Response to Dr. Paul Jaminet’s Rebuttal on Fructose

This rebuttal of sorts by Dr. Paul Jaminet was recently brought to my attention through a comment left on my Facebook page.  Danny Roddy was nice enough to lay out the arguments for me point by point.  Dr. Jaminet’s comments are in red.

1) “I think there’s substantial evidence that high fructose intake promotes endotoxemia” –PJ

This is not what I have found.

Diabetics and the obese have higher lipopolysaccharide (LPS) levels in their blood and they consume more fructose, primarily via HFCS, than people who are not diabetic or obese.   But as to specific food effects, the generation of LPS is buffered against on the ingestion of simple sugars because, for the most part, simple sugars are completely digested and absorbed in the upper part of the small intestines where microbial activity is minimal to non-existent. 

It is, however, conceivable that HFCS could lead to the generation of LPS because of the the presence of large starch molecules, if you recall.  Starch molecules, particularly when insufficiently cooked, can circumvent digestion and provide fodder for bacteria in the lower intestines, leading to the generation of LPS.

Endotoxemia occurs, though the definition is arbitrary, when blood levels of LPS rise by about 2- to 3-fold above normal levels.  Fats, in this regard, by permitting the passage of LPS into the body at high rates via newly made chylomicrons, execute the damages of LPS initiated by the increased proliferation of microbes in the intestines that was promoted by starches.

 

2) “The fact that many researchers use very high doses of fructose (in order to generate clear results in a reasonably short period of time) doesn’t prove that fructose is benign at lower doses” –PJ

This is a straw man.  I’m not saying that fructose is safe or beneficial merely because researchers employ high doses of it for the purpose of hastening the development of toxic effects in animals.  I’m instead saying that arguments should be established on studies in which fructose is (1) administered in the way it’s eaten in the real world (i.e., with glucose) and (2) given in more moderate and realistic doses (i.e., as reflected by consumption data).

3) “Kim seems to think it’s a good sign that “fructose ingestion induces thermogenesis”. However, in my view thermogenesis is a bad sign. It implies the presence of an energy excess (or a toxic macronutrient) which had to be disposed of.” –PJ

Diet-induced thermogenesis consists of (1) the energy costs of digesting, absorbing, and storing ingested nutrients and (2) the dissipation as heat, by the activation of the brown adipose tissue, which is blunted in obesity,¹ diabetes,² and old age, of ingested nutrients.

I don’t see this as a ‘bad sign’ or even the presence of ‘nutrient excess.’  This is because when isocaloric amounts of fructose and glucose are compared, studies show that fructose increases energy expenditure and total carbohydrate oxidation significantly more than glucose does throughout the whole body.  Studies also show that when fructose is exchanged calorie-for-calorie for glucose, weight loss becomes accelerated.

One way that fructose leads to greater thermogenesis than glucose is by shifting the cell’s energy charge.  Although this effect is subtle, fructose accomplishes this by (1) rapidly consuming phosphate via bypassing a key regulatory step in glycolysis and (2) by converting more readily to glycogen, while consuming twice as much ATP in the process, compared glucose.

Also, fructose, without insulin, apparently activates brown adipose tissue (that are loaded with uncoupling proteins) in conjunction with thyroid hormone, adrenalin, and noradrenalin^3–5.  Nutrients, therefore, are processed for heat rather than energy (ATP).

To what extent diet-induced thermogenesis contributes to long-term body fat regulation, I’m not sure.  But fructose (and sucrose) is less likely to lead to an increase in body fat than glucose (and starch) because compared to glucose, the ingestion of fructose, as a conservative estimate, leads to a 10-fold greater increase in energy expenditure than glucose does for hours after consuming it.

Consider what would happen if you conducted a study, where 100 subjects were enrolled and instructed to consume a 2,000 calories diet, 50 percent of which would come from carbohydrates.  You then assign half of the subjects to consume only sucrose, and the other half of the subjects to consume only glucose for a year.

The subjects would eat 3 square meals a day, so they can be conceived to be in the “fed-state” for about 16 hours of the day. Again, we would employ the conservative estimate that fructose leads to a 10-fold greater increase in energy expenditure during the “fed-state” than glucose does.

So, let’s say that fructose increases energy expenditure by 0.08 calories per hour per gram of fructose ingested, and glucose increases energy expenditure by 0.008 calories per hour per gram of glucose ingested.  Based on these rates, fructose leads to an increase in energy expenditure of 320 calories over the course of a day.

(.08 calories/hour) x (16 hours) x (250 grams of fructose) = 320 calories.

Glucose, on the other hand, leads to an increase in energy expenditure of 32 calories over the course of a day.

(.008 calories/hour) x (16 hours) x (250 grams of glucose) = 32 calories.

Therefore, the sucrose only group would be expending an extra 176 calories per day (160 + 16), whereas the glucose only group would be expending an extra 32 calories per day.  At the end of the study, the sucrose only group would expend an extra 63,360 calories (175 x 30 x 12), whereas the glucose only group would expend an extra 11,520 calories (32 x 30 x 12)—a difference of 51,840 calories. 

Because a pound of fat contains approximately 3,5000 calories, simply replacing sucrose for glucose in the diet, changing nothing else, would, in theory, lead to a decrease of slightly less than 15 pounds of body fat over the course of a year (51,840 ÷ 3,500).

4) “…the healthiest diet is the diet that eliminates hunger with the smallest calorie intake.” –PJ

Rather than the one that terminates hunger, I posit that the healthiest diet is the diet that allows us to eat the most, while minimizing the likelihood of gaining weight.  In other words, the healthiest diet is the diet that keeps the body temperature and metabolic rate optimized.  After all, heat is necessary for optimal biochemical activity of enzymes throughout the body, and the continuous supply of energy (ATP) is the basis for the organization and functioning of living cells.  Carbohydrates serve these purposes well, and they do so much better than fats do.

5) “…We even know the mechanism by which this happens: fructose depletes ATP in the liver, causing the release of adenosine, which is degraded to uric acid.” – PJ on fructose and uric acid

This has been overturned recently.  It turns out that at least 200 grams of pure fructose is needed for the toxic, uric acid increasing effect to kick in.⁶

Fructose does, in fact, deplete ATP more than glucose does simply because of the nature of its metabolism, but the effect is subtle and not necessarily undesirable.  By rapidly depleting the high-energy phosphate bonds of ATP, fructose (1) forces glucose to be used at a higher rate and (2) depletes the reducing cofactor called NADH, which is a good thing (and a topic for a whole other post).

So, through these dynamic processes the excessive accumulation of ADP, AMP, and adenosine (which irreversibly diffuses out of the cell and is ultimately degraded to uric acid) is effectively kept in check, and ATP levels inside cells don’t decrease too much.

6) “I won’t go further through his whole series, I’ll just observe that it’s easy to go astray when you focus on molecular biomarkers, hormones, or short-term responses to meals…If you look at our book, very rarely do we mention any of the body’s hormones or intermediate signaling molecules and base any argument on their levels. We argue from evolutionary lines of argument, or from direct links between nutrients themselves and diseases. This greatly reduces the chances of going astray.” - PJ

I tend to stay clear of  ‘evolutionary lines of argument’ because they are subject to a bit too much speculation for my taste, put too much focus on “traditional diets” that differ wildly between populations, and ignore the experiments in which animals reared in “artificial” settings live significantly longer than their counterparts living in the wild. 

Diseases with direct links to nutrient deficiencies have been established, and for the most part, conquered in developed parts of the world.  Keshan disease, for instance, which is a syndrome that occurs where selenium is deficient in the soil, has been largely eradicated by the fortification of foods with selenium.  In parts of China, for instance, where selenium is lacking selenium is given in salt, and this has dramatically reduced the incidence of Keshan disease.

The subtleties of the effects of nutrients in the body, however, can only be appreciated with an integrated understanding of nutrients’ metabolism in the body, and this includes their interactions with hormones and intermediate signaling molecules.  Take for example iodine, which is needed for thyroid hormone synthesis.  Too much iodine suppresses the thyroid gland but when given in just the right amount, optimizes thyroid hormone synthesis.  Thyroid hormone, in turn, donates iodine to immune system cells called neutrophils that then, using iodine, produce bactericidal compounds to clear away infections.

This bidirectional effect of iodine on the thyroid gland occurs fairly quickly, so the anti-infective effect of iodine can’t be comprehended, nor can doses of iodine be properly titrated, in the absence of hormonal data.

Although I agree with Dr. Jaminet that the short-term effects of meals should be taken with a grain of salt, I don’t think that they should be all together ignored, as they can serve as cues for consequences to come.

For instance, people who have a tendency to become hypoglycemic several hours after eating are at a very high risk for developing diabetes.  This is because, in response to hypoglycemia, the counterregulatory hormones are released, and the habitual, intensive release of these counterregulatory hormones over time could lead to insulin resistance and inhibit insulin secretion.⁷ 

These people require more support than others in the form of fructose that buffers against hypoglycemia and helps to moderate blood glucose levels, extra fat and protein with meals to slow the absorption of nutrients, more frequent meals, etc.

References

1.        Jung, R. T., Shetty, P. S., James, W. P., Barrand, M. A. & Callingham, B. A. Reduced thermogenesis in obesity. Nature 279, 322–3 (1979).

2.        Golay, A. et al. Glucose-induced thermogenesis in nondiabetic and diabetic obese subjects. Diabetes 31, 1023–8 (1982).

3.        Acheson, K., Jéquier, E. & Wahren, J. Influence of beta-adrenergic blockade on glucose-induced thermogenesis in man. The Journal of clinical investigation 72, 981–6 (1983).

4.        De Pergola, G., Giorgino, F., Benigno, R., Guida, P. & Giorgino, R. Independent influence of insulin, catecholamines, and thyroid hormones on metabolic syndrome. Obesity (Silver Spring, Md.) 16, 2405–11 (2008).

5.        Young, J. B., Weiss, J. & Boufath, N. Effects of dietary monosaccharides on sympathetic nervous system activity in adipose tissues of male rats. Diabetes 53, 1271–8 (2004).

6.        Wang, D. D. et al. The Effects of Fructose Intake on Serum Uric Acid Vary among Controlled Dietary Trials 1 – 4. (2012).doi:10.3945/jn.111.151951.kidney

7.        Ahrén, B. & Lundquist, I. Effects of alpha-adrenoceptor blockade by phentolamine on basal and stimulated insulin secretion in the mouse. Acta physiologica Scandinavica 125, 211–7 (1985).