Fructose, a New Truth? Meta-Analyses Exonerate Fructose... as Part of Non-Hypercaloric Diets and in Normal Amounts

Editorial provides compelling evidence from meta-analyses, but their results are context-dependent ...

"The story of fructose reflects the cyclic nature of much in nutrition." That's what John Sievenpiper writes in his latest editorial in The American Journal of Clinical Nutrition; and he's right. If you review the history of the science on fructose you will see that it went full circle - not once, but repeatedly.

As Sievenpiper points out, the latest meta-analyses by Evans et al. (2017a,b) found (a) beneficial effects on blood glucose especially in people with already messed up glucose management, when sucrose (=sugar) was replaced with fructose, and (b) lowered fasting blood glucose and HbA1c, and triglycerides, plus body weight.

Learn more about fructose at the SuppVersity

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Fructose is Not Worse Than Sugar

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How's that possible? Well, Sievenpiper writes: "[Fructose] is now in a position to be endorsed again on the basis of the accumulated evidence" (Sievenpiper 2017). He does yet admit that "[s]ources of uncertainty, however, remain with the inconsistency and imprecision in the estimates for chronic fructose intake" (ibid.). In other words, ...

"There is a need for more long-term (>6 mo) randomized trials to clarify the benefits of the replacement of glucose-containing sugars and starches with fructose with the use of “real world” food applications in people with diabetes or at risk of diabetes" (Sievenpiper 2017)

And the Evans studies are neither the first nor the only meta-analyses that highlight the existence of studies which show the advantages of the use of fructose as a replacement for glucose-containing sugars or starches (Agostoni 2011). The European Food Safety Authority provided a scientific opinion on the substantiation of health claims related to fructose and the reduction in postprandial glycemic responses. It was concluded that “a cause and effect relationship has been established between the consumption of fructose in place of sucrose or glucose in foods or beverages and reduction of postprandial glycaemic responses” (Agostini 2011) and there's more:

• On blood glucose management
• Livesey and Taylor (2008) found that fructose intake < 90 g/d significantly improved HbA1c concentrations dependent on the dose, the duration of study, and the continuous severity of dysglycemia throughout the range of dysglycemia. There was no significant change in body weight at intakes <100 g fructose/d. Fructose intakes of <50 g/d had no postprandially significant effect on triacylglycerol and those of ≤100g/d had no significant effect when subjects were fasting. At ≥100 g fructose/d, the effect on fasting triacylglycerol depended on whether sucrose or starch was being exchanged with fructose, and the effect was dose-dependent but was less with increasing duration of treatment. Different health types and sources of bias were examined; they showed no significant departure from a general trend.
• Cozma, et al. (2012) reviewed eighteen trials (n = 209) and found that isocaloric exchange of fructose for carbohydrate reduced glycated blood proteins (SMD −0.25 [95% CI −0.46 to −0.04]; P = 0.02) - albeit with significant intertrial heterogeneity (I2 = 63%; P = 0.001). This reduction is equivalent to a ∼0.53% reduction in HbA1c. Fructose consumption did not significantly affect fasting glucose or insulin. A priori subgroup analyses showed no evidence of effect modification on any end point.
• On blood lipids
• Sievenpiper et al. (2009) reviewed sixteen trials (236 subjects) in which isocaloric fructose exchange for carbohydrate raised triglycerides and lowered total cholesterol under specific conditions without affecting LDL cholesterol or HDL cholesterol. A triglyceride-raising effect without heterogeneity was seen only in type 2 diabetes when the reference carbohydrate was starch (mean difference 0.24 [95% CI 0.05–0.44]), dose was >60 g/day (0.18 [0.00–0.37]), or follow-up was ≤4 weeks (0.18 [0.00–0.35]). Piecewise meta-regression confirmed a dose threshold of 60 g/day (R2 = 0.13)/10% energy (R2 = 0.36). A total cholesterol–lowering effect without heterogeneity was seen only in type 2 diabetes under the following conditions: no randomization and poor study quality (−0.19 [−0.34 to −0.05]), dietary fat >30% energy (−0.33 [−0.52 to −0.15]), or crystalline fructose (−0.28 [−0.47 to −0.09]). Multivariate meta-regression analyses were largely in agreement.
• Wang, et al. (2014) reviewed 16 trials, again, the scientists distinguished studies with isocaloric and hypercaloric diets and found that fructose supplemented the background diet with excess energy from high-dose fructose compared with the background diet alone (without the excess energy). There was no significant effect in the isocaloric trials (SMD: 0.14 [95% CI: −0.02, 0.30]) with evidence of considerable heterogeneity explained by a single trial. Hypercaloric trials, however, showed a significant postprandial triglyceride raising-effect of fructose (SMD: 0.65 [95% CI: 0.30, 1.01]).
• On weight gain
• Sievenpiper et al. (2012) distinguished between isocaloric and hypercaloric trials and found that fructose does not seem to cause weight gain when it is substituted for other carbohydrates in diets providing similar calories. Free fructose at high doses that provided excess calories modestly increased body weight, an effect that may be due to the extra calories rather than the fructose.
• On blood pressure
• Ha et al. (2012) who focussed on the potential ill effects of fructose on blood pressure found 13 human clinical trials in which fructose was isocalorically exchanged for other carbohydrate sources for ≥7 days and 2 trials in which the subjects ate hypercalorically. Their analysis shows that the fructose intake in isocaloric exchange for other carbohydrates significantly decreased diastolic (mean difference: −1.54 [95% CI: −2.77 to −0.32]) and mean arterial pressure (mean difference: −1.16 [95% CI: −2.15 to −0.18]). There was no significant effect of fructose on systolic blood pressure (mean difference: −1.10 [95% CI: −2.46 to 0.44]). Furthermore, the hypercaloric fructose feeding trials found no significant overall mean arterial blood pressure effect of fructose in comparison with other carbohydrates. 
• On uric acid
• Wang, et al. (2012) conducted a meta-analysis to investigate the effects of fructose replacement on uric acid and came to the conclusion that there's no increase in uric acid if realistic amounts of fructose are consumed. More specifically, the 21 trials in 425 participants suggest that the isocaloric exchange of fructose for other carbohydrate did not affect serum uric acid in diabetic and nondiabetic participants [MD = 0.56 μmol/L (95% CI: −6.62, 7.74)], with no evidence of inter-study heterogeneity. Hypercaloric supplementation of control diets with fructose (+35% excess energy) at extreme doses (213–219 g/d), on the other hand, significantly increased serum uric acid compared with the control diets alone in nondiabetic participants [MD = 31.0 mmol/L (95% CI: 15.4, 46.5)] with no evidence of heterogeneity. Confounding from excess energy cannot be ruled out in the hypercaloric trials. 
• On non-alcoholic fatty liver disease (NAFLD)
• Chiu et al. (2014) conclude based on 13 trials with respect to the effects on NAFLD that the effects on NAFLD markers can only be observed in hypercaloric trials, where both IHCL (SMD=0.45 (95% confidence interval (CI): 0.18, 0.72)) and ALT (MD=4.94 U/l (95% CI: 0.03, 9.85)) increased significantly. In isocaloric trials, on the other hand, there was no effect of fructose to be observed.

Eventually, these results are in line with the long-estalished mechanistic effects of fructose on glycemia. In view of its low GI it cannot be surprising that fructose acutely ameliorates the postprandial increase in glucose.

One thing we should not forget in the debate is that 10g of sugar from coke/liquid food may actually do significantly more harm than the same amount from cookies/solid food.

Previous studies highlight the particular problem with liquid sugars, but they don't show that fructose was either exclusively or especially problematic: 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), a previously discussed study 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.

What is important, though, is that this beneficial effect occurs only with isocaloric replacement of sucrose or other glucose releasing carbohydrates and critically depends on the dosage.

Figure 1: Estimated rates of glycogen synthase flux (left), and net hepatic glycogen synthesis (right) in control and fructose studies under euglycemic (5 mmol/l) hyperinsulinemic (400 pmol/l) conditions (Peterson 2001).

As Sievenpiper points out, low-dose fructose (≤10 g/meal) may even improve glycemic control through a “catalytic” effect on hepatic glucose metabolism by inducing glucokinase activity. You may remember this from my previous elaborations on the potential benefits of fructose for glycogen repletion which has been observed to be increased by 13C-nuclear magnetic resonance spectroscopy under euglycemic clamp conditions in participants without diabetes (Peterson 2001), as well as to decrease the hepatic glucose production under hyperglycemic clamp conditions in people with type 2 diabetes (Hawkins 2002).

Fructose-Equivalent of <1L Apple Juice or 1.25L Coke & Co Clogs Human Livers Without Visibly Affecting Body Weight or Fat in 12Wk RCT - Study Highlights: Liquid Fructose is Particularly Problematic | more

To use the previously cited evidence to conclude that fructose was not a problem at all is in my humble opinion still problematic: If you review the "accumulating evidence" (which was by the way mostly generated by Sievenkemper himself or his lab), each and every study that seems to exonerate fructose does so only if (a) the diet is isocaloric (not hypercaloric) and (b) the fructose intake is <50g (in Livesey & Taylor 2008 even 75g had initial effects on trigs) per day. Both, however, is not the case in the so-called "developed world"; including the US, where the average teen consumes more than those 75g of fructose (Vos 2008), of which Taskinen et al. have recently shown that they suffice to trigger the storage of extra fat in the liver in the absence of measurable overall weight or fat gain.

In the gluttonous real-world of our consumerist society, it is thus questionable for whom it is true that the previously discussed beneficial effects of fructose outweigh "the mechanisms invoked to explain the purported adverse effects of fructose, such as an increase in de novo lipogenesis" (Sievenpiper 2017). That's not because fructose is the devil. It's because everything, from portion sizes to food design, promotes the overconsumption of energy dense, nutrient-poor foods and beverages. With the latter being specifically problematic, because the rapidly absorbed fructose can overwhelm the liver and stimulate, as Taskinen et al. have shown it only recently, "significantly increase liver fat content and hepatic DNL and decreased β-hydroxybutyrate" (Taskinen 2017).

It is thus only logical that a recent study from the Icahn School of Medicine at Mount Sinai is not the first to show that the consumption of high vs. low amounts of fructose from soft drinks, fruit drinks, and apple juice is associated with a 2.8-fold increase in coronary heart disease risk in 1230 men and women aged 45–59 (DeChristopher 2017). In this context, it is important to literally keep a sense of proportion, though. The comparison is after all not drinking fructose sweetened beverages once in a while vs. never. It's drinking them almost every day (≥5 times/wk) vs. ≤3 times/mo. The notion that the occasional coke is going to kill you is thus as hilarious as the assumption that apples were toxic, because they have a high fructose content. In fact, there is absolutely zero evidence that fructose from other dietary sources, is remotely as problematic as the previously referenced juices, sodas, and co. And DeChristopher et al. also observed that moderate consumers (1–4 times/wk) of orange juice were half as likely to have CHD as seldom/never consumers (OR 0.45; 95% CI-0.26-0.77; P = 0.005)" (DeChristopher 2017) - whether that's due to or in spite of fructose, is obviously open to debate.

Eventually, food-specific analyses and further longer term trials (>6 months) investigating the exact dose/effect relationship, its dependence on individual subject characteristics (the subjects in the Taskinen study, for example, had a belly, even though they were normal-weight, already - in athletes, those 75 g of fructose may well not have triggered de novo lipogenesis, the relevance of which is debated quite nicely in these letters to the editor, in case you're interested), and dietary context (total carb, fat and caloric content of the diet, etc.) are still warranted | Comment!

References:

• Agostoni, C., J. L. Bresson, and S. Fairweather-Tait. "Scientific opinion on the substantiation of health claims related to fructose and reduction of post-prandial glycaemic responses (ID 558) pursuant to Article 13 (1) of Regulation (EC) no 1924/2006." EFSA J 9 (2011): 2223-2238.
• Chiu, S., et al. "Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials." European journal of clinical nutrition 68.4 (2014): 416.
• Cozma, Adrian I., et al. "Effect of fructose on glycemic control in diabetes." Diabetes care 35.7 (2012): 1611-1620.
• DeChristopher, Luanne Robalo, Jaime Uribarri, and Katherine L. Tucker. "Intake of high fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent coronary heart disease, in US adults, ages 45–59 y." BMC Nutrition 3.1 (2017): 51.
• Evans, Rebecca A., et al. "Fructose replacement of glucose or sucrose in food or beverages lowers postprandial glucose and insulin without raising triglycerides: a systematic review and meta-analysis." The American Journal of Clinical Nutrition (2017a): ajcn145151.
• Evans, Rebecca A., et al. "Chronic fructose substitution for glucose or sucrose in food or beverages has little effect on fasting blood glucose, insulin, or triglycerides: a systematic review and meta-analysis." The American Journal of Clinical Nutrition (2017b): ajcn145169.
• Ha, Vanessa, et al. "Effect of fructose on blood pressure." Hypertension (2012): HYPERTENSIONAHA-111.
• Hawkins, Meredith, et al. "Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes." Diabetes 51.3 (2002): 606-614.
• Livesey, Geoffrey, and Richard Taylor. "Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies." The American Journal of Clinical Nutrition 88.5 (2008): 1419-1437.
• Petersen, Kitt Falk, et al. "Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans." Diabetes 50.6 (2001): 1263-1268.
• Sievenpiper, John L., et al. "Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes." Diabetes care 32.10 (2009): 1930-1937.
• Sievenpiper, John L., et al. "Effect of Fructose on Body Weight in Controlled Feeding TrialsA Systematic Review and Meta-analysis." Annals of internal medicine 156.4 (2012): 291-304.
• Sievenpiper, John L. "Fructose: back to the future?." The American Journal of Clinical Nutrition 106.2 (2017): 439-442.
• Taskinen, M.-R., et al. (2017), Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J Intern Med. Accepted Author Manuscript. doi:10.1111/joim.12632
• Vos, Miriam B., et al. "Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey." The Medscape Journal of Medicine 10.7 (2008): 160.
• Wang, D. D., et al. "Effect of fructose on uric acid: a meta-analysis of controlled feeding trials." J Nutr 142 (2012): 916-23.
• Wang, D. David, et al. "Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials." Atherosclerosis 232.1 (2014): 125-133.

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).

You can learn more about citrulline at the SuppVersity

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Arginine & citrulline for blood lipid control

EAA, BCAA, or citrulline for anti-catabolism?

Glutamine not citrulline to heal the gut?

Citrulline to ignite fatty acid oxidataion?

High & low dose arginine ineffec- tive NO boosters

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.

It's True: Fructose Makes You Fat - In Fact, It Even Makes You Make Fat! Study Shows, HFCS Beverages Kickstart Endogenous Palmitic Acid Production, Sugary Ones Don't

In the fashion business, "light or not light" (light=diet as in "Diet Coke" US vs Coke Light Germany) is not really a question to ask.

Actually I have given up writing about fructose. It appears as if everyone was so bamboozled by the obvious bullsh*t you can read all over the Internet that it's useless to tell them that you are not going to get obese from eating one, two or even ten apples a day! In view of the fact that today's SuppVersity article is about the negative effects of fructose, I am yet quite confident that more than the few enlightened SuppVersity regulars will read it.

I mean, who would not want to know whether moderate amounts of various sugars (including fructose, sucrose, and glucose) in sugar-sweetened beverages (SSBs) will have differential effects on fatty acid synthesis and degradation in healthy young men?

Now that I'd probably even have Dr. Lustig attention, let's first take a look at what exactly Michel Hochuli and his colleagues from the University Hospital Zurich did to answer this question.

The study we are dealing with is a randomized controlled crossover trial with a total of four different dietary interventions. During each of these, subjects were supplied with SSBs containing various sugars in different concentrations in random order during 3 weeks:

• 40 g fructose per day [medium fructose (MF)]
• 80 g fructose per day [high fructose (HF)]
• 80 g glucose per day [high glucose (HG)]
• 80 g sucrose per day [high sucrose (HS)]

In the second part of the study, in addition, hyperinsulinemic euglycemic clamps were performed with nine participants after each intervention to assess glucose metabolism and the dynamics of acylcarnitines. What adds to the significance of the data is the fact that the subjects were 34 healthy, normal-weight men - no rats, or type II diabetics and thus a study population of which you can expect that the things that happen to them, after the ingestion of the differently sweetened SSBs could happen to you, as well.

Figure 1: Relative levels of palmitate to linoleic acid ratio (left) and palmitoylcarnitine (right) after the ingestion of the four test-SSBs; values expressed rel. to baseline (Hochuli. 2014)

Apropos "things that can happen, when you consume too much SSBs", as you can see in Figure 1 the things that did happen were (a) a significant increase in fatty acid synthesis as it can be seen from the relative abundance of palmitate (16:0) and the molar fatty acid ratio of palmitate to linoleic acid (16:0 to 18:2; Figure 1, left) in the high fructose (HF) and medium fructose groups (MF).

These changes went hand in hand with increases in fasting palmitoylcarnitine (=palmitic acid that's "carried" by carnitine to the mitochondria for oxidation) that signifies impaired or at least insufficient fatty acid oxidation  and, last but not least, a decreased inhibition of lipolysis by insulin in the clamp condition.

Now, this is what happens next...

In a lab setting and after the consumption of an isolated test beverage this obviously isn't much of a problem, but if you think of a real-life SSB-consumption scenario, you will have to agree that people tend to use their fructose sweetened beverage to wash down a greasy piece of pizza ... and, believe it or not, this is where the whole fructose problem begins.

Learn more about EVOO

Tip - Use Extra Virgin Olive Oil to minimize hepatic lipid production: The results will obviously still have to be confirmed in a human study, but based on the effects scientists from the University of Salentoobserved in the petri dish it would appear that the inhibition of hepatic fatty acid production, ie. exactly what happened in the study at hand, is yet another feature on the list of beneficial health effects of the polyphenols in extra virgin olive oil (Priore. 2014). In that, hydroxytyrosol (-41%) and oleuropein (−38%) are the most, tyrosol (−17%) the least potent polyphenol.

It's the combination of sugar (➲ insulin), fructose (➲ palmitic acid production + blockade of the inhibitory effect of insulin on the former) and fat from your delicious piece of pro-obesogenic Americanized and super-sized Italian cuisine (➲ influx of triglycerides via the portal vein) that will elevate their blood lipids to a degree which impairs their glucose metabolism (Roden. 1996). This, in turn will keep the insulin up, the palmitic acid production running (remember, fructose reduced the ability of insulin to blunt this process) and the blood lipds (in this case palmitic acid and its breakdown products) accumulating.

Now even that wouldn't be a problem. People could, after all, burn the fat off by fasting. Unfortunately, the combination of insulin resistance and impaired fatty acid oxidation leaves them starving in abundance. What nutrients are their cells supposed to use? Glucose? Doesn't work, because of the insulin resistance. Fats? Can't be oxidized because of the elevated insulin levels. The consequence? Well, if we are talking about the average overweight inhabitant of the Western obesity belt, he will find himself sneaking through the kitchen, opening the fridge and annihilating a family packet of ice-cream only 30 minutes after his 1,500kcal+ "all American" version of the Italian way of making use of leftovers... eventually al this takes us - you won't believe it - back to the simple but undeniable truth that eating processed foods promotes overeating and overeating promotes obesity, hyperlipidemia and diabetes. My gosh! Who would have thought that?

Figure from " 6x Bananas a Day!? Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" | read more

Is all this going to happen if you have an apple with a meal? NO! It isn't. And that's exactly, why I hate news like these. It is true: We are not made to handle the sudden influx of several grams of fructose and I am all for avoiding fructose sweetened beverages, fruit juices and other processed foods for this reason. What I am not willing to accept, though, is that the overgeneralizing anti-fructose propaganda-machinery scares people away from eating whole, fresh fruit... and yes(!), when I am talking about "fruit" I am not referring to berries, only.

References: 

• Hochuli, et al. "Sugar-Sweetened Beverages With Moderate Amounts of Fructose, but Not Sucrose, Induce Fatty Acid Synthesis in Healthy Young Men: A Randomized Crossover Study."  J Clin Endocrinol Metab (2014). Early Release.
• Priore, Paola, et al. "Extra virgin olive oil phenols down-regulate lipid synthesis in primary-cultured rat- hepatocytes." The Journal of Nutritional Biochemistry (2014). Accepted Manuscript.
• Roden, Michael, et al. "Mechanism of free fatty acid-induced insulin resistance in humans." Journal of Clinical Investigation 97.12 (1996): 2859.

Bad Fructose? Increased Glycogen Synthesis, Reduced Glycemia, Higher Glucose Oxidation - When Do These Beneficial Effects Occur? And Why Don't They Prevail?

Are there good and bad fructose sources according to the amount, concentration, and availability of the super-sweet super-cheap sweetener?

Believe it or not: Fructose was not send by the devil to expel us from the gluttonous paradise of all-you-can-eat buffets. Rather than that, fructose is an important nutrient found naturally in fruit and a component of most healthy diets of which the following paragraphs will highlight that it plays a very important role in normal sugar metabolism.

In contrast to the majority of the recently published literature on fructose, of which Maren R. Laughlin from the NIH writes in a recent paper that it is "not relevant for the purpose of understanding the metabolism of low levels of fructose eaten as a minor fraction of the carbohydrate found in a well-balanced meal", the article at hand will not deal with the ill-consequences of isolated fructose consumption, as they would never occur if people consumed a whole foods diet.

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.

This constraint does obviously reduce the pool of studies we can draw on to those whose authors are mindful of the fact that all foods, even "high fructose" fruit, always contain both, fructose and glucose.

Figure 1: Free fructose content of popular beverages made with and without high-fructose corn syrup (Walker. 2014); Popular beverages made with HFCS have a fructose-to-glucose ratio of approximately 60:40, and thus contain 50% more fructose than glucose. Some pure fruit juices even have twice as much fructose as glucose and are not generally better than Pepsi, Coke & Co - better stay away!

Fructose absorption is one of the few problems that have been known even before the whole fructose scare began. In practice, diarrhea and co will yet only occur, when fructose is ingested in (unnaturally) large quantities and in the absence of glucose. When fructose is consumed as part of the disaccharide sucrose (simple table sugar), or together with glucose at roughly similar or even higher levels of glucose, on the other hand, even those who develop diarrhea from fructose sweetened industrial foods will usually have no problem digesting it (Latulippe. 2011).

The malabsorption issue, is yet only one out of several problems that occur in response to the extraction of fructose from its natural "sugar matrix". If we want to understand the synergy between fructose and glucose and why its disturbance has significant ill health effects, it's necessary to first look at how both are metabolized.

While fructose enters the bloodstream more slowly than glucose and its serum levels are much lower, it will persist longer in the circulation. Le et al. (2012), for example, report that the fructose concentration in the peripheral venous blood rose >60-fold from a fasting level of about 0.005 mM to a maximum of 0.317 mM, and returned toward baseline levels by about 3 h when the subjects, 20 healthy adults, ingested 24 oz. of a regular soft drink containing 69 g sucrose (half of which, 34.5 g, is fructose). The glucose levels, on the other hand, rose from about 5.5 mM to 6.8 mM and returned to baseline after 90 min, already.

A single soft drink is already more than the recommendations allow: I am certainly not a fan of the dietary guidelines, but when it comes to added sugars, the <26.2g/day (100kcal/day) limit of which you can argue that it may still be way too high would actually preclude any American who adheres to the dietary recommendations to consume more than 9oz (women) respectively 14oz (men) of the soft drink Le et al. used in their study.

The ups and downs in glucose were accompanied by an increase in insulin release which peaked at about 30 min and the passage of fructose through the liver lead to a significant increase in lactate production, a major byproduct of hepatic fructose and glucose anaerobic metabolism, from 0.7 to 2 mg/dL at 60 min, (levels returned to baseline after 3h).

The changes in lactate metabolism already gave it away: The liver is the major site for fructose metabolism. Fructose enters the portal circulation from the gut. It is transported to the liver and only a very small amount will leave the liver (and pancreas) again to be transported to other non-splanchnic organs such as brain, skeletal muscle and heart. This does not mean that the other organs cannot use fructose, though. In fact, studies have shown that next to the three specialized enzymes, ketohexokinase (KHK, fructokinase), aldolase B, and triokinase which are responsible for the metabolism of fructose in the liver, KHK-A is also expressed in pancreas, intestine, brain, lung, eye, adipose, spleen, skeletal muscle, heart, uterus, and the adrenals. Moreover, the genetic ablation of KHK-A in rodents has shown that the peripheral use of fructose appears to limit the strain on the liver, so that KHK-A null mice will have increased liver fructose levels and liver fat compared to normal rodents on a high fructose diet (Ishimoto. 2012)

Is fructose good for active individuals and athletes?

In animal studies, scientists observed that even with an intake of 2 g/kg sucrose (in solution via tube feeding) there was only a minimal increase in the fructose levels in arterial blood from the aorta and peripheral venous blood, which both rose from 0.02 mM to about 0.15 mM. In the portal ein, on the other hand, the fructose concentration rose from 0.1 mM at baseline to ~1 mM after 30 min, and persisted at 0.6 mM when measured 60 min after gavage.

Figure 2: Glucose and insulin response during oral glucose tolerance test in healthy (left) and type II diabetic (right) subjects when the OGGT was done with (+F) or without (-F) additional fructose (Moore. 2000 & 2001)

In contrast to the current sentiment that fructose would contribute to the omnipresent deterioration of blood glucose control, experimental evidence from human studies by Moore and colleagues (2000; 2001) shows that the provision of 7.5g of extra fructose reduces the glycemia in response to the ingestion of 75g of glucose by 19% in healthy and by 14% in type II diabetic subject (Moore. 2000 & 2001). Rodent studies comparing natural high fructose sweeteners like agave or honey, show similar benefits on glucose metabolism, as well as body fatness (Nemoseck. 2011; Hooshmand. 2014)

Small amounts of fructose appear to be especially healthy for type II diabetics

What's intriguing is that the aforementioned improvements in blood glucose occurred in the presence of a 21% reduction in plasma insulin in the type II diabetics, when fructose was present. Similarly, a low dose of fructose infused intravenously into type 2 diabetic patients restored the ability of hyperglycemia (and high insulin) to suppress hepatic glucose production and thus restored a major pillar of active glucose management in a 2009 study by Coss-Bu et al. (2009).

As Laughlin points out in the previously mentioned paper, "a large part of the means by which fructose increases glucose disposal is due to its powerful ability to catalyze liver carbohydrate storage." (Laughlin. 2014) This effect was demonstrated in people using 13C nuclear magnetic resonance spectroscopy (MRS) during a hyperinsulinemic, euglycemic clamp (Delarue. 1993).

"C-1-glucose, which is an MRS-visible version of normal glucose, was infused into healthy fasted people with or without the addition of 3.5 μol/kg/min unlabeled fructose, which had the effect of doubling venous plasma fructose to 0.28 mM. This is similar to blood fructose seen after ingestion of a high sugar meal. Even though plasma glucose was kept constant at a basal level of 5 mM, hepatic glucose uptake was more than doubled by the presence of fructose, from 0.31 to 0.79 mmol/L/min. Liver glycogen made from the 13C-labeled glucose was monitored over time. Net liver glycogen synthesis increased almost four-fold from 0.14 to 0.54 mmol/L/min when fructose was added." (my emphasis in Laughlin. 2014)

Since the source of carbon for this extra glycogen was predominantly glucose, not fructose, the increase in glycogen storage did obviously correlate with a reduction in blood glucose levels.

Figure 3: Relationship between net hepatic glucose uptake and the sinusoidal blood fructose concentration - more fructose, higher glucose uptake; but beware (!) there is a ceiling effect, i.e. when a certain threshold is reached the marginal benefit of even more fructose is minimal (Shiota. 1998).

The results of a dog study Shiota et al. present in a 1998 even suggest that the addition of fructose to a high glucose intake can increase the an increase in glucose uptake at constant glucose and insulin levels that's 10-fold larger than the increase in fructose uptake by the liver.

If you take a closer look at the corresponding graph that depicts the hepatic glucose uptake as a function of the serum fructose levels in Shiota's dogs (see Figure 3) you will yet be reminded of the "more is not better principle" which - in this instance - indicates that the more fructose there is, the lower the marginal benefit is going to be. A negative effect at very high fructose levels as it you may have expected it based on the contemporary "fructose is the devil" scare does yet not exist.

Although some of the beneficial effects on glucose levels may, in fact, be mediated by competitive absorption at the level of the GLUT-2 (glucose + fructose) transporters in the gut, it is thought that the major fructose effect on glucose uptake is via direct effects of fructose-1-phosphate on glucokinase activity, the hepatic isoform of hexokinase, which catalyzes the transfer of a phosphate group from ATP to glucose to form glucose-6-phosphate.

Hold on, isn't fructose bad for the liver? Well, when you achieve abnormally high fructose infusion rates by simply injecting a fructose solution in animals or people this may in fact lead to hepatic ATP depletion in response to the very quick transfer of its phosphate group to form fructose-1-phosphate. This energy loss will than induce detrimental changes in the energy status of the organ and have detrimental effects on your metabolism. However, severe ATP depletion is likely an artifact of fructose infusion. Hepatic ATP loss is minimal and transient after rats ate substantial fructose, enough to raise fructose-1-phosphate from 0.1 to 3.3 μmol/g wet wt (Niewoehner. 1984 & 1986).

Or, put simply: Fructose controls / increases the storage of glycogen in the liver. Since the glycogen stores in the liver are limited, it should yet be obvious that the beneficial effects of fructose on glucose metabolism fail, when the hepatic glycogen stores are as topped off as they are in the average sedentary Western glutton on 365 days of the year.

Figure 4: Blood glucose, insulin and GLP-1 levels in response to the ingestion of oral glucose (-x-) 75 g, oral fructose (-+-) 75 g or oral glucose 75 g followed by oral fructose 75 g (-•-) 60 min later (Kong. 1999)

Apropos! Let's talk about the average Western glutton for a moment. In spite of the beneficial effects of fructose in different contexts, his habit of washing down his French fries and burgers with some neat high fructose corn syrup sweetened sodas is certainly not healthy. In the presence of already elevated glucose levels, the ingestion of high amounts of fast absorbing fructose has after all been shown to augment insulin secretion (Kong. 1999); and while this happens in the absence of a further substantial increase in blood glucose, it is still a hallmark feature of beginning insulin resistance.

The data Kong et al. generated in healthy volunteers (Figure 4) does also indicate that fructose, when it is consumed in liquid, fast absorbing form and in amounts you can hardly get from whole foods (75g in a few seconds) will trigger both, a small transient insulin, as well as a GLP-1 (learn more) response, even if it is consumed in the absence of fructose (overall the effect is yet not physiological meaningful).

It is likely that this is at least partly due to direct effects of fructose on the pancreatic islet beta cell, since high concentrations of fructose (10–30 mM) elicit insulin secretion from isolated human and rodent islets. Whether this is solely a result of active fructose uptake, or (also) the interaction of fructose with sweet taste receptors, will still have to be elucidated.

What we do know already is that fructose will influence both the storage (see previous paragraph) and oxidation of glucose.

What does the latest review say? The latest meta-analysis and review of the literature on "Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health" says "the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake" (Chung. 2014) and does therefore highlight one of the important confounding factors discussed in this article.

In people during cycling exercise, for example, the combustion of ingested carbohydrate is 55% higher when fructose was present with glucose in a 1:2 ratio vs.glucose alone (see Table 1; Jentjens. 2005).

Table 1: Oxygen uptake, respiratory exchange ratio, total carbohydrate oxidation, total fat oxidation,
endogenous carbohydrate oxidation, and exogenous glucose and fructose oxidation during
the 60- to 120-min period of exercise (Jentjens. 2005)

Whether that's advantageous for cyclists is debatable, though. If we assume they are constantly replenishing their glucose levels via oral supplementation during the race, the answer is "yes"; if we assume they fail to do so, a reduced glucose and increased fatty acid oxidation would be more favorable.

Needless to say, that the previously mentioned increase in lactate production and its usages as a substrate for gluconeogenesis contributes to a large extend to the increase in glucose oxidation (Lecoultre. 2010). Against that background it's yet somewhat surprising that fructose-specific GLUT5 is the second most abundant sugar transporter in human skeletal muscle, with expression levels of about a third of that of the major transporter GLUT4.

High potential fructose uptake in those muscles, strength trainees love the most!

In that, it's even more surprising that it's not the oxidative red fibers (type I) which tend to be particularly rich in GLUT4 and GLUT12 (the third most abundant sugar transporter) which express the majority of GLUT5 transporters, but rather the extremely "fast twitch" Type IIb (Stuart. 2006).

And in fact, skeletal muscle has the ability to metabolize considerable fructose when plasma fructose is highly elevated, although it is not clear whether fructose is oxidized directly in muscle at the plasma levels found after a fructose-rich meal, we do know hat young healthy fasted men exercised on a bicycle during continuous infusion of fructose will use the fructose preferentially as muscle, not liver fuwl (fructose uptake during exercise (4.7 mmol/min) exceeded splanchnic uptake (3.8 mmol/min); cf. Ahlborg, 1990).

Table 2: Regional disposal of infused fructose at 90 min of exercise and 20 min of recovery

Interestingly, the use of fructose to fuel the muscle had no effect on the utilization of glucose during the workout and would thus have to be considered as either extra-fuel of fat replacement - since the oxygen uptake (not shown in Table 2) was identical, the second option does yet sound unlikely.

What needs to be mentioned, though, is that the available data only confirms that These human skeletal muscle can directly metabolize fructose when plasma levels and energy demand are both high. In the average Westerner, it's yet usually only the former, i.e. high plasma levels, but not the latter, i.e. high energy demands, so that most of the obviously beneficial effects of glucose mentioned before won't even occur in the sedentary couch potato.

Apropos couch potatoes, let's not forget the negative potential of fructose

While recent in vitro studies show that high concentrations of fructose may be involved in the maturation of pre-adipocytes to "grown up" fat cells, evidence that similar effects could occur in vivo is not available yet. However, even at lower levels, which mimic those found in the venous circulation following a fructose-rich meal (0.05–0.55 mM), fructose will potentiate adipogenesis and increase lipid stores in 3T3-L1 cells - albeit only in the presence of hyperglycemic concentrations of glucose. Therefore, physiological levels of fructose and glucose together can accelerate the expansion of body fat and contribute to the storage of carbohydrates in the adipose organ.

It does thus appear realistic to assume that any form of fructose + glucose over-consumption, which is - as pointed out before - feasible only via processed foods, will abolish the beneficial effects that occur in the lean whole foods eating active individual and trigger all those nasty obesogenic pro-diabetic effects you will read about on the Internet on a daily basis.

Suggested read: "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" | read more

Bottom line: I am well aware that today's SuppVersity article lacks the popular hyperbole that is so characteristic of the debate about fructose and sugar in general. The fact that you still made it do the bottom line does yet tell me that you appreciate this diversion.

I am not sure if the information changed your stance on fructose, but I hope that it lessened your (unwarranted) fear of the comparatively small amount of fructose in fruits and other whole foods that have falsely been lumped together with processed sugar-sweetened foods in the debate about the ill health effects of fructose and sugar in general.

Reference: 

• Ahlborg, Gunvor, And O. L. A. Bjijrkman. "Splanchnic And Muscle Fructose Metabolism During And After Exercise." Work 100.3021 (1990): 28-32.
• Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. "Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis." Am J Clin Nutr. (2014) [Ahead of print]
• Coss-Bu, Jorge A., Agneta L. Sunehag, and Morey W. Haymond. "Contribution of galactose and fructose to glucose homeostasis." Metabolism 58.8 (2009): 1050-1058.
• Delarue, J., et al. "The contribution of naturally labelled 13C fructose to glucose appearance in humans." Diabetologia 36.4 (1993): 338-345.
• Hooshmand S, Holloway B, Nemoseck T, Cole S, Petrisko Y, Hong MY, Kern M. "Effects of Agave Nectar Versus Sucrose on Weight Gain, Adiposity, Blood Glucose, Insulin, and Lipid Responses in Mice." J Med Food (2014).
• Ishimoto, Takuji, et al. "Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice." Proceedings of the National Academy of Sciences 109.11 (2012): 4320-4325. 
• Jentjens, Roy LPG, et al. "Oxidation of combined ingestion of glucose and fructose during exercise." Journal of Applied Physiology 96.4 (2004): 1277-1284.
• Kong, Marie-France, et al. "Effects of oral fructose and glucose on plasma GLP-1 and appetite in normal subjects." Peptides 20.5 (1999): 545-551.
• Latulippe, Marie E., and Suzanne M. Skoog. "Fructose malabsorption and intolerance: effects of fructose with and without simultaneous glucose ingestion." Critical reviews in food science and nutrition 51.7 (2011): 583-592. 
• Laughlin, Maren R. "Normal Roles for Dietary Fructose in Carbohydrate Metabolism." Nutrients 6.8 (2014): 3117-3129.
• Le, MyPhuong T., et al. "Effects of high-fructose corn syrup and sucrose on the pharmacokinetics of fructose and acute metabolic and hemodynamic responses in healthy subjects." Metabolism 61.5 (2012): 641-651.
• Lecoultre, Virgile, et al. "Fructose and glucose co-ingestion during prolonged exercise increases lactate and glucose fluxes and oxidation compared with an equimolar intake of glucose." The American journal of clinical nutrition 92.5 (2010): 1071-1079.
• Moore, M.C.; Cherrington, A.D.; Mann, S.L. "Davis, S.N. Acute fructose administration deceases the glycemic response to an oral glucose tolerance testin normal adults." J. Clin. Endocrinol. Metab. 85 (2000):4515–4519.
• Moore, M.C.; Mann, S.L.; Davis, S.N.; Cherrington, A.D. "Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes". Diabetes Care 24 (2001):1882–1887. 
• Nemoseck TM, Carmody EG, Furchner-Evanson A, Gleason M, Li A, Potter H, Rezende LM, Lane KJ, Kern M. "Honey promotes lower weight gain, adiposity, and triglycerides than sucrose in rats." Nutr Res. 31,1 (2011):55-60.
• Niewoehner, Catherine. B., et al. "Metabolic effects of oral fructose in the liver of fasted rats." Am. J. Physiol 247 (1984): E505-E512.
• Niewoehner, Catherine B. "Metabolic effects of dietary versus parenteral fructose." Journal of the American College of Nutrition 5.5 (1986): 443-450.
• Stuart, Charles A., et al. "Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle." American Journal of Physiology-Endocrinology and Metabolism 291.5 (2006): E1067-E1073.
• Stuart, Charles A., et al. "Cycle Training Increased GLUT4 and Activation of mTOR in Fast Twitch Muscle Fibers." Medicine and science in sports and exercise 42.1 (2010): 96.
• Walker RW, Dumke KA, Goran MI. "Fructose content in popular beverages made with and without high-fructose corn syrup." Nutrition 30, 7-8 (2014):928-35.

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.

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.