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Wednesday, August 12, 2015

Sugar Addiction & Minerals ... Accidental Evidence Countering Addiction

Blogstress Note:

I wrote most of the analysis in this post around a year ago when I was looking for some additional examples of what I call "accidental evidences" against the concept of sugar addiction (and food addiction in general), just never got to tidying it up.  Therefore this post will be formatted a little oddly as it's what I have time for.  I'll do some general conclusions as regards sugar addiction, and then include the detail afterwards.  Whatever conclusions one might make vis a vis the minerals involved in this study are welcomed in comments, with the understanding that I'll likely not engage on those points due to time constraints.  In the end it seems difficult to arrive at any consistent conclusion  from the study I'll discuss, as results often contradicted themselves from one of the three experiments to the next.   While perhaps not as striking as the image I've chosen here, I believe the size (and thus age) differentials of the animals used is a confounding issue.

Accidental evidences

I don't know if I coined the phrase, but I've referred to stories as "accidental anecdotes" before here or in my comments in social media.  When a person thinks they're sharing an experience that supports their position when they are actually giving contradictory anecdotes, I call these accidental anecdotes.  Some of these may simply be related "side effects" one could say, effects the teller of the tale often doesn't consider to be related to whatever they're talking about.    

But experiments are not anecdotes, so I decided to broaden the scope to include this phenomenon in the scientific literature.  Accidental evidences then, are the results of some experiment that did not set out to show a particular effect or examine a particular hypothesis.   Sometimes such evidences can be better than confirming evidence in a study constructed to investigate the phenomenon proper.  Why?  Well, it seems to me that there can be no less biased an investigator out there than a disinterested one!  Such an investigator who "accidentally" designs an experiment controlling for various factors without intending to see some particular outcome is unlikely to present their data in a way such as to favor their particular hypothesis.

Food Addiction Research - A Scientific Mish Mosh Mess!

As I immersed myself in the food (and thus sugar) addiction literature, beginning almost two years ago now, I began to notice that the human studies tend to begin with a preconceived idea and set out to demonstrate it.  For example, bingeing is defined as a behavior associated with food addiction, binge eating disorders are more prevalent amongst the obese than in the general population, therefore, by definition, the obese are food addicts and that's how they got that way.  This doesn't study whether the binge behavior is actually a product of genuine substance dependence per accepted addiction models.    After all, when deprived of food for a sufficiently lengthy time, almost everyone would overeat food when it became available, so we're all addicted to food to some degree.  (There's also that whole death without it thing to consider ...)

But the vast majority of all addiction research has been conducted in animals, for no other reason than that it would be unethical to get a human addicted to something like alcohol or cocaine for experimental purposes.   While there's little controversy over the addictive qualities of these two and other substances, there remains significant controversy over the animal models used to evaluate this behavior.  Off the top of my head I can think of one study where the design of the dispenser was the deciding factor in whether or not a known addictive substance produced addictive behaviors in the test animals (sorry I can't place it at the moment).  That's pretty huge!  

In terms of sugar addiction, one of the reasons I bumped up the Fatty Diets & Diabetes post the other day, was that it was just such a study providing accidental evidences against the concept.  The researchers were looking at caloric intake, weight/fat gain and metabolic consequences of sugar and fat in the diet.  It was an extremely well designed study in this regard as purified diet components were mixed to carefully match both macronutrient (and type) and micronutrient composition.   The researchers did not intend to look into addiction.  Here are the results again, two strains of mice and four diet compositions.  LL low fat/low sugar, LH low fat/high sugar, HL high fat/low sugar, and HH high fat/high sugar.  I expanded just the low fat diet results below.

All low fat mice received the same fat, other carb, protein, vitamins and minerals in their chow.  The only difference was that the low sugar chow contained 60% cornstarch and the high sugar chow contained 60% pure white crystals of death.  The LH mice are being *forced* to consume an inordinate amount of sugar as it is an incorporated component of their only food source.   The mice neither ate more nor gained more weight.  Indeed in the more obesity prone strain the contrary effect -- eating less and weighing less -- was magnified considerably.  If sucrose were an inherently addictive substance, we would not expect to see these results.  Rather we would expect the mice to develop a tolerance for sugar, eat more and more and get fatter and fatter.  This is but one example of evidence to the contrary that is pretty difficult to counter.   Here's another:

Mineral Content of the Diet Alters Sucrose-Induced Obesity in Rats

As stated at the outset, I'm going to summarize this study and its outcomes vis a vis sugar addiction, and then leave the rest of my prior analysis to the end of this post.  Thus if it seems to lack a punchline, or seems repetitive, this is why.  

In this study they took ordinary Sprague Dawley rats and fed them a variety of purified diets composed of casein, cornstarch, maltodextrin, vegetable oil, vitamins, minerals, etc.   The sucrose/supplementation regimen in Experiments 1 & 2 was the same.  To the basic "diet" additional supplementation with Zn,Cr&Se was made and/or sucrose was made available as solution to the rats in an additional water bottle.  This created a four-way matchup similar to the study just discussed:  SS = sucrose/supplement, SN = sucrose/no supplement, NS = no sucrose/supplement, NN = no sucrose/no supplement.

The sucrose water was a 32% solution which is rather concentrated.  By comparison, sugar/HFCS-sweetened sodas average around 10% so this is 3X as concentrated.  The rats were all provided with fresh water.  The water intake is only reported for one of these two experiments and total fluid intake for the sugar rats is not reported.  One can calculate from the calories of sucrose consumed what the volume/mass of solution consumed would be, but we're offered no water intake data in Expt-1.  In Expt-2, the mineral supplemented rats drank roughly 5 fewer grams (milliliters) of water per day.  The NNs drank ~40 mL of water while the SNs drank ~15 mL water and ~35 mL sucrose solution = ~50 mL "fluids".  No conclusions can be drawn from this, but the mode of delivery is often overlooked as is something known as osmolarity.  Osmolarity can alter sensations of fullness, gastric disturbances, etc.  

turns out rats don't like
this stuff all that much
My point being, that the rats may simply prefer to drink liquid calories than eat dry food.  In the macronutrient choice studies, the fat diet is often described as liquid and rodents seem to generally prefer this, a factor that should be addressed.   The best way to get rodents to consume sugar and increase total calories appears to be by adding it to water.  Putting it in chow or offering it in dry form doesn't seem to do the trick.  Even so, at more normal concentrations, rodents tend to self-adjust chow (eat less) to compensate for the liquid calories.  In this study the researchers stated specifically that rats did NOT consume more total calories with the 32% sucrose solution in preliminary work, yet consistently the sugar rats consumed more total calories in this study.  

The ridiculous Caltons
image link
One of the explanations for why people tend to overeat refined foods is this idea that we are somehow craving missing micronutrients.   With three minerals tested, and others supplemented, this study certainly didn't explore anything approaching a full gamut of possible deficiency-cravings, but at least in the case of Zn, Cr or Se, the results seemed to counter this notion of craving.  

In this study, the rats ate consistently less of the "diet" (to which the minerals were added)  with Zn supplementation, and either the same amount or more of the sucrose solution.  Only Cr supplementation increased intake of the chow but it also increased sucrose intake.  To my interpretation, this indicates the rats may have had some aversion to the Zn in the supplement, a factor not addressed by the researchers.   In Expts-1&2, supplementing with Zn, Cr and Se either did not alter sugar intake or mildly increased it as rats ate less of the fortified chow.  The rats in Expt-2 that drank more sugar were smaller (and likely younger) than those who did not.  This would be consistent with some sort of aversion to the supplement as these rats were more actively growing.

In a third experiment, the rats supplemented with Zn consumed almost 50% more sucrose than those supplemented with Cr while consuming roughly 70% of the chow and roughly 90% of the total calories consumed by the Cr supplemented rats.  These rats -- the sugar guzzlers, getting 45% of their calories from sucrose -- weighed less and had smaller WAT depots.

If sucrose were addictive, and some deficiency in the diet is driving over-consumption of sugar which would then trigger the addiction cycle  -- tolerance, withdrawal, increased consumption, rinse, repeat -- then the high Zn rats should have continued to ramp up their sugar consumption over the course of the 9 weeks and gotten fatter.  There was no reporting of anything of this nature.

Going back to the first two experiments, in Expt-1 both sets of sugar rats consumed roughly 57 kcal of sugar daily.  If there's anything to the Zn aversion idea here, the rats eat less chow and would be more motivated to find calories elsewhere if anything.  Yet despite that alternative being an "addictive" substance, the older/fatter rats did not do so in Expt-1.  In Expt-2 the younger, smaller, growing rats, when unsupplemented, only ate around 45 kcal/day of sugar (38% of 117 kcal/day total).    When supplemented, the reduction in chow consumption is almost perfectly balanced by an increase in sugar calories such that these rats consumed 116 kcal/day of which 43% consisted of sugar (50 kcal/day).   The rats replaced about 5% of their nutrient rich balanced diet out for addictive Lustigian poison, and quite possibly were motivated to do so by an aversion to the Zn supplemented chow, and still no spiral into uncontrollable sugar intake.  

The results of this study are not consistent with the hypothesis that the sucrose molecule is physiologically addictive.

"Original Analysis"

The effects of dietary mineral levels on caloric intake, nutrient choice, body weight, adipose tissue weight, interscapular brown adipose tissue (IBAT) weight, and thermogenic capacity, and plasma insulin and glucose levels were examined in adult male Sprague -Dawley rats. In Experiments 1 and 2, rats were fed a purified diet with zinc (Zn), chromium (Cr), and selenium (Se) added, or the same diet without the addition of these minerals. In Experiment 3, the effects of Zn and Cr were examined separately. In all experiments, half of the rats in each diet group were given a 32% sucrose solution in addition to their standard diet and water. Rats given sucrose consumed more calories and gained more weight than rats not given sucrose. However, mineral levels altered the effects of sucrose on these measures. Added minerals increased percent sucrose intake, reduced weight gain and feed efficiency, increased GDP binding in MAT mitochondria, improved glucose tolerance, and reduced plasma insulin levels. The reduction in weight gain and increased feed efficiency found when Zn alone was added to the diet was independent of sucrose condition. In comparison, the alterations observed in these measures when Cr alone was added to the diet varied as a function of sucrose availability.

One of the theories on why refined food diets result in overeating is this notion of micronutrient malnutrition in the face of caloric overnutrition.  That somehow we crave or desire more food to meet our micronutrient needs.  This seems plausible, but I haven't seen much in the way of evidence to support it.    Where sugar is concerned, more specifically the fructose moiety (part) of the sucrose molecule, the "rub" against white table sugar vs. fruit is that it lacks all of the vitamins, minerals, antioxidants, and fiber.  In terms of the metabolic impact of sucrose, these theories have more legs, except then how about dates, honey and pure maple syrup?

This study certainly didn't seek to answer all of the questions, or even come close, but it did look at three minerals.   All of the experiments were conducted on males of a normal strain of rats (Sprague Dawley).  Here is the dietary composition for all protocols.  During all experiments the rats were allowed ad libitum access to all food and liquids supplied.  This included plain water as used to make the sucrose solutions.

In all experiments, those rats that received sucrose received a 32% (w/v) solution (in addition to plain water).  It should be pointed out that this is roughly 3X the concentration of sugar in a soft drink.     The chows were all fortified with USP XIV minerals that did not contain Zn, Cr or Se.  It was specifically noted that maintenance on these diets had not previously demonstrated any deficiencies.

The following was stated in the introduction to this paper:
  • In a preliminary experiment, rats given a 32% sucrose solution in addition to a purified diet failed to gain more weight or have more adipose tissue than rats given the diet alone (24)
  • The only difference between the purified diet used in this experiment and the diet used in previous work (25) was that the minerals zinc (Zn), chromium (Cr), and selenium (Se) were added to the mineral mix (U.S.P. XIV mineral mix)   [ I could not even find links to abstracts for these references. ]   
Note for all experiments, tables below are crunched together and highlighted and deal only with the intake, body and fat weights.  There may be something there in the metabolic responses but I just didn't have the time to decipher.  Bullet points below each table are from the text of the paper.  Use of the word "significant" relates to results that reached the level of statistical significance and is not used to indicate the relative magnitude.

Note also:  Retroperitoneal and epididymal fat are white adipose tissue, IBAT stands for Interscapular Brown Adipose Tissue.

Experiment One:   + Minerals = Zn, Cr and Se

Beginning rat weights 340-370 grams , Duration 60 Days

  • Total caloric intake did not differ as a function of mineral levels in the diet. 
  • Caloric intake was significantly higher for rats consuming sucrose
  • When given sucrose, the rats supplemented with minerals consumed significantly less of the "diet" than those that were not.
  • The sucrose intake was similar with or without additional minerals.
  • There was an insignificant trend towards the mineral supplemented rats consuming a higher percentage of their diet as sucrose.
  • "Across sucrose conditions, rats given the diet containing minerals gained significantly less weight on average (141.5 g) than those given the unsupplemented diet (190.5 g)"    Note:  141.5 = (127+156)/2 , 190.5 = (225+156)/2
  • "For rats fed the diet without added minerals, those consuming sucrose gained significantly more weight than those that had the diet alone. In contrast, for rats fed the mineral supplemented diet, those consuming sucrose gained less weight than those fed the diet alone."
  • In unsupplemented rats, the white adipose fat pads were significantly larger in the rats given sucrose.  In mineral supplemented rats, sucrose had no effect on white adipose fat weight.
  • IBAT:  Overall, sucrose fed rats had significantly heavier IBAT than rats fed the diet only.   This overall effect is dominated by the mineral supplemented rats as there was no difference in IBAT weights for the unsupplemented rats.

My General Comments:  
  • The rats in this experiment were rather large and no indication is given as to why they were used, or how old the rats were.   Overall in this experiment the rats averaged a gain of a little over 45% of initial body weight in 8.5 weeks.  
  • In this experiment, any differences in intake and weight are accounted for by the rats consuming LESS of the chow.  Increasing these three minerals in the diet had no effect on how much sugar water the rats drank.  Could this be explained by some sort of taste/sensitivity to the supplement?  
  • There is no mention of overall fluid intake in this section of the study.  

Experiment Two:   + Minerals = Zn, Cr and Se

Beginning rat weights 225-245 grams , Duration 63 Days (9 weeks)

  • Total caloric intake did not differ as a function of mineral levels in the diet. 
  • Caloric intake was significantly higher for rats consuming sucrose.
  • In sucrose fed rats when fed the mineral supplemented diet, they ate less diet and more sucrose though these absolute amounts are not noted to be significant.  Combined, however, the percentage of total calories as sucrose was significantly greater in the mineral supplemented rats.
  • All rats consuming sucrose gained an average of 288.5 grams, vs. the non-sucrose consuming rats averaging 274 grams.  This increased gain was statistically significant.
  • All together, mineral supplemented rats drank significantly less water than unsupplemented rats.    Water intake:  "supplemented diet and sucrose = 10.7 g; unsupplemented diet and sucrose = 14.8 g; supplemented diet without sucrose = 35.0 g; unsupplemented diet without sucrose = 39.5 g"
  • White Adipose Tissue:  "Across sucrose conditions, a trend toward lower epididymal fat pads weights was seen in rats fed the mineral-supplemented diet ... Retroperitoneal fat pad weights did not vary as a function of either diet or sucrose condition."   (note:  IBAT not measured)
My General Comments:  
  • As I got to Experiment 2, I started to get confused.  There is a lot of inconsistency in what is reported, etc.  
  • These rats are considerably smaller compared to those of Expt-1, and thus presumably younger.  That they gained considerably more weight in roughly the same time (63 vs 60 days), this would be expected of younger rats in a more rapid growth phase.  In Expt-1, rats began at ~355 grams and ended up averaging between 482 and 580 grams, in this experiment the ~ 235 gram rats grew to averaging between 497 and 530 grams.
  • For some reason water intake is reported in this experiment but not in Expt-1.   As the values for the sucrose rats are much lower, this intake is for the water provided to all rats and does not include water contained in the sucrose solution.  
  • Water as sucrose solution:  Using an average of around 48 kcal/day sucrose, divide by 4 gives us 12 grams sucrose.  These 12 grams in a 32% solution nets 37.5 grams sucrose solution.  If my calculations are correct, the sucrose consuming rats are drinking considerably more total fluid but I am unsure what, if any, conclusions can be drawn from this.
  • In terms of micronutrient deficiency or "craving" -- at least with respect to the three minerals studied -- if anything, supplementing resulted in slightly increased sugar intake.  It also again (compared with Expt-1) resulted in decreased intake of the supplemented diet.    As these were younger growing rats, the aversion to supplemental minerals idea floated in Expt-1 may be fostered by these results.  With the regular diet, the older/bigger rats consumed 55% of their calories as sugar as compared to only 45% for the younger/lighter rats.  The older rats might experience less hunger with mild aversion to chow than the younger rats who are relying on it for a majority of calories in a growth phase.   

Experiment Three:   + Minerals = Zn and Cr only 
Four groups of mineral supplementation
CrZn(high) = 600 mg Zn and 37.5 mg Cr per kg mineral mix
Zn(high)  = 600 mg Zn per kg mineral mix
CrZn(low) = 200 mg Zn and 37.5 mg Cr per kg mineral mix
Zn(low) = 200 mg Zn per kg mineral mix
Additional:  no contact to metal cages and de-ionized water used instead of tap water that might contain Zn and/or Cr.

Beginning rat weights 255-300 grams , Duration 63 Days (9 Weeks)

  • Regardless of mineral supplementation, all rats given sucrose consumed significantly more calories than those fed diet only.
  • All rats given sucrose consumed the same number calories except the high Zn supplemented group (no Cr) consumed significantly fewer calories.
  • Intake proportions between sucrose and diet were variable in the sucrose fed rats with a significant difference between the highest and lowest percents sucrose:  44% sucrose in Zn(high) vs. 28% sucrose in CrZn(low)
  • Rats consuming sucrose gained significantly more weight than those consuming diet only.
  • The rats consuming Zn(high) diet, with or without sucrose, gained the least body weight compared with other diets.
  • Feed efficiency varied with mineral content and sucrose feeding.
  • No differences in water intake were seen among diet conditions.
  • Rats given the sucrose solution drank significantly less water than animals not given the sugar solution
  • Rats consuming sugar had higher WAT mass and BAT mass.

My General Comments:  
  • These rats were between those from Expt-1 and Expt-2 in size (and likely age), with the widest of all ranges of starting weights of 45 grams!  Using an an average starting weight of ~278 grams, final weight averages would span from 506 to 595 grams.
  • Although it is mentioned in the discussion, it is not stressed that the Zn(low) diet is essentially their unsupplemented control here.  There was concern that lack of trace Zn available in tap water might have caused a deficiency and weight loss so a minimum of 200 mg/kg of mineral mix was used.   Given the variation in the animals used in these experiments, it seems they could have at least done a NN group using tap water to compare.  Alternately, the minimum Zn supplementation should have been in the water as this was the source for rats in Expts-1&2.
  • Together with Expt-1 where older rats may not have been as "motivated" to consume calories, and Expt-2 where younger rats may have been seeking calories more than anything else, these results make a case for Zn aversion.

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