The not-so-sweet side of fructose

Choi ME. The not-so-sweet side of fructose. J Am Soc Nephrol 2009;20:457-9.

Background
This editorial comes from the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. It is written in support of the paper published simultaneously in theJournal of the American Society of Nephrology by Cirillo et al in RJ Johnson’s group in Florida entitled, “Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells.”(1)

Author Justification
Metabolic syndrome has become a global epidemic over the past 20 years, largely attributed to a parallel rise in obesity. Though there are many contributing factors, including the shift to a junk food diet with excessive calorie intake and sedentary lifestyle, an increase in fructose intake is also implicated.

Choi’s not-so-sweet side of fructose

• We have “morphed insidiously into a fructose nation.”(2)
• There has been a marked increase in daily intake of fructose, largely due to widespread use of high fructose corn syrup (HFCS) in beverages (3).
• Links between soda consumption, HFCS and chronic kidney disease (CKD):
  • Metabolic syndrome
  • Insulin-resistant diabetes
  • Kidney disease
  • Albuminuria (4)
  • Kidney stones (5)
  • Gout (6)

Author: Mechanism by which fructose increases risk for CKD
A high-fructose diet induces features of metabolic syndrome in rats (7, 8 [RJ Johnson]): hyperinsulinemia, hypertriglyceridemia, hypertension, weight gain, glomerular hypertension and hyperuricemia. Proposed mechanisms include: insulin resistance, lipotoxicity, oxidative stress, endothelial dysfunction and hemodynamic alterations. And fructose-induced hyperuricemia likely has a pathogenic role (8).

Cirillo/Johnson work and significance
This group previously reported that high-fructose diets accelerate progression of CKD in the rodent remnant kidney model associated with an inflammatory response in the kidney (9 [RJ Johnson]). Cirillo et al (1) report in this paper that fructose induces a proinflammatory response in human proximal tubular epithelial cells through a ketohexokinase-dependent mechanism.

Choi views this work as significant because it:

• Establishes a potential role for direct and detrimental effects of fructose on proximal tubular [kidney] epithelial cells;
• Takes a step toward unraveling the mechanism that may be a causal link between high-fructose intake and metabolic syndrome and the development of renal disease; and
• Extends previous reports of fructose-induced inflammatory state in the kidney that may contribute to the progression of CKD.

Author conclusions and recommendations

1. The potential importance of Cirillo’s work to humans remains to be established, though it provides mechanistic insight into the renal consequences of high-fructose intake.
2. Cirillo’s work raises concern regarding short- and long-term effects of fructose and its risk to humans. Further human studies are needed to determine whether fructose is causally implicated or there are yet-unmeasured factors, such as lifestyle and other confounders.
3. There is urgent need to determine whether policy recommendations regarding sugary soda and high-fructose consumption should be implemented in the strongest terms.
4. Tackling this issue will be a major challenge ahead, given the enormous public health implications posed by the worldwide epidemic of metabolic syndrome, especially in children and adolescents who will grow into adulthood,before it becomes a tsunami of CKD that cannot be prevented.

Critique

• Choi’s metabolic syndrome-based justification is an extension of the well-publicized HFCS/obesity hypothesis of Bray (3) and an endorsement of the RJ Johnson view on fructose. Many of the key citations are to Johnson’s work. It is an attempt to build urgency for fructose as a key player in metabolic syndrome and obesity. Note that Choi attempts to elevate the risk of fructose by creating a new and equilateral triumvirate of obesity causes: excessive caloric intake, insufficient caloric expenditure and too much dietary fructose. No perspective is offered to support the promotion of fructose to such prominence.
• The argument that fructose intake has increased in recent decades fails to address the concomitant and equivalent increases in all macronutrient categories over the same period (10).
• Though there is abundant literature demonstrating untoward effects of fructose at excessive levels, there is no evidence to support a unique causative role for fructose in either obesity or the metabolic syndrome at common intake levels.
• The rat diet of Cirillo is a serious distortion of the way in which humans consume sweeteners.
  • The primary nutritive sweeteners (sucrose, HFCS, honey, fruit juice concentrates) contain roughly half glucose and half fructose. A diet of fructose as the only simple sugar does not reflect the diet of any human population.
  • Comparing rats fed diets in which carbohydrates are either pure fructose or completely complex has no meaning in the real world, since humans consume mixtures of carbohydrates.
  • It is a huge extrapolation from rat and tissue culture studies at excessive fructose doses to humans at a fraction of the exposure level. That humans are similarly affected has not been established.
  • Feeding rats 60% of calories as fructose exceeds typical human exposure by 6-fold (11). Translating this regimen to humans creates an impossible and preposterous scenario: relying on common nutritive sweeteners (half fructose, half glucose) as the source of fructose, subjects would be forced to consume all their calories as sweetener. This is clearly an inappropriate experimental setup from which to make predictions of real world medical outcomes.
• Choi’s call for development and implementation of public policy based on Cirillo’s experimentation gives it undeserved significance and is ill advised, given the highly contrived nature of study designs and exaggerated levels of dietary fructose.
• Choi is entirely justified in concluding that Cirillo’s work provides mechanistic insight into the renal consequences of high-fructose intake—this is its proper and defensible contribution to the literature.

References

• Cirillo P, Gersch MS, Mu W, et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol 2009;20:545-53.

• Neilson EG. The Fructose Nation. J Am Soc Nephrol 2007.

• Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 2004;79:537-43.

• Shoham DA, Durazo-Arvizu R, Kramer H, et al. Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999-2004. PLoS ONE 2008;3:e3431.

• Taylor EN, Curhan GC. Fructose consumption and the risk of kidney stones. Kidney Int 2008;73:207-12.

• Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008;336:309-12.

• Sanchez-Lozada LG, Tapia E, Jimenez A, et al. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am J Physiol Renal Physiol 2007;292:F423-429.

• Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006;290:F625-631.

• Gersch MS, Mu W, Cirillo P, et al. Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol Renal Physiol 2007;293:F1256-61.

• White JS. Straight talk about high-fructose corn syrup: what it is and what it ain’t. Am J Clin Nutr 2008;88:1716S-1721S.

• Vos MB, Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J Med 2008;10:160.

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A new study on fructose and weight loss has shown that “fructose does not seem to cause weight gain when it is substituted for other carbohydrates in diets providing similar calories.”

Since fructose is metabolized differently than glucose, some have wondered if fructose may play a role in the obesity epidemic.  The study by Sievenpiper et al published in Annals of Internal Medicine aimed to determine the role of fructose in weight gain.

Researchers identified 31 studies that compared how free fructose and non-fructose carbohydrates affected body weight in diets that provided similar amounts of calories as well as 10 studies that examined body weight in people whose diets were supplemented with free fructose to provide more calories than their usual diet.   They extracted the data from those studies and then combined and analyzed them.

Researchers found that when fructose was swapped for another carbohydrate, it did not appear to cause weight gain.  High doses of fructose seemed to cause a modest increase in body weight, but, according to the researchers, the weight gain may have been due to the extra calories, not the fructose itself.

The study was limited in that it pulled data from a variety of studies with differing study designs, and that the participants in most studies were only followed for a few months.

Click here to read the study abstract (http://www.annals.org/content/156/4/291.abstract)

The post Fructose Not Linked to Weight Gain appeared first on FructoseFacts.

Prevalence of daily hyperglycemia in obese type 2 diabetic men compared with that in lean and obese normoglycemic men: effect of consumption of a sucrose-containing beverage.

Manders RJ, Pennings B, Beckers CP, Aipassa TI, van Loon LJ. Am J Clin Nutr 2009;90:511-8

In their recent paper, Manders et al. reported that moderate consumption of sucrose-sweetened beverages — equivalent to more than two 12-oz cans of cola—did not increase the prevalence of hyperglycemic or reactive hypoglycemia under normal free-living conditions in a variety of study subjects, including lean normoglycemic, obese normoglycemic and type 2 diabetic individuals.¹

The American Heart Association recently called for setting a “prudent daily upper limit of just over 30 g (6 teaspoons or 100 calories) of added sugars for average-sized women and just over 45 g (9 teaspoons or 150 calories) for average-sized men.” ² It should be noted, however, that their recommendations were admittedly based on limited trial data, observational studies and national survey data.

The Manders paper, therefore, offers important experimental counter-evidence that the addition of moderate sugars to the diet—in this case twice the “prudent” limit called for by AHA—is well tolerated and does not influence normal daily blood glucose fluctuations in lean or obese subjects, with or without type 2 diabetes.

References
1. Manders RJ, Pennings B, Beckers CP, Aipassa TI, van Loon LJ. Prevalence of daily hyperglycemia in obese type 2 diabetic men compared with that in lean and obese normoglycemic men: effect of consumption of a sucrose-containing beverage. Am J Clin Nutr 2009;90:511-8.

2. Johnson RK, Appel LJ, Brands M, et al. Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation 2009;120:1011- 20

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Meta-Analyses and Meta-Regression Models of Intervention Studies

ABSTRACT
Background: The glycemic response to dietary fructose is low, which may improve concentrations of glycated hemoglobin (HbA1c, a marker of dysglycemia). Meanwhile, adverse effects on plasma triacylglycerol (a marker of dyslipidemia) and body weight have been questioned. Such effects are reported inconsistently.

Objective: We aimed to evaluate the effect of fructose on these health markers, particularly examining treatment dose and duration, and level of glycemic control.

Design: A literature search was conducted for relevant randomized and controlled intervention studies of crystalline or pure fructose (excluding high-fructose corn syrup), data extraction, metaanalyses, and modeling using meta-regression.

Results: 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 dosedependent 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.

Conclusions: The meta-analysis shows that fructose intakes from 0 to 90 g/d have a beneficial effect on HbA1c. Significant effects on postprandial triacylglycerols are not evident unless 50 g fructose/d is consumed, and no significant effects are seen for fasting triacylglycerol or body weight with intakes of 100 g fructose/d in adults. Am J Clin Nutr 2008;88:1419 –37.

For the full length version of this article, click here.

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C. Chotiwat , C. Sharp, K. Teff and R.B.S. Harris. Appetite. 2007; 49: 284.

Background
This research report will be more difficult to critique since we have only the abstract to review.

This research was intended to test whether a high-fructose diet would induce leptin resistance in rats, justified by the following rationale:

• There is a suggested association between increased consumption of high fructose corn syrup (HFCS) and the recent increase in the incidence of obesity — this is assuredly the correlative hypothesis of Bray, Nielsen & Popkin (1).
• Leptin is a hormone released by fat cells that has been shown to inhibit food intake and increase energy expenditure. It has been reported that elevated triglyceride levels inhibit leptin transport to brain receptors (2, 3) and that a high fructose diet increases post-meal triglycerides (no reference provided).

Experiment 1: Researchers fed rats either a high-fructose (60% of calories as fructose) or low-fructose diet (no fructose) for 3 weeks

• Triglycerides increased by 75% in high-fructose rats vs. low-fructose rats. o The infusion of leptin interperitoneally (abdominally) for 2 weeks reduced body fat in the low-fructose rats by 25% o High-fructose rats had lower body fat than low-fructose rats (3% vs. 5%)

Experiment 2: Researchers fed high- and low-fructose diets as above for 4 weeks, and then injected the rats interperitoneally with increasing doses of leptin.

• All leptin doses inhibited 2h food intake of low-fructose rats, but had no effect on high-fructose rats.

Conclusions:

• Consumption of a high-fructose diet induces leptin resistance.
• Resistance may be via inhibition of leptin transport across the blood brain barrier by elevated levels of circulating triglycerides.

Justification
The basic Bray, et al hypothesis is that HFCS is uniquely (aside from caloric contribution) responsible for rising obesity rates in the U.S. over the past 30 years. The hypothesis is correlative in nature, based on the strong statistical association between HFCS availability and obesity incidence since 1970. While correlations are useful for hypothesis generating, they constitute the weakest form of scientific proof (see Forshee, et al). o While it appears certain that leptin influences food intake and energy expenditure, it should be remembered that many appetite regulators have been discovered in the last five years and that their intricate interplay is still being worked out. The authors do not mention that Banks used a high-fat diet (31% fat) to disrupt leptin processing in the brain (3). So leptin function is influenced by many more factors than dietary fructose levels.

The tacit reference for high fructose diets increasing post-meal triglycerides is likely the authors’ contemporaneous work at Monell Chemical Senses Center, Philadelphia (4). Teff, et al fed 30% of calories as fructose vs. glucose. As has been mentioned in other critiques, such a diet is prejudicial in two ways: 1) this represents a 4-5 fold excess in dietary fructose vs. typical intake levels; and 2) fructose is never consumed alone in the foods we eat — it is always accompanied by an equal or greater amount of glucose from a sweetener, cereal grain, maltodextrin, corn syrup or glucose.

Experiments

• While the justification is based on increasing HFCS in the diet, the authors fail to acknowledge that:
  • HFCS use increased at the expense of sucrose, so that the overall increase in dietary fructose exposure mirrors the increase in total calories over the past 30 years – less than 20%;
  • Pure fructose is a poor model for HFCS; sucrose – untested – would be a far better model due to composition similarities.
• It is hard to imagine how rats could tolerate 60% of calories as fructose. Elevated levels in humans with no compensating glucose causes bloating, gas and osmotic diarrhea (5). This represents a 7.5-fold excess in fructose vs. typical intake levels. Though metabolic anomalies can be observed at this exposure level, extrapolation to the typical human diet is meaningless for reasons mentioned above:
  • Test levels of fructose are highly prejudicial;
  • Fructose is always consumed with glucose, a moderating metabolic influence.

Conclusions

• The authors demonstrated that grossly-excessive levels of fructose elevate triglycerides and impair leptin metabolism, however, they did not demonstrate this in a physiologically relevant experimental system. The dietary construct was highly prejudicial and guaranteed to produce an untoward metabolic effect.
• They did not demonstrate that HFCS impairs leptin metabolism.

References

• Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 2004;79:537-43.

• Banks WA, Coon AB, Robinson SM, et al. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 2004;53:1253-60.

• Levin BE, Dunn-Meynell AA, Banks WA. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol 2004;286:R143-50.

• Teff KL, Elliott SS, Tschop M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004;89:2963-72.

• Riby JE, Fujisawa T, Kretchmer N. Fructose absorption. Am J Clin Nutr 1993;58:748S-753S.

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