Lifeworld

One common outcome of doing glycogen-depleting exercise (e.g., strength training, sprinting) in combination with intermittent fasting is an increase in growth hormone (GH) levels. See this post for a graph showing the acute effect on GH levels of glycogen-depleting exercise. This effect applies to both men and women, and is generally healthy, leading to improvements in mood and many health markers.

It is a bit like GH therapy, with GH being “administered” to you by your own body. Both glycogen-depleting exercise and intermittent fasting increase GH levels; apparently they have an additive effect when done together.

Still, a complaint that one sees a lot from people who have been doing glycogen-depleting exercise and intermittent fasting for a while is that their fasting blood glucose levels go up. This is particularly true for obese folks (after they lose body fat), as obesity tends to be associated with low GH levels, although it is not restricted to the obese. In fact, many people decide to stop what they were doing because they think that they are becoming insulin resistant and on their way to developing type 2 diabetes. And, surely enough, when they stop, their blood glucose levels go down.

Guess what? If your blood glucose levels are going up quite a bit in response to glycogen-depleting exercise and intermittent fasting, maybe you are one of the lucky folks who are very effective at increasing their GH levels. The blood glucose increase effect is temporary, although it can last months, and is indeed caused by insulin resistance. An HbA1c test should also show an increase in hemoglobin glycation.

Over time, however, you will very likely become more insulin sensitive. What is happening is compensatory adaptation, with different short-term and long-term responses. In the short term, your body is trying to become a more efficient fat-burning machine, and GH is involved in this adaptation. But in the short term, GH leads to insulin resistance, probably via actions on muscle and fat cells. This gradually improves in the long term, possibly through a concomitant increase in liver insulin sensitivity and glycogen storage capacity.

This is somewhat similar to the response to GH therapy.

The figure below is from Johannsson et al. (1997). It shows what happened in terms of glucose metabolism when a group of obese men were administered recombinant GH for 9 months. The participants were aged 48–66, and were given in daily doses the equivalent to what would be needed to bring their GH levels to approximately what they were at age 20. For glucose, 5 mmol is about 90 mg, 5.5 is about 99, and 6 is about 108. GDR is glucose disposal rate; a measure of how quickly glucose is cleared from the blood.


As you can see, insulin sensitivity initially goes down for the GH group, and fasting blood glucose goes up quite a lot. But after 9 months the GH group has better insulin sensitivity. Their GDR is the same as in the placebo group, but with lower circulating insulin. The folks in the GH group also have significantly less body fat, and have better health markers, than those who took the placebo.

There is such a thing as sudden-onset type 2-like diabetes, but it is very rare (see Michael’s blog). Usually type 2 diabetes “telegraphs” its arrival through gradually increasing fasting blood glucose and HbA1c. However, those normally come together with other things, notably a decrease in HDL cholesterol and an increase in fasting triglycerides. Folks who do glycogen-depleting exercise and intermittent fasting tend to see the opposite – an increase in HDL cholesterol and a decrease in triglycerides.

So, if you are doing things that have the potential to increase your GH levels, a standard lipid panel can help you try to figure out whether insulin resistance is benign or not, if it happens.

By the way, GH and cortisol levels are correlated, which is often why some associate responses to glycogen-depleting exercise and intermittent fasting with esoteric nonsense that has no basis in scientific research like “adrenal fatigue”. Cortisol levels are meant to go up and down, but they should not go up and stay up while you are sitting down.

Avoid chronic stress, and keep on doing glycogen-depleting exercise and intermittent fasting; there is overwhelming scientific evidence that these things are good for you.

Let me start this post with a warning about spirits (hard liquor). Taken on an empty stomach, they cause an acute suppression of liver glycogenesis. In other words, your liver becomes acutely insulin resistant for a while. How long? It depends on how much you drink; possibly as long as a few hours. So it is not a very good idea to consume them immediately before eating carbohydrate-rich foods, natural or not, or as part of sweet drinks. You may end up with near diabetic blood sugar levels, even if your liver is insulin sensitive under normal circumstances.

The other day I was thinking about this, and the title of this article caught my attention: Alcohol Consumption and the Risk of Type 2 Diabetes Mellitus. This article is available here in full text. In it, Kao and colleagues show us a very interesting table (Table 4), relating alcohol consumption in men and women with incidence of type 2 diabetes. I charted the data from Model 3 in that table, and here is what I got:


I used the data from Model 3 because it adjusted for a lot of things: age, race, education, family history of diabetes, body mass index, waist/hip ratio, physical activity, total energy intake, smoking history, history of hypertension, fasting serum insulin, and fasting serum glucose. Whoa! As you can see, Model 3 even adjusted for preexisting insulin resistance and impaired glucose metabolism.

So, according to the charts, the more women drink, the lower is the risk of developing type 2 diabetes, even if they drink more than 21 drinks per week. For men, the sweet spot is 7-14 drinks per week; after 21 drinks per week the risk goes up significantly.

A drink is defined as: a 4-ounce glass of wine, a 12-ounce bottle or can of beer, or a 1.5-ounce shot of hard liquor. The amounts of ethanol vary, with more in hard liquor: 4 ounces of wine = 10.8 g of ethanol, 12 ounces of beer = 13.2 g of ethanol, and 1.5 ounces of spirits = 15.1 g of ethanol.

Initially I thought that these results were due to measurement error, particularly because the study relies on questionnaires. But I did some digging and checking, and now think they are not. In fact, there are plausible explanations for them. Here is what I think, and it has to do with a fundamental difference between men and women – sex hormones.

In men, alcohol consumption, particularly in large quantities, suppresses testosterone production. And testosterone levels are inversely associated with diabetes in men. Heavy alcohol consumption also increases estrogen production in men, which is not good news either.

In women, alcohol consumption, particularly in large quantities, increases estrogen production. And estrogen levels are (you guessed it) inversely associated with diabetes in women. Unnatural suppression of testosterone levels in women is not good either, as this hormone also plays important roles in women; e.g., it influences mood and bone density.

What if we were to disregard the possible negative health effects of suppressing testosterone production in women; should women start downing 21 drinks or more per week? The answer is “no”, because alcohol consumption, particularly in large quantities, increases the risk of breast cancer in women. So, for women, alcohol consumption in moderation may also provide overall health benefits, as it does for men; but for different reasons.

The “great blogosphere debate” rages on regarding the effects of carbohydrates and insulin on health. A lot of action has been happening recently on Peter’s blog, with knowledgeable folks chiming in, such as Peter himself, Dr. Harris, Dr. B.G. (my sista from anotha mista), John, Nigel, CarbSane, Gunther G., Ed, and many others.

I like to see open debate among people who hold different views consistently, are willing to back them up with at least some evidence, and keep on challenging each other’s views. It is very unlikely that any one person holds the whole truth regarding health matters. Unfortunately this type of debate also confuses a lot of people, particularly those blog lurkers who want to get all of their health information from one single source.

Part of that “great blogosphere debate” debate hinges on the effect of low or high carbohydrate dieting on total calorie consumption. Well, let us see what the China Study II data can tell us about that, and about a few other things.

WarpPLS was used to do the analyses below. For other China Study analyses, many using WarpPLS as well as HealthCorrelator for Excel, click here. For the dataset used here, visit the HealthCorrelator for Excel site and check under the sample datasets area.

The two graphs below show the relationships between various foods, carbohydrates as a percentage of total calories, and total calorie consumption. A basic linear analysis was employed here. As carbohydrates as a percentage of total calories go up, the diet generally becomes a high carbohydrate diet. As it goes down, we see a move to the low carbohydrate end of the scale.


The left parts of the two graphs above are very similar. They tell us that wheat flour consumption is very strongly and negatively associated with rice consumption; i.e., wheat flour displaces rice. They tell us that fruit consumption is positively associated with rice consumption. They also tell us that high wheat flour consumption is strongly and positively associated with being on a high carbohydrate diet.

Neither rice nor fruit consumption has a statistically significant influence on whether the diet is high or low in carbohydrates, with rice having some effect and fruit practically none. But wheat flour consumption does. Increases in wheat flour consumption lead to a clear move toward the high carbohydrate diet end of the scale.

People may find the above results odd, but they should realize that white glutinous rice is only 20 percent carbohydrate, whereas wheat flour products are usually 50 percent carbohydrate or more. Someone consuming 400 g of white rice per day, and no other carbohydrates, will be consuming only 80 g of carbohydrates per day. Someone consuming 400 g of wheat flour products will be consuming 200 g of carbohydrates per day or more.

Fruits generally have much less carbohydrate than white rice, even very sweet fruits. For example, an apple is about 12 percent carbohydrate.

There is a measure that reflects the above differences somewhat. That measure is the glycemic load of a food; not to be confused with the glycemic index.

The right parts of the graphs above tell us something else. They tell us that the percentage of carbohydrates in one’s diet is strongly associated with total calorie consumption, and that this is not the case with percentage of fat in one’s diet.

Given the above, one may be interested in looking at the contribution of individual foods to total calorie consumption. The graph below focuses on that. The results take nonlinearity into consideration; they were generated using the Warp3 algorithm option of WarpPLS.


As you can see, wheat flour consumption is more strongly associated with total calories than rice; both associations being positive. Animal food consumption is negatively associated, somewhat weakly but statistically significantly, with total calories. Let me repeat for emphasis: negatively associated. This means that, as animal food consumption goes up, total calories consumed go down.

These results may seem paradoxical, but keep in mind that animal foods displace wheat flour in this dataset. Note that I am not saying that wheat flour consumption is a confounder; it is controlled for in the model above.

What does this all mean?

Increases in both wheat flour and rice consumption lead to increases in total caloric intake in this dataset. Wheat has a stronger effect. One plausible mechanism for this is abnormally high blood glucose elevations promoting abnormally high insulin responses. Refined carbohydrate-rich foods are particularly good at raising blood glucose fast and keeping it elevated, because they usually contain a lot of easily digestible carbohydrates. The amounts here are significantly higher than anything our body is “designed” to handle.

In normoglycemic folks, that could lead to a “lite” version of reactive hypoglycemia, leading to hunger again after a few hours following food consumption. Insulin drives calories, as fat, into adipocytes. It also keeps those calories there. If insulin is abnormally elevated for longer than it should be, one becomes hungry while storing fat; the fat that should have been released to meet the energy needs of the body. Over time, more calories are consumed; and they add up.

The above interpretation is consistent with the result that the percentage of fat in one’s diet has a statistically non-significant effect on total calorie consumption. That association, although non-significant, is negative. Again, this looks paradoxical, but in this sample animal fat displaces wheat flour.

Moreover, fat leads to no insulin response. If it comes from animals foods, fat is satiating not only because so much in our body is made of fat and/or requires fat to run properly; but also because animal fat contains micronutrients, and helps with the absorption of those micronutrients.

Fats from oils, even the healthy ones like coconut oil, just do not have the latter properties to the same extent as unprocessed fats from animal foods. Think slow-cooking meat with some water, making it release its fat, and then consuming all that fat as a sauce together with the meat.

In the absence of industrialized foods, typically we feel hungry for those foods that contain nutrients that our body needs at a particular point in time. This is a subconscious mechanism, which I believe relies in part on past experience; the reason why we have “acquired tastes”.

Incidentally, fructose leads to no insulin response either. Fructose is naturally found mostly in fruits, in relatively small amounts when compared with industrial foods rich in refined sugars.

And no, the pancreas does not get “tired” from secreting insulin.

The more refined a carbohydrate-rich food is, the more carbohydrates it tends to pack per unit of weight. Carbohydrates also contribute calories; about 4 calories per g. Thus more carbohydrates should translate into more calories.

If someone consumes 50 g of carbohydrates per day in excess of caloric needs, that will translate into about 22.2 g of body fat being stored. Over a month, that will be approximately 666.7 g. Over a year, that will be 8 kg, or 17.6 lbs. Over 5 years, that will be 40 kg, or 88 lbs. This is only from carbohydrates; it does not consider other macronutrients.

There is no need to resort to the “tired pancreas” theory of late-onset insulin resistance to explain obesity in this context. Insulin resistance is, more often than not, a direct result of obesity. Type 2 diabetes is by far the most common type of diabetes; and most type 2 diabetics become obese or overweight before they become diabetic. There is clearly a genetic effect here as well, which seems to moderate the relationship between body fat gain and liver as well as pancreas dysfunction.

It is not that hard to become obese consuming refined carbohydrate-rich foods. It seems to be much harder to become obese consuming animal foods, or fruits.

The term “diabetes” is used to describe a wide range of diseases of glucose metabolism; diseases with a wide range of causes. The diseases include type 1 and type 2 diabetes, type 2 ketosis-prone diabetes (which I know exists thanks to Michael Barker’s blog), gestational diabetes, various MODY types, and various pancreatic disorders. The possible causes include genetic defects (or adaptations to very different past environments), autoimmune responses, exposure to environmental toxins, as well as viral and bacterial infections; in addition to obesity, and various other apparently unrelated factors, such as excessive growth hormone production.

Type 2 diabetes and the “tired pancreas” theory

Type 2 diabetes is the one most commonly associated with the metabolic syndrome, which is characterized by middle-age central obesity, and the “diseases of civilization” brought up by Neolithic inventions. Evidence is mounting that a Neolithic diet and lifestyle play a key role in the development of the metabolic syndrome. In terms of diet, major suspects are engineered foods rich in refined carbohydrates and refined sugars. In this context, one widely touted idea is that the constant insulin spikes caused by consumption of those foods lead the pancreas (figure below from Wikipedia) to get “tired” over time, losing its ability to produce insulin. The onset of insulin resistance mediates this effect.



Empirical evidence against the “tired pancreas” theory

This “tired pancreas” theory, which refers primarily to the insulin-secreting beta-cells in the pancreas, conflicts with a lot of empirical evidence. It is inconsistent with the existence of isolated semi/full hunter-gatherer groups (e.g., the Kitavans) that consume large amounts of natural (i.e., unrefined) foods rich in easily digestible carbohydrates from tubers and fruits, which cause insulin spikes. These groups are nevertheless generally free from type 2 diabetes. The “tired pancreas” theory conflicts with the existence of isolated groups in China and Japan (e.g., the Okinawans) whose diets also include a large proportion of natural foods rich in easily digestible carbohydrates, which cause insulin spikes. Yet these groups are generally free from type 2 diabetes.

Humboldt (1995), in his personal narrative of his journey to the “equinoctial regions of the new continent”, states on page 121 about the natives as a group that: "… between twenty and fifty years old, age is not indicate by wrinkling skin, white hair or body decrepitude [among natives]. When you enter a hut is hard to differentiate a father from son …" A large proportion of these natives’ diets included plenty of natural foods rich in easily digestible carbohydrates from tubers and fruits, which cause insulin spikes. Still, there was no sign of any condition that would suggest a prevalence of type 2 diabetes among them.

At this point it is important to note that the insulin spikes caused by natural carbohydrate-rich foods are much less pronounced than the ones caused by refined carbohydrate-rich foods. The reason is that there is a huge gap between the glycemic loads of natural and refined carbohydrate-rich foods, even though the glycemic indices may be quite similar in some cases. Natural carbohydrate-rich foods are not made mostly of carbohydrates. Even an Irish (or white) potato is 75 percent water.

More insulin may lead to abnormal fat metabolism in sedentary people

The more pronounced spikes may lead to abnormal fat metabolism because more body fat is force-stored than it would have been with the less pronounced spikes, and stored body fat is not released just as promptly as it should be to fuel muscle contractions and other metabolic processes. Typically this effect is a minor one on a daily basis, but adds up over time, leading to fairly unnatural patterns of fat metabolism in the long run. This is particularly true for those who lead sedentary lifestyles. As for obesity, nobody gets obese in one day. So the key problem with the more pronounced spikes may not be that the pancreas is getting “tired”, but that body fat metabolism is not normal, which in turn leads to abnormally high or low levels of important body fat-derived hormones (e.g., high levels of leptin and low levels of adiponectin).

One common characteristic of the groups mentioned above is absence of obesity, even though food is abundant and often physical activity is moderate to low. Repeat for emphasis: “… even though food is abundant and often physical activity is moderate to low”. Note that having low levels of activity is not the same as spending the whole day sitting down in a comfortable chair working on a computer. Obviously caloric intake and level of activity among these groups were/are not at the levels that would lead to obesity. How could that be possible? See this post for a possible explanation.

Excessive body fat gain, lipotoxicity, and type 2 diabetes

There are a few theories that implicate the interaction of abnormal fat metabolism with other factors (e.g., genetic factors) in the development of type 2 diabetes. Empirical evidence suggests that this is a reasonable direction of causality. One of these theories is the theory of lipotoxicity.

Several articles have discussed the theory of lipotoxicity. The article by Unger & Zhou (2001) is a widely cited one. The theory seems to be widely based on the comparative study of various genotypes found in rats. Nevertheless, there is mounting evidence suggesting that the underlying mechanisms may be similar in humans. In a nutshell, this theory proposes the following steps in the development of type 2 diabetes:

    (1) Abnormal fat mass gain leads to an abnormal increase in fat-derived hormones, of which leptin is singled out by the theory. Some people seem to be more susceptible than others in this respect, with lower triggering thresholds of fat mass gain. (What leads to exaggerated fat mass gains? The theory does not go into much detail here, but empirical evidence from other studies suggests that major culprits are refined grains and seeds, as well as refined sugars; other major culprits seem to be trans fats, and vegetable oils rich in linoleic acid.)

    (2) Resistance to fat-derived hormones sets in. Again, leptin resistance is singled out as the key here. (This is a bit simplistic. Other fat-derived hormones, like adiponectin, seem to clearly interact with leptin.) Since leptin regulates fatty acid metabolism, the theory argues, leptin resistance is hypothesized to impair fatty acid metabolism.

    (3) Impaired fat metabolism causes fatty acids to “spill over” to tissues other than fat cells, and also causes an abnormal increase in a substance called ceramide in those tissues. These include tissues in the pancreas that house beta-cells, which secrete insulin. In short, body fat should be stored in fat cells (adipocytes), not outside them.

    (4) Initially fatty acid “spill over” to beta-cells enlarges them and makes them become overactive, leading to excessive insulin production in response to carbohydrate-rich foods, and also to insulin resistance. This is the pre-diabetic phase where hypoglycemic episodes happen a few hours following the consumption of carbohydrate-rich foods. Once this stage is reached, several natural carbohydrate-rich foods also become a problem (e.g., potatoes and bananas), in addition to refined carbohydrate-rich foods.

    (5) Abnormal levels of ceramide induce beta-cell apoptosis in the pancreas. This is essentially “death by suicide” of beta cells in the pancreas. What follows is full-blown type 2 diabetes. Insulin production is impaired, leading to very elevated blood glucose levels following the consumption of carbohydrate-rich foods, even if they are unprocessed.

It is widely known that type 2 diabetics have impaired glucose metabolism. What is not so widely known is that usually they also have impaired fatty acid metabolism. For example, consumption of the same fatty meal is likely to lead to significantly more elevated triglyceride levels in type 2 diabetics than non-diabetics, after several hours. This is consistent with the notion that leptin resistance precedes type 2 diabetes, and inconsistent with the “tired pancreas” theory.

Weak and strong points of the theory of lipotoxicity

A weakness of the theory of lipotoxicity is its strong lipophobic tone; at least in the articles that I have read. See, for example, this article by Roger H. Unger in the Journal of the American Medical Association. There is ample evidence that eating a lot of the ultra-demonized saturated fat, per se, is not what makes people obese or type 2 diabetic. Yet overconsumption of trans fats and vegetable oils rich in linoleic acid does seem to be linked with obesity and type 2 diabetes. (So does the consumption of refined grains and seeds, and refined sugars.) The theory of lipotoxicity does not seem to make these distinctions.

In defense of the theory of lipotoxicity, it does not argue that there cannot be thin diabetics. Many type 1 diabetics are thin. Type 2 diabetics can also be thin, even though that is much less common. In certain individuals, the threshold of body fat gain that will precipitate lipotoxicity may be quite low. In others, the same amount of body fat gain (or more) may in fact increase their insulin sensitivity under certain circumstances – e.g., when growth hormone levels are abnormally low.

Autoimmune disorders, perhaps induced by environmental toxins, or toxins found in certain refined foods, may cause the immune system to attack the beta-cells in the pancreas. This may lead to type 1 diabetes if all beta cells are destroyed, or something that can easily be diagnosed as type 2 (or type 1.5) diabetes if only a portion of the cells are destroyed, in a way that does not involve lipotoxicity.

Nor does the theory of lipotoxicity predict that all those who become obese will develop type 2 diabetes. It only suggests that the probability will go up, particularly if other factors are present (e.g., genetic propensity). There are many people who are obese during most of their adult lives and never develop type 2 diabetes. On the other hand, some groups, like Hispanics, tend to develop type 2 diabetes more easily (often even before they reach the obese level). One only has to visit the South Texas region near the Rio Grande border to see this first hand.

What the theory proposes is a new way of understanding the development of type 2 diabetes; a way that seems to make more sense than the “tired pancreas” theory. The theory of lipitoxicity may not be entirely correct. For example, there may be other mechanisms associated with abnormal fat metabolism and consumption of Neolithic foods that cause beta-cell “suicide”, and that have nothing to do with lipotoxicity as proposed by the theory. (At least one fat-derived hormone, tumor necrosis factor-alpha, is associated with abnormal cell apoptosis when abnormally elevated. Levels of this hormone go up immediately after a meal rich in refined carbohydrates.) But the link that it proposes between obesity and type 2 diabetes seems to be right on target.

Implications and thoughts

Some implications and thoughts based on the discussion above are the following. Some are extrapolations based on the discussion in this post combined with those in other posts. At the time of this writing, there were 90 posts on this blog, in addition to many comments. See under "Labels" at the bottom-right area of this blog for a summary of topics addressed. It is hard to ignore things that were brought to light in previous posts.

    - Let us start with a big one: Avoiding natural carbohydrate-rich foods in the absence of compromised glucose metabolism is unnecessary. Those foods do not “tire” the pancreas significantly more than protein-rich foods do. While carbohydrates are not essential macronutrients, protein is. In the absence of carbohydrates, protein will be used by the body to produce glucose to supply the needs of the brain and red blood cells. Protein elicits an insulin response that is comparable to that of natural carbohydrate-rich foods on a gram-adjusted basis (but significantly lower than that of refined carbohydrate-rich foods, like doughnuts and bagels). Usually protein does not lead to a measurable glucose response because glucagon is secreted together with insulin in response to ingestion of protein, preventing hypoglycemia.

    - Abnormal fat gain should be used as a general measure of one’s likelihood of being “headed south” in terms of health. The “fitness” level for men and women shown on the table in this post seem like good targets for body fat percentage. The problem here, of course, is that this is not as easy as it sounds. Attempts at getting lean can lead to poor nutrition and/or starvation. These may make matters worse in some cases, leading to hormonal imbalances and uncontrollable hunger, which will eventually lead to obesity. Poor nutrition may also depress the immune system, making one susceptible to a viral or bacterial  infection that may end up leading to beta-cell destruction and diabetes. A better approach is to place emphasis on eating a variety of natural foods, which are nutritious and satiating, and avoiding refined ones, which are often addictive “empty calories”. Generally fat loss should be slow to be healthy and sustainable.

    - Finally, if glucose metabolism is compromised, one should avoid any foods in quantities that cause an abnormally elevated glucose or insulin response. All one needs is an inexpensive glucose meter to find out what those foods are. The following are indications of abnormally elevated glucose and insulin responses, respectively: an abnormally high glucose level 1 hour after a meal (postprandial hyperglycemia); and an abnormally low glucose level 2 to 4 hours after a meal (reactive hypoglycemia). What is abnormally high or low? Take a look at the peaks and troughs shown on the graph in this post; they should give you an idea. Some insulin resistant people using glucose meters will probably realize that they can still eat several natural carbohydrate-rich foods, but in small quantities, because those foods usually have a low glycemic load (even if their glycemic index is high).

Lucy was a vegetarian and Sapiens an omnivore. We apparently have not evolved to be pure carnivores, even though we can be if the circumstances require. But we absolutely have not evolved to eat many of the refined and industrialized foods available today, not even the ones marketed as “healthy”. Those foods do not make our pancreas “tired”. Among other things, they “mess up” fat metabolism, which may lead to type 2 diabetes through a complex process involving hormones secreted by body fat.

References

Humboldt, A.V. (1995). Personal narrative of a journey to the equinoctial regions of the new continent. New York, NY: Penguin Books.

Unger, R.H., & Zhou, Y.-T. (2001). Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes, 50(1), S118-S121.