Artificial Sweeteners & Liver Cancer - Is There a Link? 6% Increased Risk of Hepatocellular Carcinoma per 330ml of Artificially Sweetened Soft Drink in Human Study

Are we "pouring liver cancer", when we consume soft drinks regularly? Recent data from the EPIC study appears to suggest just that - specifically if the soft drinks are artificially sweetened.

I certainly don't belong to the anti-sweetener faction on the Internet, but the results scientists from the International Agency for Research on Cancer, the University Paris Sud, the Institut Gustave Roussy and the Centre for Research in Epidemiology and Population Health (CESP) in France, the Winship Cancer Institute in Atlanta, the Hellenic Health Foundation and the University of Athens Medical School in Greece, the Harvard School of Public Health in Boston, Aarhus University and the Danish Cancer Society Research Center in Denmark and the Cancer Council Victoria and the University of Melbourne in Australia in the latest issue of the European Journal of Nutrition are serious enough to not to discard them as another unwarranted horror-story of the anti-sweetener lobby (Stepien. 2014).

You can learn more about sweeteners at the SuppVersity

Unsatiating Truth About Artif. Sweeteners?

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Sweeteners & the Gut Microbiome Each is Diff.

Sweeter Than Your Tongue Allows!

Stevia, the Healthy Sweetener?

Sweeteners In- crease Sweet- ness Threshold

The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artifiially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries.

After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95 % confidence intervals (HR; 95 % CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity level of educational attainment and self-reported diabetes status).

Don't be fooled by the size and name of the EPIC cohort! For the laypress the large cohort size will make this study appear as if the results must be God given. Personally, I am yet not impressed by scientists handing food frequency questionnaires out to almost half a million people (65%-68% correlation with what the people actually eat | Streppel. 2013), but it obviously blurs the errors. Personally, I still wouldn't take this as a complementary ticket for the exuberant consumption of artificially sweetened soft drinks.

As the researchers rightly point out, this makes the study at hand one of the few to study the possible link between soft drink consumption and cancers of the liver and biliary tract, which could - "[g]iven the rising consumption of sweetened non-alcoholic beverages and their likely link to several metabolic disorders that play a role in the development of these cancers" (Stepien. 2014) - be a major contributor to the ever-increasing number of liver carcinoma.

Figure 1: HR (95 % CI) for HCC by categories of soft drink and juice consumption compared to non-consumers in the EPIC cohort | % above the bar indicate risk increase / decrease - all trends are significant, but only the risk increase in the highest consumption group reaches individual significance (Stepien. 2014).

As you can see in Figure 1 (risk increase in % is sign. only for the high consumption), the scientist found a general link between soft drink consumption and hepatocellular carcinoma risk: +83% risk increase for those who consume soft drinks habitually (= more than 6 drinks per week) and +38% for the "juicers" (people who consume fruit and vegetable juices on a daily basis) - those are quite impressive numbers, even if there was no link to any of the other forms of cancer the scientists investigated.

A 6% risk increase does not equate a risk of 6%! I just realized on Facebook that people are still misinterpreting risk increases as absolute risks. If you have a risk increase of 6% of a crude baseline risk of 101/476968 [number of cancer patients / number of subjects] = 0.021%, a 6% risk increase will bring you up to a risk of 0.024% which means that 2.24 people out of 10,000 are at risk of developing hepatocellular cancer. This is not an exact calculation, obviously, because I don't have all the data to do it properly, but it gives you an estimate of the absolute risk, which is minimal!

In view of the previously cited way in which the consumption of these drinks contributes to the metabolic disorders that "play a role in the development of these cancers" (Stepien. 2014 | I would even say they trigger them), it is yet not half as surprising as the results of the scientists' sub-group analysis. In spite of that, the data Stepien et al. generated suggests that it's not the consumption of the "bad" + obesogenic sugary version of the drinks which shows an incremental risk increase of +6% for heaptocellular carcinoma on a per serving base, but its artificially sweetened cousins!

Figure 2: Spline regression models for the intake of soft drinks (left) and juices (right) in relation hepatocellular carcinoma risk. Reference 0 mL/ week. Knots correspond to 10th, 25th, 50th, 75th and 90th percentile of intake. The maximum corresponds to the 99th percentile. Solid lines- HR, dashed lines- 95 % CI (Stepien. 2014).

While the data from the spline regression models in Figure 2 clearly indicates that every 330ml serving of soft drinks (+21% in the crude and +22% in the fully adjusted model), and for every 200ml of juices (+3% in the crude model, but no association in the fully adjusted model) was associated with a significant increase in hepatocellular carcinoma risk in this cohort, the difference between artificially sweetened and sugar sweetened soft-drinks surfaced only in a subsequent sub-group analysis:

"In additional analyses by the type of drinks (sugar-sweet ened vs. artificially sweetened), each additional serving of artificially sweetened soft drink was positively associated with HCC risk (HR 1.06, 95 % CI 1.03–1.09, n_cases = 101), while for sugar-sweetened soft drinks, this association was null (HR 1.00, 95 % CI 0.95–1.06, n_cases = 127). The difference between both estimates was borderline significant (p_heterogeneity = 0.07)." (Stepien. 2014)

No such difference was observed for sex, BMI category, alcohol intake pattern, nor the categories of juices (i.e. apple or other fruit juices were not worse than vegetable juice).

Before you panic, you should take into consideration that as large as the total cohort may have been the number of cases of hepatocellular carcinoma in the regular and artificially sweetened soft drink drinkers was N=127 and N=101, respectively. That's not just not half as impressive as the total number of participants (N = 477,206); it also raises the question how reliable the results actually is.

This is particularly true in view of the fact that Previously reported findings from the EPIC cohort have shown that high sugar intakes are positively significantly associated with HCC risk. A result which contradicts the link non-existing link between sugar sweetened beverage (SSB) intake and hepatocelular carcinoma in the study at hand and put another question-mark behind the results of the subgroup analysis.

I wrote only recently about the results of a rodent study by Suez et al. which may trace the increased HCC risk with artificial sweetener consumption back to unwanted changes in the gut microbime | read more

They stand in line, however, with the results presented by Schlesinger et al. (2013) and Romaguera et al. (2013) who found an association between artificially sweetened soft drinks and diabetes risk in their analysis of the EPIC data from France and, in this case more importantly, the results Suez et al. published in Nature recently (Suez. 2014). In said study, about which I also wrote about on the SuppVersity (read more), the researchers found that the consumption of non-caloric artificial sweeteners affects the intestinal microbiota composition in a way that leads to the development of glucose intolerance and could eventually also be responsible for the observations Stepien et al. made when they correlated the intake of artificially sweetened beverages of the 101 HCC patients in their with the intake of the 476978 "healthy" (=HCC-free) study participants.

Overall, I would still say that more research has to be done before we can safely say that the consumption of high amounts of artificially sweetened soft drinks, let alone the consumption of artificial sweeteners, in general, will put you at a significantly increased risk of developing hepatocellular cancer. An absolute risk, by the way, of which my elaborations in the 2nd red box tell you that it is still far below 0.03% | Comment of Facebook!

References: 

• Romaguera, D., et al. "Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct." Diabetologia 56.7 (2013): 1520-1530.
• Schlesinger, S., et al. "Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort." Annals of oncology 24.9 (2013): 2449-2455.
• Stepien, et al. "Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort." Eur J Nutr (2014). Ahead of print. 
• Streppel, Martinette T., et al. "Relative validity of the food frequency questionnaire used to assess dietary intake in the Leiden Longevity Study." Nutr J 12 (2013): 75. 
• Suez, Jotham, et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature 514.7521 (2014): 181-186.

Obesity Research Update: SSBs vs. Artificially Sweetened Beverages, Food Availability, Prices, Variety & Palatability, or Eating Frequency - Is One or Are All Making Us Fat?

Food variety increases binge eating risk, studies show.

With the publication of the latest issue of "Advances in Nutrition" came a whole host of studies that may provide novel insights into potential causes of and solutions to the obesity epidemic. Among the things the researchers investigated and presented at the 20th International Congress of Nutrition were also studies on the possible involvement of artificial sweetened beverages, the availability and convenience of food, the effects of food prices on obesity, the effectiveness of changing the eating frequency, the importance of portion sizes in weight control, the impact of eating a highly variable and palatable diet.

You can learn more about meal frequency at the SuppVersity

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Frequent Protein Consumption

Myth: Few Meals More Bodyfat

8 Meals = Stable, But High Insulin

Int. Fasting & Exercise

• Sugar-Sweetened and Artificially-Sweetened Beverages in Relation to Obesity Risk - In his latest review, Mark A. Pereira set out to "critically evaluate the scientific evidence in humans on the potential effect of sweetened beverages on weight gain and risk of obesity in youth and adults" (Pereira. 2014).
  
  In particular, he compared the association of sugar-sweetened beverages (SSBs) include soft drinks, colas, other sweetened carbonated beverages, and fruit drinks with added sugar and their artificially sweetened counter-parts on obesity risk - with an expected outcome:
  

  "The totality of evidence to date demonstrates a pattern across observational and experimental studies of an increased risk of weight gain and obesity with higher intake of SSBs" (Pereira. 2014).

  The actual problem is that it is difficult to establish the strength of the association and the independence from other potentially confounding factors. In that, Pereira highlights that the primary reason for unclear conclusions regarding the robustness of any effect of SSBs is due to the heterogeneity and methodologic limitations of both observational and experimental studies on this topic.
  
  

  

  Experimental evidence shows artificial sweeteners help weight loss | more

  The latter is all the more true for studies investigating the effects of artificial sweetened beverages on obesity risk. As Pereira points out, "there is no clear mechanism for this pathway, and the epidemiologic studies are highly inconsistent" (Pereira. 2014).
  
  More specifically, none of the currently available epidemiologial studies was able to make sure that the associations the scientists observed were not the result of reverse causality, i.e. obese people consuming artificially sweetened beverage, because they are (already) obese and not the other way around. As Pereira points out, this is more than just a theoretical issue, "higher-quality studies demonstrate this possibility" (Pereira. 2014).
  
  Accordingly, the field needs "higher-quality experimental studies in humans, with relevant direct comparisons between sweetened beverages and their sweetened solid-food alternatives" (Pereira. 2014).
• Food Availability/Convenience and Obesity - Penny Gordon-Larsen reviewed the ever-increasing number of studies investigating the impact of certain qualities of the neighborhood environments on obesity risk. As Gordon-Larsen points out, "there are inconsistencies in the evidence base, suggesting a nuanced association between neighborhood environment, food availability, diet behaviors, and obesity" (Gordon-Larsen. 2014).
  
  With the currently available evidence being limited by a predominance of cross-sectional studies, a high reliance on commercial business listings, a lack of attention to the process by which diet resources are established and expanded within neighborhoods and the potential for individuals to selectively migrate to locate near such facilities, it is difficult to make a reliable conclusion with respect to the influence of food availability and convenience on obesity risk.
  
  Against that background it is difficult to tell, whether the results of a recent study from New York which shows that there is an inverse association between BMI and food outlet density (−0.32 BMI units across the IQR, 95% CI −0.45 to −0.20) is actually significant.
  

  

  Figure 1: Adjusted association between body mass index and food environment measures (Stark. 2014)

  Specifically in view of the fact that there is a positive association between BMI and the proportion of BMI-unhealthy food outlets (0.26 BMI units per IQR, 95% CI 0.09 to 0.43) and no association with outlet diversity. If we went by the results of this study, though, it would appear that living close to food outlets serving donuts, hotdogs and pizza will increase your obesity risk - according to a detail analysis of the New Yorker researchers, this risk is specifically pronounced for people living in areas with "poverty zip codes" (Stark. 2014).
• Food Prices and Obesity - is there a link? As a SuppVersity reader you will know that politics and researchers have repeatedly been debating about taxes on unhealthy foods. To estimate, whether these taxes would work, we would yet have to know "the extent to which overall energy intake or weight outcomes" are actually influenced by food prices.
  

  

  Table 1: Few people know that there are already food taxes in several countries all around the world - with little sucess | öow taxation is defined as less than 10 %; and moderate as 10 % or greater. *the dates for Denmark and Ireland indicate the dates during which the tax was in operation (Mytton. 2014)

  Finkelstein's et al.'s review is one of the first to access this link between food or beverage price changes and energy intake or weight outcomes among U.S. consumers. According to the researchers from the Duke University, the Yale University, and the University at Buffalo School of Medicine and Biomedical Sciences,
  

  "the current evidence indicates that, by themselves, targeted food taxes and subsidies as considered to date are unlikely to have a major effect on individual weight or obesity prevalence." (Finkelstein. 2014)

  Unlike the researchers I am thus not really optimistic that "food taxes and subsidies may play an important role in a multifaceted approach to reducing obesity incidence" (Johnson. 2014) - in particular, if the taxes are determined in accordance with the current US food pyramid, so that "healthy grains" are not taxed at all and "unhealthy eggs" are taxed in a way that even an "industrially" produced egg will costs a dollar.
• Evidence for Efficacy and Effectiveness of Changes in Eating Frequency for Body Weight Management - As Ashima Kant point out, in self-reported diets of free living individuals, frequent eating is associated with higher energy intake. In spite of the scientific evidence, beliefs about the possible beneficial effect of higher eating frequency for managing body weight persist.
  
  In her review of prospective cohort studies and controlled trials of manipulation of eating frequency published by 31 December 2012, Kant included four prospective cohort studies were identified - 2 of these included adults followed for 10 y and 2 followed  pre-adolescent / adolescent girls for 6 or10 y.
  
  

  

  Less Frequent Large(r) Meals & Caffeine - Proven Ways to Increase Your Energy Expenditure & Conserve Your Metabolic Rate While Dieting | more.

  As so often, the findings of the studies that were conducted with young subjects were contradictory.
  

  "Six controlled trials with adult subjects serving as their own controls found no significant changes in body weight due to manipulation of eating frequency interventions lasting 6–8 wk."

  In six additional intervention trials of 8–52 wk duration, free-living adults were counseled to change the eating frequency of self-selected food intake with no significant differences in weight loss attributable to eating frequency.
  
  Currently, the overwhelming majority of the available evidence does thus suggest that manipulation of eating frequency will not promote weight loss. The available scientific evidence is thus once more in conflict with common belief about "best practice", when it comes to losing weight - a "common belief", by the way that was, as so often, influenced by epidemiological data of which people simply don't understand that it cannot establish reliable causal relationships.
• Portion Size and Obesity - In their review of the contemporary literature on the effects of portion size on obesity and weight control, M. Barbara E. Livingstone and L. Kirsty Pourshahidi leave little doubt that "portion size has a powerful and proportionate effect on the amount of food consumed." (Livingstone. 2014).
  
  In spite of the fact that the positive effect of portion size on energy intake has been demonstrated for different types of foods and beverages, and is particularly pronounced with energy-dense foods, though, it is as of now not clear what types of interventions targeted at portion size are likely to be effective, in what settings, and among which target groups.
  

  

  Figure 2: You don't need to conduct a study to realize that portion sizes for foods and beverages - specifically the unhealthy ones - are ever-increasing (image from scienceinseconds.com)

  As the researchers point out, further research is thus urgently needed - specifically in view of the fact that the contemporary evidence indicates that the predisposition to overeat in response to large portions is pervasive and occurs regardless of demographic characteristics, such as socioeconomic status, age, body mass index, and sex. This is all the more true in view of the "secular trend toward greater availability of large portions. coupled with value-size pricing, effectively distorted consumption norms and perceptions of what is an appropriate amount to eat" (Livingstone. 2014).
• Variety and Palatability - Reasons We Get fat? As Fiona Johnson and Jane Wardle point out, "among the key characteristics of the Western obesogenic food environment is a highly palatable and varied food supply" (Johnson. 2014). At first, this sounds yummy and healthy. Unfortunately, the possibility to switch back and forth between a large variety of highly palatable salty and sweet junk food has been shown in both humans and animals to (a) have appetite stimulating effects, to (b) delay satiety, and to (c) promote excessive energy intake.
  
  

  

  Figure 3: When men are offered a sandwiches with identical or varied (4 different) fillings, they will consume significantly more if they are allowed to switch back and forth between the different fillings (Rolls. 1981).

  No wonder that the scientists found that there is a robust effect of food palatability and variety on short-term food intake, and increased variety and palatability also cause weight gain in animal models.
  

  "However, laboratory paradigms do not replicate the complexities of eating in a natural setting [...and t]here are substantial individual diffe- rences in susceptibility to the palatability effect and this may be a key determinant in individual vulnerability to weight gain" (Johnson. 2014).

  Or, put more simply, as long as we do not fully understand the pathways through which palatability and variety can affect eating, it is difficult to identify what helps those who can abstain from overeating maintain their weight and what we can do for those who fall for the temptations to help them stand the test of chocolate, chips, pizza and beer.

There are no simple solutions for complex problems: Obesity is a multifaceted problem. Against that background it's hardly surprising that the one thing all of the previously presented studies have in common is that none of them appears to offer a standalone solution to the obesity epidemic.

If you are working out and dieting like a maniac and still not losing weight, you should revisit your self-torture.. ah training and nutrition regimen and make sure that you didn't already shut down your thyroid by overtraining and undereating | learn more.

Sugar-sweetened beverages are certainly a problem - artifically sweetened ones rather not. The availability of food and more specifically the availability of a high variety of highly palatable food contributes to the obesity epidemic as well - the issue of portion sizes is still not settled and myths that eating more frequently would help to lose weight are still propagated by the mainstream media.

Against that background it seems questionable, whether there's ever going to be a one-size-fits-it-all solution... but hey, maybe that's the solution! We probably just have to stop looking for the one-size-fits-it-all solution and start working towards personalized nutrition programs that evolve as you evolve, e.g. from ketogenic to low carb to moderate carb as you progressively lose weight.

References:

• Finkelstein et al. "Food Prices and Obesity: A Review." Adv Nutr. 5 (2014): 818-821.
• Gordon-Larsen, Penny. "Food Availability/Convenience and Obesity". Adv Nutr 5 (2014):809-817 
• Johnson, et al. "Variety, Palatability, and Obesity." Adv Nutr. 5 (2014): 851-859.
• Kant, Ashima K. "Evidence for Efficacy and Effectiveness of Changes in Eating Frequency for Body Weight Management." Adv Nutr 5 (2014): 822-828.
• Livingstone, et al. "Portion Size and Obesity." Adv Nutr. 5 (2014): 829-834.
• Mytton, Oliver T., Helen Eyles, and David Ogilvie. "Evaluating the Health Impacts of Food and Beverage Taxes." Current Obesity Reports (2014): 1-8.
• Pereira, A. P. "Sugar-Sweetened and Artificially-Sweetened Beverages in Relation to Obesity Risk."  Adv Nutr 5 (2014): 851-859.
• Rolls, Barbara J., et al. "Variety in a meal enhances food intake in man." Physiology & Behavior 26.2 (1981): 215-221.
• Stark, James H., et al. "Neighbourhood food environments and body mass index among New York City adults." Journal of epidemiology and community health 67.9 (2013): 736-742.

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).

Learn more about alternatives to sugar sweetened beverages at the SuppVersity

Unsatiating Truth About Sweeteners?

Will Artificial Sweeteners Spike Insulin?

Sweeteners & the Gut Microbiome Each is Diff.

Sweeter Than Your Tongue Allows!

Stevia, Much More Than Sweet?

Artif. Sweetened Foods Good, Not Bad for Fat Loss.

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.

Sugar Sweetened Beverages, Bottled Water & the Obesity Epidemic: Evidence, Counter-Evidence & Scapegoatism

SSBs worse than an obesity pill?

It is a given fact that neither I nor any sane researcher is going to debate the over-consumption of sugar sweetened beverages are part of the reasons why we are fat. The way they are currently portrayed as the worst invention since trans fats, could however fire back on us. You do just have to look how willingly the oil refiners are bashing the corn refiners, how the fruit "juice" industry claims that their "healthy 100% fruit juices were less obesogenic" than a coke (which is clearly not the case) and how consumers are standing in the line at their local fast-food outlet thinking about taking the diet coke with their menu to be able to have an additional "healthy fruit smoothie" as a dessert.

I had all that in the back of my head already, when I hit on a related "Pro v Con Debate" in the early views (articles that are not yet available in the print edition) of the Obesity Reviews and thought that you might be interest in some of the arguments F.B. Hu and K.A. Kaiser et al. are presenting in their "debate" (in fact we are talking about to separate position papers) on the "Role of sugar sweetened beverages in Obesity", as well.

Point: Sugar sweetened beverages, obesity & diabetes - Scientist says the evidence is there

(Hu. 2013) I would assume that the vast majority of you is not going to have to be convinced by rational or irrational arguments that sugar sweetened beverages will increase your risk of obesity and diabetes. Still, F.B. Hu, a scientists from the Departments of Nutrition and Epidemiology at the Harvard School of Public Health in Boston must have thought of the rest of the public and the bribed, ah... pardon "mislead" policy makers, when they compiled their latest paper with the tell-tale title "Resolved: there is sufficient scientific evidence that decreasing sugar-sweetened beverage consumption will reduce the prevalence of obesity and obesity-related diseases". According to Hu,

Figure 1: Relative risk of the development of obesity per increment of 10 risk alleles, according to intake of sugar-sweetened beverages; data based on the Nurses’ Health Study (NHS) and Health Professionals + follow up (HPFS), the Women’s Genome Health Study (WGHS) and the three cohorts together (Hu. 2013)

"Consumption of SSBs has increased markedly across the globe in recent decades, tracking closely with the growing burdens of obesity. These beverages are currently the largest source of added sugar intake and the top source of daily energy in the U.S. diet. The cumulative evidence from observational studies and experimental trials is sufficient to conclude that regular consumption of SSBs causes excess weight gain and these beverages are unique dietary con- tributors to obesity and T2D. Compelling evidence indicates that reducing SSBs will have significant impact on the prevalence of obesity and its related diseases, especially T2D. [...] Although reducing SSB consumption alone is unlikely to solve the obesity epidemic entirely, limiting intake of SSBs is one simple change that could have a measurable impact on weight control and prevention of T2D and other metabolic diseases" (Hu. 2013; my emphasis)

Hu also points to the "strong resistance from the beverage industry" and the few, but increasingly numerous  public policies and regulatory strategies to reduce intake of SSBs that are already in place or being developed. The importance of a grass-roots approach, on the other hand appears to escape him. After all, it often does not look like this, but in the end the US is still a free country: You don't have to drink Pepsi, Coke and Mountain Dew, folks and neither do your friends and family.

Counterpoint: Sugar sweetened beverages are bad - in theory, but what about the reality?

(Kaiser. 2013) Now that your conviction that sugar sweetened beverages are bad, has been confirmed. let's shake the evidence and take a peak at what K. A. Kaiser, J. M. Shikany. K. D. Keating and D. B. Allison have to say about the question whether reducing sugar-sweetened beverage consumption will reduce obesity and why they feel that "[The e]vidence supporting conjecture is strong, but evidence when testing effect is weak".

Theory vs. experimental evidence: In fact the theoretical slope of the line depicting the increase in weight gain due to the consumption sugar sweetened beverages is more than 10x steeper than the one that has been observed in scientific studies (see figure 3).

What is particularly interesting is that the theoretical prediction is accurate only in the lowest 10-15% of the SSB intakes investigated in the study, for the "real SSB junkies" the gab widens significantly.

Figure 2: Rise in obesity rates (round markers) and bottled water consumption (square markers) in the US (Kaiser. 2013)

If you take a look at the graph to the right (figure 2) you will notice right away: We can as well blame the obesity epidemic to the increase in bottled water consumption (or the decrease in tap water consumption?) - the epidemioloical "evidence" is conclusive!

This figure is yet not the only thing Kaiser at al. enlist to make you at least reconsider how conclusive the evidence of which Hu just argued that it is "there" actually is. The most important factors Kaiser, Shikany, Keating and Allison want to remind us of, when it comes to the interpretation and evaluation of the hitherto available studies are...

• the risk of bias -- Most scientists start out with the same conviction we do: "Sugar sweetened beverages make you fat!" Against that backround it is even more detrimental that  "some study designs failed to adequately isolate treatment effects from the attention researchers paid to some groups." (Kaiser. 2013) The researchers also point out that not all studies had an objective measure of participant compliance (returned containers, urinary sucralose measures) and did not report whether the people who accessed the effects were blinded as well (10 out of 15 studies did not). Publication bias, on the other hand, did not appear to be a factor to skew the results (Kaiser. 2013)
• missing / insufficient sensitivity analysis -- In their re-analysis the researchers found sign. differences in the obesogenic effects of SSBs on young vs. old, male vs. female and lean vs. obese participants, yet the majority of the studies does not accordingly differentiate the outcomes.
  

  

  Figure 3: Observed (30,34,40–42,62) versus theoretical (63) weight gain effect of mandatory sugar-sweetened beverage (SSB) consumption (Kaiser. 2013)

  "[...] we evaluated the overall summary effects by excluding the studies referenced above. The overall SMD for the added SSB studies (adults only) increased by 0.06 (to 0.34; 95% CI: 0.15 to 0.54). The overall SMD for the reduction of SSBs in children of all weight categories was reduced by 0.01 (to 0.07; 95% CI:  -0.01 to 0.15). The overall SMD for the reduction studies in children only who were overweight or obese at baseline increased by 0.05 (to 0.30; 95% CI: 0.13 to 0.46)." (Kaiser. 2013)

  The general heterogenity (all variables included) is yet not another contributor to significant changes in the study outcomes.
• data interpretation / analysis - The scientists suggest that analyzing only absolute weight / BMI levels is not an adequate measure and propose two different methods to evaluate the data
  
  1. Asking the question, whether a person that is in the "SSB" group would increase or decrease weight / BMI if he or she switched to the other group - This analysis yielded a +2% and +7% change of weight / BMI reduction.
  2. Using the correlation data as basis to calculate the explanatory value of SSB consumption - This analysis showed that only 1.92% of the variance in body weight or BMI change is explained by SSB consumption, for the variance weight reductions in persons of all weight categories the figure is a hilariously irrelevant 0.09%
  As you can see, looking at the data from a marginally different angle can easily make all the difference. 

I know what you are thinking now "but XY said..." or "but what about..." and obiously Kaiser et al. must also have thought about objections like these and added a brief adjunct to their paper in which they point towards three major reasons that explain why the influence of sugar sweetened beverages is perceived as larger than life by the public:

1. 

   Don't get me wrong, I love the "ads" of the NYC Dept. of Health & Mental Hygiene campaign against sugar sweetened beverages, and used it as title picture for a previous post on the fattening effects of SSBs, but they are part of the problem Kaiser et al. are pointing at in their paper. People will sit next to them think about the gym and say: "Well I drink diet coke, so I don't have to go to the gym today - after all sugar is the problem!"

   Emotion-raising language - Emotion-raising language has often been used in discussions of SSBs and obesity. Some authors have used words like ‘plague’, ‘toxic’, ‘hazardous’ (4,53) and ‘deadly’ when describing SSBs or the sugars they contain and have tried to promote perceived connections between SSB marketers and the worst behaviour of tobacco marketers . Although such words may help to advance an agenda, they do not educate or inform the public.
   
   Moreover, they likely raise emotions and impair logical reasoning. As Kersh and Morone wrote, ‘Scientific findings never carry the same political weight as does a villain threatening American youth.
   
   If critics successfully cast portions of the industry in this way, far-reaching politi- cal interventions are possible, even likely. When an industry becomes demonized, plausible counterarguments (privacy, civil liberties, property rights, and the observation that “everyone does it”) begin to totter.’
2. Distortion of scientific information - A second factor that has likely contributed to misperceptions in this area is the distortion of scientific information by some authors and commentators. [...] Clearly, such practices mislead and have likely contributed to misperceptions in the scientific and lay communities about the strength of the evidence regarding the proposition debated here.
3. The mere exposure effect - The final factor that we believe has led to the erroneous perception that the evidence showing that the proposition of this debate has been unequivocally proven is the ‘mere exposure effect.’
   
   The mere exposure effect is the label psychologists use for the phenomenon that the more a person is exposed to an idea, the more they come to like and accept it. As the Nobel Prize-winning economist Daniel Kahneman described, ‘A reliable way to make people believe in falsehood is frequent repetition, because familiarity is not easily distinguished from truth. Authoritarian institutions and marketers have always known this fact. But it was psychologists who discovered that you do not have to repeat the entire statement of a fact or idea to make it appear true’
   
   The number of articles on SSBs and obesity and the number of statements that SSBs are especially problematic in obesity are extraordinary, especially in comparison to the modest amount of probative data. Thus, opinions about SSBs may have been offered so often that these opinions have become accepted as fact by many in the scientific community, media and lay public.

I probably could quote addtional parts of the excellently written paper here, but I guess you are getting the notion and will be able to understand that neither my nor the scientists who wrote the original paper intend to support the position of the SSBs industry that have long realized that this war cannot be won on the scientific stage and have long focused all their efforts having their "lifestyle" drinks being marketed by the "cool and hip" celebrities, athletes and super models to the "wanna be cool and hip" normals.

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Bottom line: I am well aware that some of you are now probably already dialing the Dr. Lustig's phone number or calling the blogosphere's vice police to accuse me of making a pact with the Coca Cola company.

You all know I am an opponent of the consumption all sugar & HFCS sweetened drinks and foods and well aware of the "fat consequences" (learn more), but overemphasizing the roles of SSBs or HFCS, is not going to help us solve the global obesity problem.

But let's be honest, you all know that I neither drink nor recommend anyone to drink sugar sweetened beverages. My interest is in understanding the contributions each and every of the myriad of dietary, behavioral, endocrine, paracrine, neurological, environmental, social, ... to the obesity epidemic and if you take a look the 1.92% explanatory value of SSBs consumption in terms of body weight and BMI, it is clear that sugar sweetened beverages are a major contributor to the obesity epidemic.

Still it is not warranted and would be a consequential mistake to expect that by taking them off the market the whole issue would be solved. We all know that this won't be the case and you just have to look at the non-existent long-term effects switching to diet sodas had on the waist lines of the obese to know that we have to do more than remove all sugar sweetened beverages from the displays of the supermarket.

Does this mean we should not tell people they are bad for them? Try to tax or ban them? No. What it does mean, though, is that the war against obesity is not a war against SSBs, only.

References:

• Hu FB. Resolved: there is sufficient scientific evidence that decreasing sugar-sweetened beverage consumption will reduce the prevalence of obesity and obesity-related diseases. Obes Rev. 2013 Jun 13.  
• Kaiser KA, Shikany JM, Keating KD, Allison DB. Will reducing sugar-sweetened beverage consumption reduce obesity? Evidence supporting conjecture is strong, but evidence when testing effect is weak. Obes Rev. 2013 Jun 7.

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.

High Fructose Consumption, Inflammation Up, LDL/HDL Ratio Down - Is That Good or Bad For Your Heart?

Remember: If anything fructose from beverages (including juices), yet not fructose from whole fruit is a problem. In fact eating whole fruits will decrease your blood lipids and high sensitivity C reactive protein (hs-CRP) inflammation markers.

Fructose is bad for you, right? Right. According to the latest study from the University of Newcastle, the consumption of only one drink containing containing 50 g of either fructose or glucose or sucrose dissolved in water will have detrimental effects on the #1 indicator of whole body inflammation, which is high sensitivity C-reactive protein (hs-CRP).

Much to the researchers surprise, though, the same amount of fructose had significant beneficial effects on the plasma lipid levels of the healthy male and female adults (n = 14) between the ages of 18-60 years who were recruited by advertisement and underwent study procedures at the Nutraceuticals Research Group Clinic rooms at the University of Newcastle in Australia.

Learn more about fructose at the SuppVersity

Bad Fructose not so Bad, After All! Learn its Benefits.

Fructose From Fruit is NOT the Problem

Americans Don't Eat More Fructose These Days!

An Apple A Day, Keeps... & More (Guestpost)

Fructose is Not Worse Than Sugar

The Obesogenic Fructose Fat Connection

Since the exclusion criteria were: diagnosed hyperlipidaemia, diabetes, gastrointestinal disorders, currently on fructose/sugar restricted diet, vegan diet or weight loss program, undergone any surgical procedure for obesity, pregnant or lactating mother, taking lipid-lowering or anti-inflammatory drugs and BMI >30kg/m², the results may well be different in "sicker" individuals, but for the guys and gals who drank the three 50g "sugar" solutions on three different occasions after an overnight fast, the "negative effects" of fructose were far from being conclusive.

Figure 1: Changes in hs-CRP, HDL and LDL in response to the ingestion of the test drinks (Jameel. 2014).

Even if you belong to the ever-increasing numbers of brainwashed fructose haters who believe that fructose and not a general overconsumption of energy was to blame for the obesity epidemic, you will have to admit that the data in Figure 1 leaves the significance of concomitant increases in hs-CRP and significant improvements in the HDL/LDL ratio, as the scientists phrase it, "to be delineated when considering health effects of feeding fructose-rich diets" (Jameel. 2014).

Apples reduce, apple juice increases hs-CRP in healthy volunteers (Ravn-Haren. 2013).

Don't mistake fruits for pure fructose: Studies indicate that a high fruit consumption is associated with reduced hs-CRP scores and a lower mRNA expression in peripheral blood mononuclear cells of some relevant proinflammatory gene markers (Oliveira. 2009; Hermsdorff. 2010). This is yet not the case for fruit juices, as you may remember from a previous SuppVersity post discussing the results of Gitte Ravn-Haren's 2013 study which showed that the intake of whole apples had beneficial, the consumption of apple juice, however, detrimental effects on plasma lipids and - as you can see in the figure to the left - hs-CRP levels of the healthy volunteers (Gitte Ravn-Haren 2013).

Well, yes, but (a) it's only an acute response and (b) while increased levels of hs-CRP have been found to be associated with heart disease (Rifai. 2001; Danesh. 2004), the same can be said for a high LDL/HDL ratio (Fernandez. 2008).

Figure 2: CRP-dependent risk levels for cardiovascular disease according to the American Hear Association.

If we also take into consideration that the baseline hs-CRP level of the subjects was 1.5mg/L and thus low to mid-range for the average Westerner (depending on his or her ethnicity | Albert. 2004), an increase of 10% to a maximal value of 1.65mg/L would not bring them to critical heights of which the Farmingham study says that they start at 3mg/L for Westerners (Wilson. 2005). That's not ana optimal level, but considering the fact that we are talking about "average Joes and Janes" who probably don't work out, eat whatever they like and give a damn about their sleep hygiene (all three factors have previously been linked to elevated hs-CRP levels) that's not astonishing and has absolutely nothing to do with the ingestion of 50g of fructose.

Furthermore, a comparison of the predictive value of different risk markers for cardiovascular disease by Folsom, et al. (2006) indicates that the hs-CRP values did not add to the prognostic value of the standard risk factors which are age, race, sex, systolic blood pressure, smoking status, diabetes and - you guessed it - total and high density lipoprotein cholesterol, which increased by almost 7% while the amount of LDL dropped by maximally 6%. Thus the LDL/HDL ratio decreased from 1.84 to 1.62. That's a 12% decrease that would be health relevant if the subjects' LDL/HDL ratio was not far away from the danger-zone (>5 | see Manninen. 1992), already. Similarly, the total cholesterol to HDL ratio dropped by -1.97 but wasn't in the danger zone before, either.

Incremental area under the curve for glucose and insulin 0-120min after consuming the test beverages (Jameel. 2014).

So what? Overall the results provide no evidence that the occasional consumption of a larg(er) bolus of fructose was unhealthier than the same amount of glucose or sucrose. If you take a parting look at the glucose and insulin response you will also see why fructose has long been haled as the "healthier" alternative to sugar for type II diabetics: there is no increase in glucose or insulin in response to the ingestion of 50g of fructose. And even the dreaded increase in triglycerides that occurs when the liver converts the fructose to fat did not occur (in fact, the levels dropped by ~4%, while they increased when the subjects consumed glucose (+11%) or sucrose (+4%).

So, if you've been drinking your first real coke of 2015 last night, don't worry. It probably didn't hurt your heart. If you plan to continue drinking 1l of the brown sugar-liquid everyday, this year, though, I would not guarantee that the extra pounds you may be gaining and the diabetes you may be developing won't have negative consequences for your heart and maybe liver health  | Comment on Facebook.

References:

• Danesh, John, et al. "C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease." New England Journal of Medicine 350.14 (2004): 1387-1397. 
• Fernandez, Maria Luz, and Densie Webb. "The LDL to HDL cholesterol ratio as a valuable tool to evaluate coronary heart disease risk." Journal of the American College of Nutrition 27.1 (2008): 1-5.
• Folsom, Aaron R., et al. "An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study." Archives of internal medicine 166.13 (2006): 1368-1373. 
• Hermsdorff, Helen Hermana M., et al. "Research Fruit and vegetable consumption and proinflammatory gene expression from peripheral blood mononuclear cells in young adults: a translational study." (2010).
• Jameel, Faizan, et al. "Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation." Lipids in Health and Disease 13.1 (2014): 195.
• Manninen, Vesa, et al. "Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment." Circulation 85.1 (1992): 37-45.
• Oliveira, A., F. Rodriguez-Artalejo, and C. Lopes. "The association of fruits, vegetables, antioxidant vitamins and fibre intake with high-sensitivity C-reactive protein: sex and body mass index interactions." European journal of clinical nutrition 63.11 (2009): 1345-1352. 
• Ravn-Haren, Gitte, et al. "Intake of whole apples or clear apple juice has contrasting effects on plasma lipids in healthy volunteers." European journal of nutrition 52.8 (2013): 1875-1889.
• Rifai, Nader, and Paul M. Ridker. "High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease." Clinical chemistry 47.3 (2001): 403-411.
• Wilson, Peter WF, et al. "C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study." Archives of internal medicine 165.21 (2005): 2473-2478.