyll and Mr. Hyde” by the Scottish author Robert Louis Stevenson; who also authored another famous novel, “Treasure Island”. In “Dr. Jekyll and Mr. Hyde”, gentle Dr. Jekyll becomes nasty Mr. Hyde (see poster below, from Wikipedia).



Mr. Hyde had a bad temper, impaired judgment, and was prone to criminal behavior. Hypoglycemia has long been associated with bad temper, impaired judgment, and criminal behavior (, ).

No fat gain while eating well during the Holiday Season: Palatability isolines, the 14-percent advantage, and nature’s special spice

Like most animals, our Paleolithic ancestors had to regularly undergo short periods of low calorie intake. If they were successful at procuring food, those ancestors alternated between periods of mild famine and feast. As a result, nature allowed them to survive and leave offspring. The periods of feast likely involved higher-than-average consumption of animal foods, with the opposite probably being true in periods of mild famine.

Almost anyone who adopted a low carbohydrate diet for a while will tell you that they find foods previously perceived as bland, such as carrots or walnuts, to taste very sweet – meaning, to taste very good. This is a special case of a more general phenomenon. If a nutrient is important for your body, and your body is deficient in it, those foods that contain the nutrient will taste very good.

This rule of thumb applies primarily to foods that contributed to selection pressures in our evolutionary past. Mostly these were foods available in our Paleolithic evolutionary past, although some populations may have developed divergent partial adaptations to more modern foods due to recent yet acute selection pressure. Because of the complexity of the dietary nutrient absorption process, involving many genes, I suspect that the vast majority of adaptations to modern foods are partial adaptations.

Modern engineered foods are designed to bypass reward mechanisms that match nutrient content with deficiency levels. That is not the case with more natural foods, which tend to taste good only to the extent that the nutrients that they carry are needed by our bodies.

Consequently palatability is not fixed for a particular natural food; it does not depend only on the nutrient content of the food. It also depends on the body’s deficiency with respect to the nutrient that the food contains. Below is what you would get if you were to plot a surface that best fit a set of data points relating palatability of a specific food item, nutrient content of that food, and the level of nutrient deficiency, for a group of people. I generated the data through a simple simulation, with added error to make the simulation more realistic.

Based on this best-fitting surface you could then generate a contour graph, shown below. The curves are “contour lines”, a.k.a. isolines. Each isoline refers to palatability values that are constant for a set of nutrient content and nutrient deficiency combinations. Next to the isolines are the corresponding palatability values, which vary from about 10 to 100. As you can see, palatability generally goes up as one moves toward to right-top corner of the graph, which is the area where nutrient content and nutrient deficiency are both high.

What happens when the body is in short-term nutrient deficiency with respect to a nutrient? One thing that happens is an increase in enzymatic activity, often referred to by the more technical term “phosphorylation”. Enzymes are typically proteins that cause an acute and targeted increase in specific metabolic processes. Many diseases are associated with dysfunctional enzyme activity. Short-term nutrient deficiency causes enzymatic activity associated with absorption and retention of the nutrient to go up significantly. In other words, your body holds on to its reserves of the nutrient, and becomes much more responsive to dietary intake of the nutrient.

The result is predictable, but many people seem to be unaware of it; most are actually surprised by it. If the nutrient in question is a macro-nutrient, it will be allocated in such a way that less of it will go into our calorie stores – namely adipocytes (body fat). This applies even to dietary fat itself, as fat is needed throughout the body for functions other than energy storage. I have heard from many people who, by alternating between short-term fasting and feasting, lost body fat while maintaining the same calorie intake as in a previous period when they were steadily gaining body fat without any fasting. Invariably they were very surprised by what happened.

In a diet of mostly natural foods, with minimal intake of industrialized foods, short-term calorie deficiency is usually associated with short-term deficiency of various nutrients. Short-term calorie deficiency, when followed by significant calorie surplus (i.e., eating little and then a lot), is associated with a phenomenon I blogged about before here – the “14-percent advantage” of eating little and then a lot (, ). Underfeeding and then overfeeding leads to a reduction in the caloric value of the meals during overfeeding; a reduction of about 14 percent of the overfed amount.

So, how can you go through the Holiday Season giving others the impression that you eat as much as you want, and do not gain any body fat (maybe even lose some)? Eat very little, or fast, in those days where there will be a feast (Thanksgiving dinner); and then eat to satisfaction during the feast, staying away from industrialized foods as much as possible. Everything will taste extremely delicious, as nature’s “special spice” is hunger. And you may even lose body fat in the process!

But there is a problem. Our bodies are not designed to associate eating very little, or not at all, with pleasure. Yet another thing that we can blame squarely on evolution! Success takes practice and determination, aided by the expectation of delayed gratification.

Refined carbohydrate-rich foods, palatability, glycemic load, and the Paleo movement

A great deal of discussion has been going on recently revolving around the so-called “carbohydrate hypothesis of obesity”. I will use the acronym CHO to refer to this hypothesis. This acronym is often used to refer to carbohydrates in nutrition research; I hope this will not cause confusion.

The CHO could be summarized as this: a person consumes foods with “easily digestible” carbohydrates, those carbohydrates raise insulin levels abnormally, the abnormally high insulin levels drive too much fat into body fat cells and keep it there, this causes hunger as not enough fat is released from fat cells for use as energy, this hunger drives the consumption of more foods with “easily digestible” carbohydrates, and so on.

It is posited as a feedback-loop process that causes serious problems over a period of years. The term “easily digestible” is within quotes for emphasis. If it is taken to mean “refined”, which is still a bit vague, there is a good amount of epidemiological evidence in support of the CHO. If it is taken to mean simply “easily digestible”, as in potatoes and rice (which is technically a refined food, but a rather benign one), there is a lot of evidence against it. Even from an unbiased (hopefully) look at county-level data in the China Study.

Another hypothesis that has been around for a long time and that has been revived recently, which we could call the “palatability hypothesis”, is a competing hypothesis. It is an interesting and intriguing hypothesis, at least at first glance. There seems to be some truth to this hypothesis. The idea here is that we have not evolved mechanisms to deal with highly palatable foods, and thus end up overeating them.  Therefore we should go in the opposite direction, and place emphasis on foods that are not very palatable to reach our optimal weight. You might think that to test this hypothesis it would be enough to find out if this diet works: “Eat something … if it tastes good, spit it out!”

But it is not so simple. To test this palatability hypothesis one could try to measure the palatability of foods, and see if it is correlated with consumption. The problem is that the formulations I have seen of the palatability hypothesis treat the palatability construct as static, when in fact it is dynamic – very dynamic. The perception of the reward associated with a specific food changes depending on a number of factors.

For example, we cannot assign a palatability score to a food without considering the particular state in which the individual who eats the food is. That state is defined by a number of factors, including physiological and psychological ones, which vary a lot across individuals and even across different points in time for the same individual. For someone who is hungry after a 20 h fast, for instance, the perceived reward associated with a food will go up significantly compared to the same person in the fed state.

Regarding the CHO, it seems very clear that refined carbohydrate-rich foods in general, particularly the highly modified ones, disrupt normal biological mechanisms that regulate hunger. Perceived food reward, or palatability, is a function of hunger. Abnormal glucose and insulin responses appear to be at the core of this phenomenon. There are undoubtedly many other factors at play as well. But, as you can see, there is a major overlap between the CHO and the palatability hypothesis. Refined carbohydrate-rich foods generally have higher palatability than natural foods in general. Humans are good engineers.

One meme that seems to be forming recently on the Internetz is that the CHO is incompatible with data from healthy isolated groups that consume a lot of carbohydrates, which are sometimes presented as alternative models of life in the Paleolithic. But in fact among influential proponents of the CHO are the intellectual founders of the Paleolithic dieting movement. Including folks who studied native diets high in carbohydrates, and found their users to be very healthy (e.g., the Kitavans). One thing that these intellectual founders did though was to clearly frame the CHO in terms of refined carbohydrate-rich foods.

Natural carbohydrate-rich foods are clearly distinguished from refined ones based on one key attribute; not the only one, but a very important one nonetheless. That attribute is their glycemic load (GL). I am using the term “natural” here as roughly synonymous with “unrefined” or “whole”. Although they are often confused, the GL is not the same as the glycemic index (GI). The GI is a measure of the effect of carbohydrate intake on blood sugar levels. Glucose is the reference; it has a GI of 100.

The GL provides a better way of predicting total blood sugar response, in terms of “area under the curve”, based on both the type and quantity of carbohydrate in a specific food. Area under the curve is ultimately what really matters; a pointed but brief spike may not have much of a metabolic effect. Insulin response is highly correlated with blood sugar response in terms of area under the curve. The GL is calculated through the following formula:

GL = (GI x the amount of available carbohydrate in grams) / 100

The GL of a food is also dynamic, but its range of variation is small enough in normoglycemic individuals so that it can be treated as a relatively static number. (Still, the reference are normoglycemic individuals.) One of the main differences between refined and natural carbohydrate-rich foods is the much higher GL of industrial carbohydrate-rich foods, and this is not affected by slight variations in GL and GI depending on an individual’s state. The table below illustrates this difference.

Looking back at the environment of our evolutionary adaptation (EEA), which was not static either, this situation becomes analogous to that of vitamin D deficiency today. A few minutes of sun exposure stimulate the production of 10,000 IU of vitamin D, whereas food fortification in the standard American diet normally provides less than 500 IU. The difference is large. So is the difference in GL of natural and refined carbohydrate-rich foods.

And what are the immediate consequences of that difference in GL values? They are abnormally elevated blood sugar and insulin levels after meals containing refined carbohydrate-rich foods. (Incidentally, the GL  happens to be relatively low for the rice preparations consumed by Asian populations who seem to do well on rice-based diets.)  Abnormal levels of other hormones, in a chronic fashion, come later, after many years consuming those foods. These hormones include adiponectin, leptin, and tumor necrosis factor. The authors of the article from which the table above was taken note that:

Within the past 20 y, substantial evidence has accumulated showing that long term consumption of high glycemic load carbohydrates can adversely affect metabolism and health. Specifically, chronic hyperglycemia and hyperinsulinemia induced by high glycemic load carbohydrates may elicit a number of hormonal and physiologic changes that promote insulin resistance. Chronic hyperinsulinemia represents the primary metabolic defect in the metabolic syndrome.

Who are the authors of this article? They are Loren Cordain, S. Boyd Eaton, Anthony Sebastian, Neil Mann, Staffan Lindeberg, Bruce A. Watkins, James H O’Keefe, and Janette Brand-Miller. The paper is titled “Origins and evolution of the Western diet: Health implications for the 21st century”. A full-text PDF is available here. For most of these authors, this article is their most widely cited publication so far, and it is piling up citations as I write. This means that not only members of the general public have been reading it, but that professional researchers have been reading it as well, and citing it in their own research publications.

In summary, the CHO and the palatability hypothesis overlap, and the overlap is not trivial. But the palatability hypothesis is more difficult to test. As Karl Popper noted, a good hypothesis is a testable hypothesis. Eating natural foods will make an enormous difference for the better in your health if you are coming from the standard American diet, and you can justify this statement based on the CHO, the palatability hypothesis, or even a few others – e.g., a nutrient density hypothesis, which would be closer to Weston Price's views. Even if you eat only plant-based natural foods, which I cannot fully recommend based on data I’ve reviewed on this blog, you will be better off.