Montag, 8. April 2013

Fructose: friend or foe? Preliminary findings.

ResearchBlogging.org
This discussion has been going on for quite some time and it is certainly not limited to the lay press and lay population. I have always been interested in double checking pop-sci claims, in this case the "evil fructose" meme.

First, I would like to emphasize that the available evidence does not change the basic Public Health Message: Yes, you should still eat more fruits unless you are already getting more than five servings/day. In that case you probably want to get more vegetables or olive oil, since a varied, plant-based Mediterranean-style diet remains the best option for health.

On to the hard science:

As of today, and as far as primary prevention is concerned, the studies I want to discuss (1-4) are only relevant for "dietary perfectionists", researchers and interested laypeople. The data is so weak and preliminary, I already feel like I am jumping the gun with my conclusions based on my ongoing, but superficial review of the data. Nevertheless I feel like sharing my hypothesis.

Reasonable fructose intakes (<60g/d) may be beneficial for cardiometabolic risk factors summa summarum (1, 2) or at the very least neutral. It has been speculated that catalytic fructose doses, below approx. 10g, free up intracellular glucokinase ("hexokinase") thereby increasing glycolytic flux. This could lower blood glucose after meals.

I am still unclear on longterm fructation vs. glycation, and their impact on aging and health. Instead I would like to highlight a different issue. Fructose and pancreatic cancer (3). Dr. "ORAC" has explained the basics if you long for an accessible review.
More recently a new meta-analysis by Aune 2012 (3) found:
Seven cohort studies [14, 15, 17, 19–22] were included in the high versus low analysis of fructose intake and pancreatic cancer and included 2831 cases among 1 156 512 [!, NB: the analysis included an early study based on the NIH-AARP cohort. See also below.] participants. The summary RR was 1.18 (95% CI: 1.01–1.37, I2 = 25%, Pheterogeneity = 0.24)... 
A positive association was observed with fructose intake, summary RR [was a modest] 1.22 (95% CI: 1.08-1.37, I(2) = 0%) per 25 g/day.
…no evidence of small study effects with Eggerapos;s test [sic]…There was no evidence for a nonlinear association between fructose intake and pancreatic cancer, Pnonlinearity = 1.00… 
Recently, it has been shown that the contribution of fructose to nucleic acid synthesis through the pentose phosphate pathway (catalyzed by transketolase) is greater than glucose [42]… The contribution of fructose to the generation of nucleic acids is further illustrated by [potentially!] increased production of uric acid [but this may depend somewhat on the study], a by-product of purine metabolism, and increased risk of gout among high fructose consumers [46].



The implication is immediately clear, if the association is causal, because a reduction in cardiometabolic risk is trivial* while "relatively few modifiable risk factors have been firmly established [for pancreatic cancer]." And let us not be fooled by the modest incidence of pancreatic cancer, which is offset by a high mortality rate: "Pancreatic cancer is the 4th leading cause of cancer-related death in the United States".

However, I am not quite sure this link is causal. First, there is "limited suggestive" evidence that fruits protect from pancreatic cancer (as discussed in ref. 3). Second, the fructose-cancer data has been heterogeneous from my reading e.g. there is reduced prostate cancer risk in men and increased risk of colorectal cancer in the same cohort (HPFS). Data recently published from the enormous NIH-AARP cohort just confirmed that... we don't know a thing about sugars, fructose and cancer (4):
An international panel of experts recently concluded that there is “limited – suggestive” epidemiologic evidence linking sugars (i.e. mainly sucrose and fructose) with colorectal cancer, and there is no evidence for an association with any other cancer sites [that was before this study was published]...
In men [but not women], added fructose, similar to total fructose, was associated with decreased risk of all cancers... [and the other results are even more confusing]
... 
An intriguing finding was the inverse association of added sucrose and added fructose with pancreatic cancer risk in women, whereas there was a suggestion of an increased risk with fructose from fruit. Contrary to the methods used here, an earlier analysis of the AARP cohort[32], which included prevalent cases of any cancer except pancreatic cancer, as well as deceased pancreatic cancer cases (n = 1,151), reported 1.3-fold increased risk of pancreatic cancer in the highest versus lowest quintile of free fructose intakes (not including fructose from sucrose). Consistent with our findings, they also observed an increased risk for fructose from fruit and fruit juice[32]. A similar suggestion came from other cohorts, which showed elevated risk for pancreatic cancer with high intake of free fructose[13, 33] and fruit, but not fruit juice[13]. Two cohorts, however, found no association between free fructose intake and pancreatic cancer risk[34–35].

Um, err..., ok? What now? What is the mechanism? The implication of this?

The data on pancreatic cancer & fructose seems most clear at the moment - and that is saying quite a lot. I speculate that the above NIH-AARP data is a fluke and the pancreatic-connection real.

So if you want to construct a perfect diet, fructose probably should be kept lowish, but only because this coincides with other goals: increasing nutrient density, avoiding speculative triglyceride-raising effects of fructose at >60g/d, cutting total calories, adding a variety of other healthy foods.
The following ideas might be sensible: you can still consume quite some fruits, but prefer vegetables over fruit, eat low fructose fruit, consume fruits with meals (to benefit from fructose induced glucose lowering), eat specific fruits that have been suggested to prevent particular ailments (e.g. berries, citrus) since they might be healthier than fruit as a group. All this is a matter of precaution, since there are no risks in doing so.

*numerous methods have been documented in the literature, but it is not necessarily trivial to implement them

1. Diabetes Care. 2012 Jul;35(7):1611-20. doi: 10.2337/dc12-0073.
Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, Mirrahimi A, Yu ME, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, Jenkins DJ.

2. Hypertension. 2012 Apr;59(4):787-95. doi: 10.1161/HYPERTENSIONAHA.111.182311. Epub 2012 Feb 13.
Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
Ha V, Sievenpiper JL, de Souza RJ, Chiavaroli L, Wang DD, Cozma AI, Mirrahimi A, Yu ME, Carleton AJ, Dibuono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, Jenkins DJ.

3. Aune, D., Chan, D., Vieira, A., Navarro Rosenblatt, D., Vieira, R., Greenwood, D., Cade, J., Burley, V., & Norat, T. (2012). Dietary fructose, carbohydrates, glycemic indices and pancreatic cancer risk: a systematic review and meta-analysis of cohort studies Annals of Oncology, 23 (10), 2536-2546

4. Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study.
Tasevska N, Jiao L, Cross AJ, Kipnis V, Subar AF, Hollenbeck A, Schatzkin A, Potischman N.
Int J Cancer. 2012 Jan 1;130(1):159-69. doi: 10.1002/ijc.25990. Epub 2011 May 25.

 

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