Are You Afraid that the Fructose Boogieman Clogs Up Your Liver? Citrulline or Alanine, Glycine, Proline, Histidine and Aspartate Mix Will Protect You + Maybe Lean You Out

If you belong to the people who simply cannot stay away from HFCS foods and beverages, you may be happy to hear that the equivalent of as little as 10g citrulline or NEAAs in your diet may do much more than "just" fully prevent its negative effects on your liver.

You will probably remember from previous articles I wrote that NAFLD, or rather the development of non-alcoholic fatty liver disease, is one of the earliest markers of metabolic syndrome and beginning type II diabetes. In the Western obesity societies in North America and Europe, NAFLD is among the most common causes of chronic liver disease and its prevalence is increasing rampantly (Marchesini. 2001).

In spite of the fact that its development is most strongly linked to the consumption of a generally unhealthy, energetically dense diet, there are several lines of evidence which suggest that the ingestion of exorbitant amounts of fast-digesting fructose from high fructose corn syrup (HFCS) sweetened beverages or processed foods is one, if not the most reliable motor of its development (Volynets. 2012).

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On a molecular level fructose has been shown to trigger the production of fat from glucose in the liver (de novo lipogenesis | DNL). It does so by activating certain enzymes via the sterol regulatory element binding protein-1c (SREBP1c) and/or the carbohydrate-responsive element-binding protein (ChREBP). In conjunction with the corollary hepatic oxidative stress and the subsequent increase in insulin resistance, the onslaught of readily absorbed fructose from processed foods and HFCS-sweetened beverages is thus  like gasoline on the fire of the obesogenic baseline diet some people refer to as the "standard american diet" (learn why the "SAD-diet" is so good at making you fat). On the whole, however, the accumulation of fatty streaks in the liver that's so characteristic of NAFLD is yet only the point of departure of the journey to the land of the super-obese type II diabetics.


Now this journey from slightly overweight to super-obese is a journey of which many previous studies studies already suggested that it could take a very different route if people consumed higher amounts of protein and/or certain amino acids (AAs):

• Theytaz et al. (2012), for example, found a "liver cleansing" increase in VLDL-TG release by the liver with an essential AA-enriched diet, and
• Bortolotti et al. (2012) showed that a protein-enriched diet can effectively reduce the fructose induced lipid accumulation in the liver through increased energy expenditure. 

As Prasanthi Jegatheesan et al. point out, "[t]hese beneficial effects of AAs or proteins may arise through lipid oxidation, decreased DNL, and modulation of genes involved in lipid metabolism" (Jegatheesan. 2015). Since citrulline is the precursor for the renal synthesis of Arg, which is known to improve insulin sensitivity and lipid metabolism, and has been shown to have beneficial effects on the level of plasma triglycerides and fat deposition in the liver, the authors of a recent study speculated that "Cit supplementations might [...] able to limit the development of fructose-induced NAFLD" (Jegatheesan. 2015). Morever, Jegatheesan et al. expected to see similar effects with other nonessential amino acids (NEAA), of which their own previous research had shown that they may offer similar anti-NAFLD effects.

Where's the control group? Previous studies show that diets which are supplemented with NEAAs (alanine, glycine, proline, aspartate, histidine, and serine) or citrulline have metabolic and nutritional effects similar to a regular control diet, alone (Osowska. 2006; Jegatheesan. 2015). The CNEAA group is thus the "control" group in the study at hand. That's "ok" and doesn't make the study results useless, but in view of the fact that the data in Figure 2 shows more than just an ameliorative effect of citrulline on NAFLD, I would have preferred a regular control group in which the rodents had been fed standard chow without added non-essential amino acids.

To confirm or falsify their hypotheses, the researchers randomized twenty-two rats into four groups on different diets:

• CNEAA as in control - control diet without added fructose + 1g/kg non-essential amino acids (for humans that's roughly 11g per day | this was the control diet in the study at hand)
• F as in fructose- control diet enriched with 60% fructose without supplements
• FNEAA as in control + fructose - fructose enriched diet (F) + 1g/kg non-essential amino acids (which happens to be the control diet in the study at hand)
• FCIT as in fructose + citrulline - fructose enriched diet (F) + 1g/kg citrulline

In that, it's important to note that the NEAA supplement contained isomolar amounts of the 6 AAs and was isonitrogenous to the Cit diet. So, a mere difference in the nitrogen content of the chow cannot explain the obvious differences that occurred over the course of the 8-week study period.

Figure 1: Relative changes in liver weight, hepatic triglyceride content as well as the liver markers AST, ALT and ALP a marker of kidney health  compared the "control" group (CNEAA | Jegatheesan. 2015)

A period, in which the rodents in the fructose enriched diet group (F) developed NAFLD. A fate the rats in the FCit and the FNEFA group did not share - even though the amount of fructose in their diets was exactly as high as it was in the F group.

Figure 2: Both FNEAA and FCit rodents had a better body composition than the rodents on the NEAA supplemented control diet, but the differences reached statistical sign. only compared to the fructose (F) group (Jegatheesan. 2015)

In that, it is unquestionably worth noting that we are not talking about a mere amelioration of the fructose induced damage. If you look at the data you will notice that the rodents with the alanine, glycine, proline, aspartate, histidine, and serine enhanced fructose enriched diets actually ended up having healthier livers than those on the non-fructose diet... if that's not convincing evidence that the commonly heard, and painfully overgeneralized claim that "fructose is the root cause of all metabolic diseases" is bogus, I don't know.

So, why would you even consider citrulline, if the NEAA combo is better for your liver? 

Well, the reason that the average physique enthusiast, may still choose citrulline as his "fructose buffer" of choice is easy: Firstly, the differences in terms of liver health are not really statistically significant. Secondly and more importantly, though, citrulline triggered a reduction in visceral and total fat mass and a relative increase lean mass that was not observed in the NEAA group. And let's be honest: Isn't this type of body recompositioning effect what many of you are striving for?

What is most astonishing though, is that you could have these fat loss and muscle gain effects not just despite, but maybe even because you're guzzling HFCS drinks all day (obviously we'd have to have a citrulline + baseline diet group to confirm that). If we assume that the results translate 1:1 to human beings, the one thing you had just ~10g of citrulline per day. Is this possible? Well, it is, but let's be honest with ourselves: The inter-group differences between the control and the citrulline + fructose were not statistically significant. So while there were improvements those were not pronounced enough to be of statistical significance even in rodents. It is thus not really surprising that you haven't heard of citrulline as the "get jacked" amino acid very often... even though, evidence that it can help you to get jacked does exist (more).

Bottom line: It is quite astonishing how commonly ignored correlates of high fructose intakes can turn an obesogenic liver killer into a regular energy supplier. I mean, look at the data in the study at hand: Where's the evidence that fructose is worse than any other energy source, when a simple increase in NEAA or citrulline intake does not just nullify its effects but has the rodents on the 60% fructose diet end up leaner and with lower liver fat and better AST and ALT levels than their peers on the control diet (these differences are only partly statistically sign., though).

Citrulline & Glutathione - GSH Amplifies & Prolongs CIT's NO Boosting Effects During + After Biceps Workout | learn more.

So, just as Jegatheesan et al. say: When combined with NEAAs or citrulline, fructose is not just harmless, but can even "produced an overall change in nutritional and metabolic status, with lower body weight and altered body composition, [in spite of identical" food/energy [...] among groups" (Jegatheesan. 2015). Unfortunately, the precise mechanisms involved still need to be investigated. Jegetheesan et al. are yet relatively convinced that NEAAs and citrulline act via different pathways: "NEAAs may act through GCN2, citrulline could act on the liver via PPARa and the down-regulation of SREBP1c, for example, via protein kinase B and mTOR pathway, but also via the improved insulin sensitivity enabled by peripheral Arg bioavailability" (ibid). Just as it is the case for the applicability in humans, though, these hypotheses require future experimental verification | Comment!

References:

• Bortolotti, Murielle, et al. "Effects of dietary protein on lipid metabolism in high fructose fed humans." Clinical Nutrition 31.2 (2012): 238-245.
• Jegatheesan, Prasanthi, et al. "Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease." Clinical Nutrition (2015).
• Jegatheesan, Prasanthi, et al. "Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats." The Journal of Nutrition (2015): jn218982.
• Marchesini, Giulio, et al. "Nonalcoholic fatty liver disease a feature of the metabolic syndrome." Diabetes 50.8 (2001): 1844-1850.
• Osowska, Sylwia, et al. "Citrulline modulates muscle protein metabolism in old malnourished rats." American Journal of Physiology-Endocrinology and Metabolism 291.3 (2006): E582-E586.
• Theytaz, Fanny, et al. "Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans." The American journal of clinical nutrition 96.5 (2012): 1008-1016.
• Volynets, Valentina, et al. "Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD)." Digestive diseases and sciences 57.7 (2012): 1932-1941.

What's Worse for Your Body Composition & Liver Health? 10g of Sugar from Coke or the Same 10g From Cookies? Plus: Liquid Sucrose is Harder on the Liver Than Fructose

Hard do believe, but the 10g from coke may actually do more harm than the same amount from cookies.

If you want to scare me away from a discussion about the "fat problems" the US and large parts of Europe are struggling with, you just have to repeat Taubs'ian statements such as "if we had not eaten carbohydrates all the mess wouldn't have happened."

It's certainly true that the exorbitant and mislead carbohydrate intake and the psyochological consequences ("Fat is bad, isn't it?") of the "low fat" decades from the 1970-1990s is part of the problem, but when we look closer, it's not as simple as to say "we don't eat enough fat".

As Yvonne Ritze and her colleagues from the University of Hohenheim, the Technische Universität München, and the Interdisciplinary Obesity Center in Rorschach (Switzerland) write in their latest paper in PLoS One, it's rather the unhealthy conglomerate of "changes in dietary and eating behavior such as preferring sugar-sweetened beverages and sugar-rich processed food, in addition to a sedentary life style", which is to blame form the "sharp rise in obesity" (Ritze. 2014).

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In said paper, Ritze and her colleagues present data from rodent and human experiments they conducted which highlight the fact the "form of sugar intake (liquid versus solid) is presumably more important than the type of sugar" (Ritze. 2014), when it comes to its ability to disturb our appetite regulation, increase the fat accumulation in the liver and promote the development of type II diabetes.

In mice, Ritze et al. observe a liquid high-sucrose diet caused an enhancement of total caloric intake which was not comparable to the effects the solid variety of the high sucrose diet had.

Figure 1: Diet (left) and energy (right) intake in the five diet groups (Ritze. 2014)

Over the course of the experiment (8 weeks), the female C57BL/6 mice (Janvier, Saint Berthevin Cedex, France) had been feed on one out of the following five ad-libitum (=eat as much as you want to) diets:

• Group 1 (controls, C) received water and mouse breeding (MZ)-diet (standard diet from Sniff, Soest, Germany) containing 10% (g/g) sugars. 
• Groups 2 (fructose liquid, Fl) and 3 (sucrose liquid, Sl) received water supplemented with fructose or sucrose at 30% (vol/vol), respectively, and enriched MZ-diet to compensate for reduced food uptake. 
• Groups 4 (fructose solid, Fs) and 5 (sucrose solid, Ss) received water and the high-fructose or -sucrose diet containing 65% (g/g) sugars, which equals the sugar amount per day that mice ingested when offered sugar water at 30%. 

Every two weeks the mice were placed in metabolic cages for 24 h, to which they had been acclimatized before. The mice were weighed, their food intake and feces analyzed and their body composition quantified; and what the scientists found was:

1. The sugar intake in groups 2-4 was significantly higher than in group 1 - obviously a simple and necessary consequence of the composition of the diet
2. The mice on the liquid diets consumed significantly more energy, sugar, liquid and food - distinct evidence that the rodent equivalent of sugar-sweetened beverages leads to overeating
3. The fructose diets were not by any means worse than the sucrose diets - an observation that confirms what I have been preaching to the choir: The fructose bashing as "lustig" (engl. "funny") as some experts believe it was, is based on a shortsighted prejudice
4. The weight increase in the solid high-sucrose groups was small compared to that of the mice in groups 2 & 3 who were fed sucrose or fructose in their water - this is the logical consequence of the increased energy intake
5. When the scientists compared the obesogenic effects (weight gain per food intake) of the diets, they found a significant difference between the liquid and solid sugars but not the sugar types - more evidence we cannot simply blame everything on fructose
6. Interestingly, all four high sugar-diets caused an increase in blood glucose and in tendency some increase in liver weight, which was more pronounced if the sugars were administered in solid form.

In addition, Ritze et al. found a strong increase in GLUT2 mRNA expression (Fl = about 90 fold;  P < 0.001; Sl = about 160 fold; P < 0.001) when sugars were dissolved in drinking water compared to the control mice - again more pronounced in the sucrose vs. fructose group. Compared to the 90x & 160x increase in the liquid groups, the likewise significan increase of ileal GLUT2 mRNA expression (P < 0.05) in the solid high sugar groups 4 & 5 was almost negligible.

"Similar results were obtained for GLUT5 mRNA expression. Comparing sugar form and type we showed a significant difference between liquid and solid sugar form for GLUT2 and GLUT5 (P < 0.001) as well as a significant difference of sugar type (fructose versus sucrose) for GLUT5 (P < 0.05) within the different dietetic groups." (Ritze. 2014)

Whether these difference in glucose transporter activity are actually relevant (they would simply speed up the uptake of glucose / fructose) is questionable.

Is absorption speed all that matters?

Figure 2: Suspiciously similar changes in glut-2 & 5 expression in the two groups fed liquid diets (top) and obese vs. lean human (bottom)

The fact that Ritze et al. observed them when they compared the GLUT2 and GLUT5 expression in obese and lean human subjects, as well, is yet quite telling. In the end, it may thus in fact all be about "speed" and the question "How fast is the sugar trickling into your body?"

Whether the speed of the sugar influx is also responsible for the slightly up-regulated ghrelin mRNA levels in mice who were fed the liquid diet compared to the solid diet (P < 0.05) is something, I cannot tell. What I can tell you though is that (a) elevated or rather not appropriately reduced ghrelin levels after a meal are characteristic of obese vs. lean humans, too (Le Roux. 2005) and that (b) there was once again no difference between fructose and sucrose diet.

Did you ever notice that none of the "fructose is bad studies" was conducted with a solid diet? The fructose was always provided on top of a solid diet with the liquid, just like the the surcose and fructose in the diet at hand. And if we are honest, it does not look like fructose was by any means significantly worse than simple sugar (which obviously is a 1:1 glucose : fructose mixture).

Figure 3: Effect of high-sugar diets on hepatic lipid accumulation. Concentrations of triglycerides in the liver (A), and liver to body ratio (B) were detected. Portal endotoxin (C), and Oil Red O staining showing fat accumulation in the liver (D) are shown

Now, what certainly comes as a surprise is the fact that it's not the liquid fructose group which had the highest liver fat concentrations, but rather the group that received the equivalent of sugar (=sucrose) sweetened beverages in their diets (see Figure 3, A). Accordingly, the Oil Red O staining in Figure 3, D is most significant in the Sl (=sucrose liquid) diet group.

The endotoxin concentration in the portal vein (see Figure 3, C), on the other hand, are the highest (yet not significantly elevated!) in the fructose groups. In conjunction with the relatively low triglyceride levels in the liver this goes against a theory by Bergheim et al. which revolves around the idea that fructose induced changes in the gut microbiome would lead to an increased endotoximia (this is true) and consequent fatty liver disease (this is at least less severe that with sucrose in the study at hand).

Bottom line: Let's get away from the "fructose vs. the rest of the world" discussion and focus on those "foods" that contain significant amounts of fructose. If you click on "foods highest in fructose" on nutritiondata.com, you will obviously find "pops, sodas, and soft drinks" on the first three ranks. And while they do have a high fructose concentration (29.8g per 200ml serving), the study at hand should remind you of another thing they have in common... ha? Yeah! Right, they are liquid fast absorbing and a real stressor for your liver.

Figure 4: Replacing SSBs or juices with water or artificially sweetened beverages has identical beneficial effects on the weight trajectory of adults (Pan. 2013) - Even low fat milk would have you gain less body weight!

I am far from suggesting that after blaming fructose for everything, we should now start blaming liquid foods for everything, but the results Ritze et al. present in their latest paper do in fact "provide evidence that liquid versus solid high-sugar diets differentially modulate feeding behavior, distinct intestinal sugar transporters and weight regulating hormones" and may thus be "a critical component for the development of obesity and fatty liver disease", not just in mice, but also in humans, where Ritze et al. found "similar enhanced sugar transporter regulation within the small intestine as in liquid high-sugar diet fed mice" and previous studies suggest that simply replacing energy containing drinks with water will inhibit or at least slow down long-term weight gain (Pan. 2013)

Reference:

• Bergheim, Ina, et al. "Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin." Journal of hepatology 48.6 (2008): 983-992. 
• Le Roux, C. W., et al. "Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects." The Journal of Clinical Endocrinology & Metabolism 90.2 (2005): 1068-1071. 
• Pan, An, et al. "Changes in water and beverage intake and long-term weight changes: results from three prospective cohort studies." International journal of obesity 37.10 (2013): 1378-1385. 
• Ritze, Yvonne, et al. "Effect of High Sugar Intake on Glucose Transporter and Weight Regulating Hormones in Mice and Humans." PloS one 9.7 (2014): e101702.

Fructose - An Update: "Fructose Has Adverse Effects Only Insofar as It Contributes to Excess Calories" Plus: The Role of Exercise + Meta-Analyses on BP, Weight Gain & T2D

It's incredible... for some, but probably not unexpected for most of us that fructose becomes problematic in overfeeding scenarios, only.

Some of you will probably have seen the press release from the St. Michel's Hospital that made it onto all the major science outlets on the Internet and up on Alex' Facebook page, where he tagged me and thus got me interested in a study that claims to provide evidence that: "Fructose does not impact emerging indicator for cardiovascular disease" | read more.

The main goal of the corresponding paper that has been published in the Atherosclerosis earlier this months (Wang. 2014) was to identify and analyze all clinical interventions that investigated the chronic effect of exchanging isocaloric or hypercaloric oral fructose for a reference carbohydrate on postprandial triglycerides.

Update - Coca Cola & Co buy a white slate for their sugar-sweetened beverages (SSB): Shortly after publishing my analysis of the meta-analysis, I hit onto a more recent review that deals with sugar sweetened beverages and the influence sponsors from the industry have on the outcome of corresponding studies and, more importantly (since easier to be biased) reviews. While the main finding of Bes-Rastrollo's et al.'s analysis is that there is a 5x higher likelihood of SSBs being portrayed as benign, when reviews are financed by the industry, the editor of PLoS|One Medicine rightly points out that "[a] major limitation of the study at hand is however that it cannot assess which interpretation of the available evidence is truly accurate" and that "scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings". In other words, financed and non-financed research are both biased" (Editorial published with Bes-Rastrollo. 2013 | learn more).

Don't forget: Nobel Laureate Peter Higgs worked with the method on the right: Conclusion first: "There is a boson that mediates gravitational forces" ➲ Years of research: "Heureka!"

It's also important that you realize that meta-analysis such as the one at hand are less prone to bias, than regular reviews (including those of Internet celebrity scientists ;-). This is particularly true, when they are conduced according to the strict criteria of the Cochrane Collaboration (something that applies to Wang et al's analysis). If the you want to pick the results of the meta-analysis at hand apart, you will thus have to (a) prove that they deliberately ignored studies although those complied to the inclusion criteria (selection bias) or (b) that important studies that have been included were so biased that the overall result of the meta-analysis (which is mostly math) gets skewed.

The scientists included ony human trials and the deadline on which they stopped looking for new studies was September 3, 2013. In other words: Wang et al. don't bother us with rodent data with questionable relevance (e.g. rodents on 70% fructose diets) and they include almost alll studies in their review that have been published in the last couple of most... well, assuming they were available on MEDLINE, EMBASE, and in the Cochrane databases and complied to the following criteria:

"We included clinical interventions that investigated the chronic effect of exchanging isocaloric or hypercaloric oral fructose for a reference carbohydrate on postprandial triglycerides in humans. Comparisons were considered “isocaloric”if oral fructose in the fructose arm was exchanged for the reference carbohydrate in the control arm in an iso-energetic and iso-glucidic manner and“hypercaloric” if the oral fructose in the fructose arm was provided as a supplement to the background diet providing excess energy (E) relative to the background diet alone in the control arm. Trials with less than 7 days follow-up, which lacked an adequate carbohydrate control, or administered IV-fructose were excluded" (Wang. 2014)

It's quite funny to see how the 1259 initial hits were decimated in the review process with 111 being identified as duplicates, 270 not being having human, but hairier subjects,  54 being only case studies, 2 being letters in disguise, 280 papers being reviews, 233 papers having only a general CHO arm, 71 studies with intravenous administration, 127 studies with "unsuitable endpoints" (e.g. measuring the effect on exercise performance), 61 having a study duration < 7 days and two simply being irretrievable in full-text form.

Now you may be asking yourselves, why I am bothering you with this!? Right? Well, firstly, I want to give yo an idea of how painful it is to write an objective review of the literature. I realized the same only recently, when I compiled the True or False item on dairy induced reductions in testosterone and its possible carcinogenicity. Secondly mentioning the fact that 1211 articles were excluded in the 1st and 48 articles in the 2nd phase of the review process may help silencing all the fructose haters who read this and consider it the work of diabolical cherry pickers, who have received grants from the devil, i.e. the Coca-Cocal Company and a whole host of other usual and unusual suspects, in the past (read the long list of "competing interests" and don't forget that the study at hand was not funded by any high fructose corn-syrup interest group).

A note on potential bias: As I have pointed out numerous times, already. A "competing interest" is no reason to discard the results of a paper / review altogether. Especially in the case of the latter, you should yet carefully evaluate the scientists interpretation of the reviewed literature, because - consciously or not - those interpretations may well be influenced and the corresponding conclusions biased by a researchers' basic assumptions. Unbiased research is - and I am sorry to say that - an illusion that's never going to manifest in the real world; and that's true irrespective of funding / research grants (Schulz. 1995).

While I do hope t hat I am not implying we were talking about scientific fraud here, you should still keep in mind that information Sievenkemper, who is the "correspond author", i.e. the media guy among the 15 scientists from 12 research institutes in Canada, gave Leslie Shepherd, the author of the the initially mentioned press release (Shepherd. 2013), is not some sort of objectively measured truth (there are philosophers of science who question such a thing does even exist). 

"[F]uctose doesn’t behave any differently than other refined carbohydrates. The increases you see are when fructose provides extra calories." (Sievenkemper in Shepherd. 2013)

The above is his (and his colleagues) professional opinion, of which I seriously doubt that it was consciously influenced by previous research grants or the current financial support from the Canadian Institutes of Health Research and the Calorie Control Council that funded the study at hand.

Effects of hypercaloric diet (+50%) w/ 30% fructose content on triglyceride production and clearance in healthy subjects in the presence and absence of exercise (Egli. 2013)

A minimalist explanation of the results: Based on the way fructose is metabolized (increased triglyceride production, reduced storage in fat cells; cf. Chong. 2007), it is only logical that there is a minimal effect on serum triglycerides. In the absence of a hypercaloric diet, this statistically and physiologically non-significant increase is yet not a threat to your health. Your body will simply use the part of fructose your liver converts to triglycerides as an energy source. Only when the total energy intake is so high that it is no longer necessary / possible to use the trigs as an energy source, the latter will begin to accumulate in the blood and. even worse, in the liver (NAFLD). For you that would mean trouble - unless, of course, you work out and use the superfluous trigs to fuel your workouts (Egli. 2013; figure to the left).

Basically, what the scientists did to form this "professional opinion" was (1) reading the papers several times, (2) weighing them by a set of pre-determined criteria from the Cochrane Handbook for systematic reviews of interventions (Higgins. 2011), (3) filtering out all relevant data, (4) calculating the SMD's (standard mean differences) for pre vs. post intervention triglycerides levels of the average study subject for each individual study, (5) pooling the data in groups (healthy subjects, overweight / obese subjects, diabetics), and finally (6) using the individual weight of the to calculated the SMDs [including 95% confidence intervals] for different subject groups. The results, i.e....

• 

  Complete results (Wang. 2014)

  otherwise health: 0.30 [-0.00, 0.60]; weight 37.8%
• overweight / obese: 0.69 [0.20, 1.19] *; weight: 6.8%
• diabetes: 0.00 [-0.15, 014]; weight: 55.4%

did then 7) serve as the basis for the magic overall SMD of 0.14 and confidence intervals of [-0.02, 0.30] ,which tell you that the 14% increase in triglycerides is statistically not significant (for someone who does not sit around all day, the same can probably be said for the physiological relevance - specifically in view of the fact that we have no reason to believe that this was not a new steady state; or, more straight forward: It's unlikely that the levels kept increasing after a short adaptation phase.

How realistic are these studies, anyway? Currently the dietary fructose intake of the average fructose intake of fructose is estimated to be contribute 10-15% to our dietary energy intake (Vos. 2008). If we do the math on only those two trials with corresponding fructose intakes, i.e. Huttenen et al. (1976; healthy subjects) and Anderson et al.(1989; diabetic subjects), we get a standard mean differences of 0.019 with 95% confidence intervals of [95% CI: -0.32, 0.35]. The 1.9% increase in postprandial triglycerides the researchers detected in these studies is thus physiologically irrelevant  and statistically in- significant.

Bottom line: There is little doubt that the researchers' conclusion that "fructose has adverse effects only insofar as it contributes to excess calories" (Sievenkemper in Shephard. 2013) is supported by ...

1. the absence of differences between diets that delivered up to 25% of the daily energy from fructose or other carbohydrate sources, respectively, as well as
2. the fact that only studies that employed hyper-caloric diets had significant negative effects on the postprandial triglyceride levels (SMD: 0.65 [95% CI: 0.30, 1.01])

Nevertheless, Sievenkemper's comment in the previously cited press release lacks the most important piece of information, i.e. the fact that the potential adverse effects of fructose are not restricted to increases in serum triglycerides and that a similar verdict of acquittal from a peer-reviewed, up-to-date meta-analysis of its effects on the development of NAFLD is still (over-)due.

What we do have, are meta-analysis for it's effects on blood pressure (Ha. 2012), weight gain (Sievenpiper. 2012) and glucose metabolism in diabetics (Cozma. 2013) which argue that replacing glucose with an isocaloric amount of fructose does not affect blood pressure or weight gain and can actually "improve long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes" (Cozma. 2013).

References:

• Anderson, J. W., Story, L. J., Zettwoch, N. C., Gustafson, N. J., & Jefferson, B. S. (1989). Metabolic effects of fructose supplementation in diabetic individuals. Diabetes Care, 12(5), 337-344.
• Bes-Rastrollo M, Schulze MB, Ruiz-Canela M, Martinez-Gonzalez MA (2013) Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews. PLoS Med 10(12): e1001578.
• Chong, M. F., Fielding, B. A., & Frayn, K. N. (2007). Mechanisms for the acute effect of fructose on postprandial lipemia. The American journal of clinical nutrition, 85(6), 1511-1520.
• Cozma, A. I., Sievenpiper, J. L., de Souza, R. J., Chiavaroli, L., Ha, V., Wang, D. D., ... & Jenkins, D. J. (2012). Effect of Fructose on Glycemic Control in Diabetes A systematic review and meta-analysis of controlled feeding trials. Diabetes care, 35(7), 1611-1620. 
• Egli, L., Lecoultre, V., Theytaz, F., Campos, V., Hodson, L., Schneiter, P., ... & Tappy, L. (2013). Exercise Prevents Fructose-Induced Hypertriglyceridemia in Healthy Young Subjects. Diabetes.
• Ha, V., Sievenpiper, J. L., de Souza, R. J., Chiavaroli, L., Wang, D. D., Cozma, A. I., ... & Jenkins, D. J. (2012). Effect of Fructose on Blood Pressure A Systematic Review and Meta-Analysis of Controlled Feeding Trials. Hypertension, 59(4), 787-795.
• Huttunen, J. K., MÄkinen, K. K., & Scheinin, A. (1976). Turku sugar studies XI: Effects of sucrose, fructose and xylitol diets on glucose, lipid and urate metabolism. Acta Odontologica, 34(6), 345-351.
• Schulz, K. F., Chalmers, I., Hayes, R. J., & Altman, D. G. (1995). Empirical evidence of bias. JAMA: the journal of the American Medical Association, 273(5), 408-412.
• Sievenpiper, J. L., de Souza, R. J., Mirrahimi, A., Matthew, E. Y., Carleton, A. J., Beyene, J., ... & Jenkins, D. J. (2012). Effect of Fructose on Body Weight in Controlled Feeding TrialsA Systematic Review and Meta-analysis. Annals of Internal Medicine, 156(4), 291-304.
• Shepherd, L. (2013)   Researchers say fructose does not impact emerging indicator for cardiovascular disease. St. Michael's | Newsroom | Our News. < http://www.stmichaelshospital.com/media/detail.php?source=hospital_news/2013/20131230_hn > retrieved on Jan. 01 2014.
• Vos, M. B., Kimmons, J. E., Gillespie, C., Welsh, J., & Blanck, H. M. (2008). Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. The Medscape Journal of Medicine, 10(7), 160.
• David Wang, D., Sievenpiper, J. L., de Souza, R. J., Cozma, A. I., Chiavaroli, L., Ha, V., ... & Jenkins, D. J. (2014). Effect of fructose on postprandial triglycerides: A systematic review and meta-analysis of controlled feeding trials. Atherosclerosis, 232(1), 125-133.

Melato Cola™ or What? Fructose for Improved Glucose Metabolism and Melatonin to Counter Fructose Overload

There was a time, when Coke still contained "coke"... so why not add some melatonin for health benefits? I am obviously just kidding here, but a combination of fructose + melatonin may actually make sense.

The title of today's SuppVersity article is confusing, I know. Firstly, it contains the almost heretical notion that fructose could actually improve instead of impair your glucose metabolism and secondly it does not appear to make sense that you would have to use melatonin to counter the pro-diabetic effects of fructose, if the latter is in fact so good for you.

Before you are getting totally confused, let me clarify how the improvements in glucose metabolism and the melatonin-powered diabesity protection go together: Both have been observed in a recent study from the Pontificia Universidad Católica Argentina in Buenos Aires, Argentina (Cardinali. 2013), in the course of which the improved glucose metabolism was nothing but a side-finding of a study Cardinali et al. conducted to  examine the effect of melatonin when it is administered to rodents simultaneously with fructose in the drinking water.

This is the Coke + sufficient sleep study ;-)

Obviously this is not as the subheading would suggest the "coke + sufficient sleep study", but in light of the fact melatonin is after all the "sleep" hormone and in view of the results of a recent study by Senador et al. who observed that fructose had a negative effect on glucose management only, when it was available during the light phase (which is the inactive phase for a rodent; cf. Senador. 2012), it comes close; and that despite the fact that fructose timing was yet not an issue in the study at hand. Instead of modifying the timing, Cardinali et al. used different amounts of fructose with half of the rodents in the experimental arm of the study having a 5% and the other half having a 10% fructose solution as their main water supply.

Figure 1: Glycemia (mg/dL) 0-140min after 2g/kg body weight  glucose tolerance test (Cardinali. 2013)

If we trust the nutritiondata.com information about the average fructose content of a "carbonated beverage, cola, with higher caffeine" ...

• the rodents in the 10% fructose group were consuming the total carbohydrate equivalent of coke, but with a 100% instead of ~50% fructose content, while
• the rodents in the 5% fructose group were consuming less total carbohydrates, but roughly the same amount of fructose someone would ingest if he drank nothing but coke.

A direct comparison of either of the groups to the "coke only"-drinking human being is thus not warranted.

It is nevertheless intriguing that the 5% fructose group showed a significantly higher glucose tolerance - not just compared to the 10% fructose group, but also compared to the control group that was fed with water, only (see figure 1).

"Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" | read more

"But isn't fructose the reason you develop diabetes?" Before we get on to the effects of melatonin, I want to emphasize that this is by no means an outlier, in fact, I have written about the catalytic effects of 36g of fructose in a previous post "6x Bananas a Day!? Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" (learn more).

Previous studies have also shown that a 2:1 mixture of glucose + fructose is at least up to the regular glucose only drinks in terms of post-workout glycogen repletion (learn more) - partly because the fructose will keep the liver occupied, while the muscles suck up the glucose.

As previously mentioned the main research interest of the Argentinian scientists was not the effect of fructose on the glucose sensitivity of their rodents, but rather if the administration of 25 μg/mL of melatonin in the tapwater the rodents received would lead to significant changes in the study outcomes.

Figure 2: Effects of melatonin in drinking water with or without 5% [left] and 10% [right] fructose on body weight, systolic blood pressure and glucose response to glucose tolerance test (Cardinali. 2013)

As you can see in figure 1 it did: Melatonin did ameliorate the weight gain, and the increase in blood pressure that was observed even with only 5% fructose in the drinking water. It did not improve the glycemic response of the rats in the 5% fructose group even more, though, but it bulnted the negative effects of the 10% fructose solution had on the glycemic response in the glucose tolerance (figure 2, right).

SuppVersity Suggested Read: "Circadian Rhythmicity - Sunlight, Bluelight, Backlight & Co Mess Learn How THey W/ Your Internal Clock. Plus: Tips & Tricks to Prevent Negative Side-Effects" | read more

Is a melatonin solution the solution? If we also consider the negative effects of 10% fructose feeding on LDL (the rodents on 10% + Mel had even lower LDL than the control), the normalization of triglycerides and the potential therapeutic reduction in uric acid (-30% even vs. control), of which Cardinali et al. point out that it could have therapeutic effects in people with gout and other uric acid related metabolic disorders, it would appear smart that do dissolve the human equivalent dose of 21-35mg melatonin in your drinking water in the morning and keep guzzling it all day long.

Well, as I said, it "would appear to be" smart, but is it really smart? I wouldn't be too sure about that. Despite the fact that that you probably won't die, the chronically increased systemic melatonin levels could have long-term negative consequences on your circadian rhythm that could undo all potential benefits.

Restricting your fructose intake to fructose from fruit, only, getting enough sleep and using melatonin timely, i.e. 20min before bed would thus appear to be a more prudent approach to improve / maintain optimal blood glucose levels and insulin sensitivity. And if you are more into hard facts than "erring on the side of caution", you may consider the acute decrease in glucose tolerance, Cagnacci et al. observed in postmenopausal women, when they participated in a blood glucose test after the administration of 1 mg melatonin more convincing (Cagnacci. 2001).

References:

• Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxf). 2001 Mar;54(3):339-46. 
• Cardinali DP, Bernasconi PA, Reynoso R, Toso CF, Scacchi P. Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats. Int J Mol Sci. 2013 Jan 25;14(2):2502-14.
• Senador D, Shewale S, Irigoyen MC, Elased KM, Morris M. Effects of restricted fructose access on body weight and blood pressure circadian rhythms. Exp Diabetes Res. 2012;2012:459087.

Dietary Fructose vs. Endogenous Fructose Production: Is The Aldose Reductase Mediated Production of Fructose to Blame for Diabesity & NAFLD? Plus: Could Amla Help?

Make you choice - cholesterol and regular sugar (left), or fat free and fructose-laden? In the end it all may not even matter.

When I stumbled upon a recent study from the University of Colorado a few days ago, my first thought was: Oh my! That sounds familiar. And indeed, if you know anything about the "cholesterol conundrum" you will probably feel reminded of the disconnect between cholesterol intake, cholesterol levels in the blood and cholesterol-related increases in cardiovascular disease risk - don't forget that this is still an issue, although it may neither be your dietary cholesterol or your total cholesterol levels that mediate the risk increases.

Looks like you cannot pick your poison, because whatever you chose, your body will produce what it considers fitting from it

According to the said study from the University of Colorado it does in fact seem that our current favorite villain, namely fructose, has more in common with its predecessor on the throne of "avoid at all costs nutritional evils", i.e. cholesterol, than we have previously thought.

Surprise! Some of you may have heard about it for the first time 8 days ago in the first serving of insulin-sensitizing supplements, here at the SuppVersity: Amla aka Emblica officinalis is a natural aldose reductase inhibitor (Pupalla. 2012) and would thus be qualified to keep the negative side effects of endogenous fructose production in check!

"Many high glycaemic foods also contain fructose. For instance, sucrose is a disaccharide of glucose and fructose, and high-fructose corn syrup is a mixture of glucose and fructose, raising the question of whether fructose is responsible for the effects of high glycaemic foods to increase the risk for metabolic syndrome. To further complicate this issue, fructose can be generated endogenously via the polyol pathway from glucose. Specifically, aldose reductase (AR) metabolizes glucose to sorbitol, which can then be converted to fructose by sorbitol dehydrogenase.

Thus, if AR were highly expressed or activated in the liver, some of the glucose absorbed might be converted to fructose, and hence possibly provide a mechanism for inducing features of the metabolic syndrome."

To render this a little more straight forward, let's get back to our cholesterol analogy: We know (or should know) that part of the reason that dietary cholesterol is not a danger / problem for us is a simple consequence of the fact that most of the cholesterol that's floating around in our blood is actually produced directly within our bodies. And for cholesterol the rule of thumb is: The less cholesterol we eat, the more we will be producing ourselves.

Do we sugar- / fruit-coat ourselves?

For fructose this should actually be different. After all, fructose is not of similar physiologic importance to us as cholesterol the "fatty acid shuttle" and steroid precursor. Still, necessary or not, at least the results of the study at hand appear to suggest that the mammalian body appears to like his fructose so much that it will just produce it on its own, even when the diet is fructose free.

Unforuntately, the consequences Lenaspa et al. observed, when they kept 4 groups of rodents (wild-type and fructokinase knockout (KO) mice, who cannot produce fructose from glucose) on diets with or without glucose (10% (wt/vol)) in the drinking water and compared the body compositional changes of these mice to a control group pm regular chow (containing 60% carbohydrate and no fructose), appear to suggest that this is exactly as bad as guzzling fructose corn syrup all day.

Figure 1 : When the aldose reductase enzyme is deactivated mice will gain significantly less weight and avoid both insulin resistance and NAFLD despite being on a high glucose (no sugar) diet (Lanaspa. 2013)

In fact, the absence of the enzymes that are necessary to do the conversion of glucose to fructose did not just lead to a major and significant reduction in weight gain, it also blunted the typical pro-non-fatty liver disease effects of high sugar diets and kept the insulin sensitivity of the knockout mice in the glucose group in check.

Figure 2: Fructose uptake (mmol/g tissue per min) increases with glucose concentration (mmol/L; Uhsijima. 1995)

"These studies suggest that under certain conditions glucose may induce metabolic syndrome in mice via an AR [=fructose production via aldose reductase], fructose-dependent pathway. Whether this is occurring in humans ingesting high glycaemic foods remains to be determined. However, as in mice, AR can be activated in humans by a number of ways, including by high glucose concentrations. Total parenteral nutrition, in which a 35% glucose solution is provided
by the vein, is associated with the development of fatty liver, andexperimental studies have shown that it is mediated by the glucose component of the infused fluids

Soft drinks containing high-fructose corn syrup also deliver markedly high-glucose solutions (4–6%) to the gut, and sucrose-containing soft drinks provide similar amounts of glucose after the sucrose is degraded in the intestine." (Lanaspa. 2013)

With these new results it becomes even more obvious why HFCS which is actually a mixture of glucose and fructose is particularly nasty. It will not only increase the absorption of fructose (see Figure 2), but also provide our bodies with the necessary substrate to top an already overabundant fructose intake off with endogenously fructose to create something even I, as an outspoken critic of the "fructose hypothesis of obesity" would say is part of the perfect obesogenic storm and could easily explain why soft drink intake is so closely associated with an increased risk for obesity, fatty liver and insulin resistance.

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Suggested read on the never-ending debate on the "fundamental difference" between glucose and fructose: "Glucose vs. Fructose and Their Effects on Glucose, Insulin & Fat Oxidation" | read more

Bottom line: No, the study at hand does not imply that HFCS is harmless (on the contrary it adds another reason it's poison), but it should remind all of us that an exuberant (but not an appropriate) glucose intake is not necessarily causing less damage than fructose. Consumed in high enough amounts it's going to set the fructose production machinery of our body in gear and will thus yield very similar metabolic problems as fructose itself, the current scape-goat for "all things metabolic syndrome".

If you want to make absolute sure you really mess yourself up, I do however strongly advice you add some saturated fats, preferentially palmitic acid, to maximize insulin resistance and make sure the glucose cannot be taken up by your muscle before it can either harm you directly, or after being converted to fuctose or triglycerides.

What? Oh yeah, you're right! That's what 90% of our fellow Westerners do. Eating a high fat, high carb diet and sitting around all day... well, I guess it's thus not the fructose from the one apple they consume per months that's to blame for their misery, is it?

References:  

• Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzicky P, Rivard C, Inaba S, Roncal-Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ. Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun. 2013 Sep 11;4:2434.
• Puppala M, Ponder J, Suryanarayana P, Reddy GB, Petrash JM, LaBarbera DV. The isolation and characterization of β-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis. PLoS One. 2012;7(4):e31399.
• Ushijima K, Riby JE, Fujisawa T, Kretchmer N. Absorption of fructose by isolated small intestine of rats is via a specific saturable carrier in the absence of glucose and by the disaccharidase-related transport system in the presence of glucose. J Nutr. 1995 Aug;125(8):2156-64.

Glucose vs. Fructose and Their Effects on Glucose, Insulin & Fat Oxidation in Men on Both Ends of the BMI Spectrum

"Fructose handles"? "Glucose handles"? "Saturated fat handles"? No, just the net result of a trashy diet.

I don't have to tell you that I don't buy into the "fructose is the devil" hysteria that's rampant in the blogosphere and certain parts of the scientific community. It's a matter of quantity and quality that determines the toxicity of a poison and in most of the "convincing" evidence on the detrimental effects fructose. I mean let's be honest, you don't have to be a rocket scientists to figure out that 5+ cans of Coke a day cannot be good for you (cf. "Fat Content Per Energy Drink 0g, Body Fat Gain Per Energy Drink 18g!"; read more) "194 Bananas in Three Weeks", on the other hand, are nothing to be afraid of (learn why).Have we been fooled again or is it just a high fructose corn syrup producer conspiracy?

Enough of the rants, let's get to the facts!

I guess that's enough for the "ranty" introduction. Let's now have a look at what a group of researchers from the School of Medicine in Portland has in stock for us: It's a paper titled "Change in postprandial substrate oxidation after a highfructose meal is related to body mass index in healthy men" that's about to be published in one of the future installments of Nutrition Research. As you will by now probably have figured out, the Anne C. Smeraglio and her colleagues had two things in mind, when they came up with the protocol that involved

• What did the subjects eat? Participants were fed an egg omelet, bagel with cream cheese, and sweetened beverage breakfast consisting of one-third of their estimated daily caloric. The meal consisted of 30% fat, 15% protein, and 55% CHO (as % of energy). The CHO energy was further divided into complex and simple CHOs; 25% of the total calories were from complex CHOs and 30% of the calories were from either glucose or fructose added to the beverage.
  12 healthy men without diabetes, with a mean age of 25 (23-31) years and a BMI less than 30 kg/m²,
• 2 visits at their labs that were separated by at least 1 week, but less than 1 month,
• two meals that were high in glucose or fructose which were served in random order as a breakfast after an overnight fast, and
• fasting for 7h after the ingestion of the standardized breakfast (sitting around watching TV or performing other, non-exciting quiet activities without the propensity to produce a catecholamine response)

During the experiment, the oxygen consumption and CO2 production were measured by indirect calorimetry to calculate resting energy expenditure and respiratory quotient (RQ; high RQ = burning predominantly glucose, low burning predominantly fat). The scientists also took blood samples at pre-defined intervals and collected the urine of their participants.

Figure 1: Insulin and glucose levels, as well as non protein respiratory quotient (high = carb oxidation; low = fat oxidation) 0-7h after the fructose and glucose breakfasts (Smeraglio. 2013)

The data in figure 1 is a summary of the the most "significant" results. In that the "quotation marks" enclosing the word "significant" is in my humble opinion the most significant information here - one that's encoded with irony, because after all, the only statistically significant effect the scientists observed were the ~2.5x higher insulin levels in the glucose group 60min after the ingestion of the test meal... yep, that's in the glucose group.

"There must be a mistake here!? Fructose is bad for you!"

The scientists have really done their homework as they did even take into account whether or not the amount of protein in the meals would have been responsible for differences in the respiratory quotient. The latter was not the case, the "baseline RQs between the fructose and glucose study visits were equivalent (0.82 ± 0.08 and 0.81 ± 0.10, respectively) and the p-value, indicating that there was a difference even rose from 0.72 to 0.75, when "when protein use was accounted for by evaluating NPRQ [non-protein respiratory quotient]" (Smeraglio. 2013)

Surprised? Well, I guess over all the lustig (=German for "funny") and unwarranted hoopla about how bad even small amounts of fructose are, you must have forgotten why scientists believed not too long ago that fructose could be the solution to, not the cause of the diabesity epidemic. After all, the paradigm of the mid to late 20th century was: Fructose does not spike glucose, so it should be the ideal sweetener for diabetics, because it is not necessary that your pancreas produces insulin to get rid of it.

I will not have to tell you, though that this assumption and the corresponding notion that totally replacing glucose with fructose would be a great idea is about as unwarranted, as the current fear of the "toxicity" of the small amounts fructose contained you'll be exposed to from a couple of pieces of fruit. I mean, let's take a peek at the data again.

Compared to the same amount of glucose, the consumption of the fructose equivalent of 5-6 medium sized (185g) apples (50-70g fructose, which is the amount of fructose the subjects in the study consumed) produces lower insulin levels and does not change either the leptin, triglyceride or glucose concentration in the blood or the ratio of glucose to fatty acid oxidation in healthy non-obese volunteers...

...apropos, non-obese, there was another thing to the headline wasn't there?

You are absolutely right, the research question involved (a) finding out what happens if you ingest a realistic breakfast where the carbohydrate content comes from (i) glucose or (ii) fructose and (b) determining whether the reaction would depend on the body weight / height² (BMI) ratio of the participants. So what about that, then? Let's see...

Did you know that there is a catalytic dose of ~40g of fructose per day (=6 normal size bananas) that will improve your glucose metabolism? (learn more)

"Although the absolute values for fat and CHO oxidation were not different between the fructose and glucose study visits, we did find a correlation between BMI and change in fat oxidation as a result of consuming the high-fructose meal compared with the high-glucose meal. The difference in fat oxidation (fat oxidation after the fructose meal minus fat oxidation after the glucose meal) was negatively correlated with BMI at the 4- and 7-hour time-points (Fig. 3; r =−0.59 [P= .04] andr=−0.59 [P= .04] for 4- and 7-hour time points, respectively) but not the 1-hour time point (Fig. 3; r=−0.52, P< .09). Nonprotein RQ displayed these same trends but did not reach significance." (Smeraglio. 2013)

As the scientists rightly point out, this suggests that the postprandial fat oxidation after the fructose meal was less than the fat oxidation after the glucose meal only among subjects with a higher BMI, and that the correlation with body weight, but not the difference itself was statistical significant.

Figure 2: Correlation of BMI with change in fat oxidation pearson correlation with linear regression trend lines between BMI and change in fat oxidation (fat oxidation after the fructose study visit minus fat oxidation after the glucose study visit; Smeraglio. 2013)

What's more, if you take a peek at the linear regression in the graph on the right hand side (figure 2) you will realize that that this does also mean that the fatty acid oxidation in lean individuals is actually increased after the ingestion of fructose. If I intended to drive my message "fructose from real foods is not your problem, folks!" home at all costs (which is what the "fructose is the devil" advocates like to do), I could seize on this observation and tell you: "Look folks, as long as you are already lean fructose will help, not impair your effort to get ridiculously shredded." I would yet hope that you are clever enough to see through this tactics and realize that neither the effect on the left hand side (=more fatty acid oxidation in the leaner folks with fructose vs. glucose), nor the one on the right hand side of figure 2 is physiologically relevant.

And that's not just because it's simply too small, but also because the ratio of glucose to fatty acid oxidation, i.e. the respiratory quotient (RQ) is not determining whether you store or lose body fat - if it were, you'd better be training in the "fat burning zone" for the rest of your (in that case) miserable lives.

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Figure 3: Adding 7.5g of fructose ( to a 75g glucose load will improve not detoriate the glucose metabolism and that without increasing the amount of insulin that's released in response to the glucose load (Moore. 2000)

Bottom line: I am confident that that even without resorting to extreme interpretations of cherry picked data, the main message of today's article is clear. The comparatively small amounts of fructose you'll get right with the appropriate polyphenols & other cofactors from fruit and other fructose containing whole foods in your diet is not your enemy (Other items? Yeah, you know that even onions have 2g fructose, right?).

On a related note, you are aware that small amounts of fructose, like the 7.5g of fructose scientists added to the 75 g of glucose their 11 healthy subjects ingested during an oral glucose tolerance test had an up to 31% lower glucose response (these were the values for the 6 subjects with the highest level on the regular test) in the absence of concomitant increases in insulin response (see figure 3; Moore. 2000)!? You did not know that? Well, I guess it was about time to take a mental note, then ;-)

References:

• Moore MC, Cherrington AD, Mann SL, Davis SN. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults. J Clin Endocrinol Metab. 2000 Dec;85(12):4515-9. 
• Smeraglio AC, et al. Change in postprandial substrate oxidation after a high-fructose meal is related to body mass index in healthy men. Nutr Res.2013 [epub ahead of print]

Four Weeks "On" Two Cans of Energy Drink = 6.6% Increase in Body Fat + Other "Adaptations" in Healthy Men & Women

Contrary to regular coffee, the majority of energy drinks ensures that you get your daily (over-)dose of diabesity promoting sugar - so, no need for additional white poison.

If you are following the SuppVersity news closely, I am sure you will remember the note on the carcinogenic, or rather "breast cancer risk increasing" effect a single cup of soda per week can have (read more). As a follower of the SuppVersity Facebook news, you will also remember that these effects could potentially be brought about by the hormonal chaos that's brought about by these sugar sweetened beverages (learn more; Schliep. 2013).

Now, these results, as well as the accumulating evidence that sugar sweetened beverages in general and high fructose corn-syrup laden sodas are among the, if not simply the #1 contributer to the rise of the obesity pandemic, certainly raise the question what exactly it is that happens to us, when we consume these delicious* yet deadly elixirs on a daily basis (*personally I lost my appetite for soda years ago... along with the fat covering my abs, by the way).

4 weeks of sugar sweetened beverages and our bodies helpless effort to adapt

You've already gotten a first peek at what happens, when we make these unsatiating calorie-bombs a staple of our diets in a previous Suppversity article from June 30, 2012, in which I exposed the truth behind the shockingly simple formula "2 Energy Drinks per day = +1kg of Body Fat in 4 Weeks" (read more).

Nutritional composition of the SSB

Aside from the effects on the body weight, the 2012 study by Sartor et al. did yet not allow much insights into the corresponding metabolic changes, the bodies of their volunteers underwent. It is exactly these changes, or "metabolic adaptation" as (sounds quite positive, doesn't it) as the researchers call them, Francesco Sartor and his colleagues were now trying to elucidate in a follow-up study.

Would you be willing to gain one kg of pure fat for $150?

To this ends, the researchers from the College of Health and Behavioural Sciences at the Bangor University in the United Kingdom and their colleagues from Italy and the US recruited another 11 subjects who had been cherry picked for their low sugar sweetened beverage (less than 500ml SSB per week) intake from a group of 213 candidates, all of whom wanted to qualify for the £100 upon completion of testing as compensation for their time.

Yeah, I know, obviously Sator et al. were not really honest with these 5 men and 6 women. After all, the scientists knew in advance that they would also be compensated for the ill health effect the consumption of ~760 mL/day of Lucozade Sport would have on their metabolic health.

"Before and after the intervention, body composition, respiratory exchange ratio (RER), insulin sensitivity, muscle metabolic gene and protein expression were assessed. Adaptive responses to hyperglycaemia (7 days, 15 mM) were tested in primary human myotubes." (Sartor. 2013)

I guess few of you will be surprised by what they are just about to see in the selected data I plotted for you in figure 1. And if you are honest, what we are seeing here is - at least in parts - actually an adaptive response.

Figure 1: Body composition, HOMA data, glucose / insulin levels, substrate oxidation, blood lipids and skeletal muscle mRNA expression relative to pre-"supplementation" levels (Sartor. 2013)

I mean take another look at the changes the scientists observed in vivo (11 subjects, 4 weeks on SSB) and in vitro (human muscle cells incubated with 15 mM glucose for 7 days; model of hyperglycemia). Despite all their desperate efforts, including

• the increase in fat mass (+1kg) that's meant to stash away the glucose that would otherwise start to form a gluey lining on the cell walls and 
• the concomitant increase in the respiratory exchange ratio (RER), which does allow for a greater oxidation of glucose (obviously at the expense of fat), 

the subjects, or rather their bodies, were not able to to ward off the statistically significant +0.3mmol/L increase in fasting blood glucose. Moreover, the changes in protein expression scientists observed in the muscle cells they had isolated from the quadriceps muscles of the participants, namely the increased activity of the glycolytic enzyme GAPDH and the corresponding decrease of PGC-1alpha in the musculature of the previously healthy subjects are yet less "logical" (=expedient).

The Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) induced increase in glycolysis (see schematic drawing over @Wikipedia) does not suffice to reduce the amount of glucose that's floating around while it contributes to the decrease in fatty acid oxidation that is further promoted by a decline in PGC-1a activity and thus the ability to handle the increased triglyceride load by burning the glycerol + free fatty acid ethers in the mitochondrial power plants of the subject's skeletal muscle.

MondaA, a "bad guy" to remember?

Against that background, it i not really surprising that the scientists did also observe an unwanted but in a way still "adaptive" (=reactive) increase in insulin resistance - an effect of which the researchers believe that it was brought about or at least facilitated by increased amounts of the glucose sensing protein MondoA:

This may be the right time to read up on the SuppVersity article about previous study by Sartor et al. "Fat Content Per Energy Drink 0g, Body Fat Gain Per Energy Drink 18g!" (go back)

"Glucose sensing in skeletal muscle cells, as part of a mechanism for the maintenance of cellular energy homoeostasis, has been demonstrated to be strongly dependent on the transcription factor MondoA.

MondoA seems to be a master regulator of glycolytic genes and indeed it activates the transcription of numerous genes encoding metabolic enzymes.. Glycolytic gene expression is highly upregulated in response to MondoA recruitment from cytoplasm to nuclei, building a complex with the transcription factor max-like protein x (Mlx), in high glucose conditions. A further target of the Mond-oA:Mlx complex is the thioredoxin-interacting protein (TXNIP). TXNIP impairs peripheral glucose uptake stimulating radical oxygen species production.

In short, the increase in MondoA protein content is directly and mechanistically involved in the etiology of a metabolic vicious circle, which is at the heart of the downward spiral that leads from "just being a somewhat chubby sedentary slob" over the "overweight pre-diabetic" right into the emergency room, where the doctors need one of those XXL operating tables, when they are trying to save the lives of people with SSB consumptions of 3-4L per day.

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Bottom line: I suppose that many of you will now be thinking. So what, I knew all that already; after all, I just got to look around and see all those SSB victims driving around in their cars. Nevertheless the details you may have learned about the enzymatic roots of the metabolic dysregulation that occurs with the consumption of "only" 2 cans of a "soda-like" sports drink per day are not the main message of the study at hand.

As of now, there is no published in vivo evidence for the beneficial effects glutamine may have on the MondoA-induced dysregulation of glucose homeostasis, but there is an interesting 2009 paper by scientists from University of Utah suggesting that the reduction in glucose uptake due to MondoA (over-)activation in the presence of high glucose levels may be ameliorated / abolished by glutamine (Kaadige. 2009) and a study that confirms the beneficial effects of glutamine on insulin sensitivity (read more).

From a mere scientific perspective, the news is the shockingly short time span in the course of which perfectly healthy, lean and reasonably active individuals can develop all the characteristics scientists have hitherto thought of as a result chronic hyperglycemia. A particular focus of future studies should now be on the time-course of the change in MondoA expression, as well as means to prevent and reverse the deteriorations of this "metabolic glucose sniffer".

Theoretically glutamine could be a potential candidate, as it has the ability to block the MondoA induced, glucose dependent activation of the thioredoxin-interacting proteinin and the subsequent blockade of glucose uptake. And while respective research on this mechanism is not yet available, those of you who have been around ever since the early beginnings of the SuppVersit, may remember the 2010 post on the "Positive Effect of L-Glutamine on Insulin Sensitivity" (read more) - who knows, maybe it is mediated by the blockade of the transcriptional activity of MondoA at the TXNIP promoter (see figure on the right)!?

References:

• Kaadige MR, Looper RE, Kamalanaadhan S, Ayer DE. Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14878-83.
• Schliep KC, Schisterman EF, Mumford SL, Pollack AZ, Perkins NJ, Ye A, Zhang CJ, Stanford JB, Porucznik CA, Hammoud AO, Wactawski-Wende J. Energy-containing beverages: reproductive hormones and ovarian function in the BioCycle Study. Am J Clin Nutr. 2013 Mar;97(3):621-30.
• Sartor F, Jackson MJ, Squillace C, Shepherd A, Moore JP, Ayer DE, Kubis HP. Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes. Eur J Nutr. 2012 Jun 26.

Science Round-Up Seconds: Rare Sugar Syrup, HFCS 2.0? Body Recomposition W/ 7 Marathons in 7 Days!? Reduced REM Sleep With Intense Workouts in the Evening.

99% of the guys & gals on this photo are not going to see anywhere similar improvements in body composition from marathon running as the highly trained 7x7 runners in the Karstoft study.

It's Friday and that means its time for the wrap-up of yesterday's installment of the Science Round-Up on SHR. Well, let's see then what this weeks Round-Up of the Round-Up has to offer. Somehow I felt like picking up something we did actually cover in the live-show yesterday (download the podcast here). I guess I want to give everyone the chance to look at the data himself in order to decide whether "rare sugar syrup" (RSS) is going to be the savior of the Western world and the unfortunate rest who's currently "westernized" by the big Ms, the big As and the rest of the corporate alphabet soup with a vested interest in the prosperity of mankind, or - to be precise - that the part of mankind who owns their shares ;-)

Rare Sugar Syrup has 90% of the sweetness of regular sugar + "cleaner taste" than HFCS

(IIda. 2013) -- Assuming that you've by now all listened to the podcast, I will stick to some additional explanations, citations and graphs in this follow up.

While D-psicose is not the only fructose epimer in rare sugar syrup, it is probable the one with the most potent beneficial effects on blood glucose management (learn more). One potential caveats of RSS is that its d-psycose content is only 5% with te rest being other hexoses including D-allose, D-sorbose, and D-mannose,

As the scientists point out, the main intention of their study was to assess whether their rare sugar syrups would suppress

"body weight gain and abdominal fat accumulation in rats fed on diets composed of different carbohydrate sources: starch, starch + HFCS (50:50), and starch + RSS (50:50) were examined. (Iida. 2013)"

Accordingly, they maintained their rodents on otherwise identical diets containing (on a per weight not per kcal basis!) 57% carbs, 18% protein, 4% fat, cellulose, added methionine and a couple of vitamin and trace elements with either plain corn starch, corn starch and HFCS or cornstarch and rare sugar syrup (see figure 1, left).

Now, as mentioned in the show, there is no debating that this feeding regimen worked and with "90% of the sweetness of sucrose, and a more rich and clean taste than HFCS" replacing HFCS with RSS could even improve the taste of respective products, but let's be honest: How likely is it that we are going to see products without HFCS and 50% of rare sugar syrup actually making up the lion's share of the processed junk in the super market anytime soon?

Figure 1: Carbohyrate content of the diets and weight of different visceral fat pads after the 8-week dietary intervention in otherwise healthy rodents on a cornstarch only, cornstarch + HFCS or cornstarch + RSS diet (Iida. 2013)

Isn't it more likely that you will see labels like "now with rare sugars" on the front of the packaging and the hardly legible figure "contains 3% carbohydrates from rare sugars" hidden on its back? I would think so and the fact that neither this study nor the general existence of this HFCS substitution did as of now hit the media certainly doesn't refute contradict this hypothesis.

7 marathons (!) in 7 days - A marathon a day keeps the fat stores at bay?

(Karstoft. 2013) -- I probably don't have to preface this part of the seconds with a "don't do this at home" (or anywhere else ;-), but I think it's nevertheless newsworthy that accordingly trained people can actually run 7 marathons  in 7 days without the dreaded negative effects the average bro is expecting when he is just walking for 40min on a treadmill.

Figure 2: Body composition before and after the race (left) and changes in markers of muscle damage as well as hormonal changes and differences in markers of blood glucose management (right) in 8 experienced recreational runners participating in a multiple-marathon running event in which 7 marathons were completed on consecutive days (Karstoft. 2013)

Doesn't look so bad, ha? The reason I still stick to the initially voiced recommendation not to copy this protocol if you intend to lose body fat is pretty simple. The main reason "nothing" happened here is that the subjects were conditioned to run marathons.

That's the same "repeated bout effect, we have seen only a couple of days ago in the "No Pain No Gain" post (click here to go back) and the ~2kg of "muscle mass" are (despite being measured with DEXA) probably rather a result of glycogen hyper-compensation from tons of energy gels and pasta (the subjects did not follow a prescribed diet, but simply ate, drank and supplemented what had helped them on previous marathons), than structural increases in muscle tissue.

No high intensity training before a good night's sleep

Unless you have read the SuppVersity Circadian Rhythm Series, you have no right to complain about being overweight or undermuscled (read it ;-)

(Wong. 2013) -- After listening to the show, you know what you got to do once you got out of the bed, namely to switch on your bright light therapy lamp, but what do you have to do before you go to bed? I did actually discuss most of the things you should do (curtains, ear-plugs, turn the temperature down, etc.) in the Circadian Rhythm Series, but with the recent publication of a study by Wong et al. there is another thing you should - or in this case should not do and that's working out at a high intensity.

According to the results the researchers present in their soon-to-be-published paper in the Journal of Sports Science, a cycling exercise at intensities of  65% and 75% VO2Max lead to significant increases in light sleep and reductions in the recuperative REM sleep from 22.5% to 19& and 18.7% of the total sleep time.

Light exercise, in this study done at 45% and 55% of the VO2max, on the other hand did not have these side effects it did however not improve sleep, which is by the way an urban myth of which Driver and Taylor wrote in a Y2k paper in the Sleep Medicine Review that it "has yet to be established empirically" (Driver & Tailor. 2000).

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That's it for today, unless you want to head over to the SuppVersity Facebook Wall and check out some of the news that are already available over there, e.g.

• 

  Newsweek title from the year 2000 - "Fat for Life?"; did his mother love her soy protein more than her son's health? (learn more)

  "High" dose supplementation with vitamin C and/or E increases cataract risk - 1,000mg of vitamin C increase the risk +36% and 100mg of vitamin E by 57% (read more)
• Aerobic fitness could have greater impact on academic achievement than obesity -- Although obesity is a concern for children, this study shows that aerobic fitness can have a greater effect on academic performance than weigh (read more) 
• Aqua Mel, Portuguese "folk medicine" works for the alleviation of simple symptoms of upper respiratory tract -- Effect probably mitigated by the phenols in the honey this product is made of (read more).
• Serum albumin carries cholesterol out of the cells -- Hitherto scientists thought that this was a prerogative of HDL (read more)

If you don't like these or the other ones I did not mention just wait for further news to be posted. Alternatively switch of the computer and your mobile devices and head off into a well deserved weekend!

Don't worry, there is going to be a whole heap of short news tomorrow, you won't get bored... ah, you don't get bored on the weekend, anyway - do you?

References:

• Driver H.S., Taylor SR. Exercise and sleep. Sleep Medicine Reviews. 2000; 4(4):387–402
• Iida T, Yamada T, Hayashi N, Okuma K, Izumori K, Ishii R, Matsuo T. Reduction of abdominal fat accumulation in rats by 8-week ingestion of a newly developed sweetener made from high fructose corn syrup. Food Chem. 2013 Jun 1;138(2-3):781-5.
• Karstoft K, James Solomon TP, Laye MJ, Pedersen BK. Daily Marathon Running for a Week - the Biochemical and Body Compositional Effects of Participation. J Strength Cond Res. 2013 Feb 25.
• Wong SN, Halaki M, Chow CM. The effects of moderate to vigorous aerobic exercise on the sleep need of sedentary young adults. J Sports Sci. 2013 Feb;31(4):381-6.