References

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

2 Henry RR, Crapo PA: Current issues in fructose metabolism. Annu Rev Nutr 1991;11:21-39.

Mayes PA: Intermediary metabolism of fructose. Am J Clin Nutr 1993;58:744S-765S. Hanover LM, White JS: Manufacturing, composition and applications of fructose. Am J Clin Nutr 1993;58:724S-732S.

Vuilleumier S: Worldwide production of high-fructose syrup and crystalline fructose. Am J Clin Nutr 1993;58:733S-736S.

Park YK, Yetley EA: Intake and food sources of fructose in the United States. Am J Clin Nutr 1993;58:73 7S-747S.

Sigman-Grant M, Keast DR: Addendum to Am J Clin Nutr 1995;62(suppl):178S-194S. Am J Clin Nutr 1997;65:1572-1574.

Bialostosky K, et al: Dietary intake of macronutrients, micronutrients and other dietary constituents: United States 1988-94. National Center for Health Statistics. Vital Health Stat 2002; 11 (245): 1-156.

Popkin BM, Nielsen SJ: The sweetening of the world's diet. Obes Res 2003;11:1325-1332. Akerblom HK, Siltanen I, Kallio AK: Does dietary fructose affect the control of diabetes in children? Acta Med Scand Suppl 1972;548:195-202.

Crapo PA, Kolterman OG, Olefsky JM: Effects of oral fructose in normal, diabetic, and impaired glucose tolerance subjects. Diabetes Care 1980;3:575-581.

Akgun S, Ertel NH: A comparison of carbohydrate metabolism after sucrose, sorbitol, and fructose meals in normal and diabetic subjects. Diabetes Care 1980;3:582-585. Jenkins DJA, Wolever TMS, Tayler RH, et al: Glycemic index of foods: a physiologic basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362-366.

Bantle JP, Laine DC, Castle GW, et al: Postprandial glucose and insulin responses to meals containing different carbohydrates in normal and diabetic subjects. N Engl J Med 1983;309:7-12. Bantle JP, Laine DC, Thomas W: Metabolic effects of dietary fructose and sucrose in types 1 and 2 diabetic subjects. JAMA 1986;256:3241-3246.

Bantle JP, Swanson JE, Thomas W, Laine DC: Metabolic effects of dietary fructose in diabetic subjects. Diabetes Care 1992;15:1468-1476.

Crapo PA, Kolterman OG: The metabolic effects of 2-wk fructose feeding in normal subjects. Am J Clin Nutr 1984;39:525-534.

Bossetti BM, Kocher LM, Moranz JF, Falko JM: The effects of physiologic amounts of simple sugars on lipoprotein, glucose and insulin levels in normal subjects. Diabetes Care 1984;7: 309-312.

Koh ET, Ard NF, Mendoza F: Effects of fructose feeding on blood parameters and blood pressure in impaired glucose-tolerant subjects. J Am Diet Assoc 1988;88:932-938. Hallfrisch J, Reiser S, Prather ES: Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose. Am J Clin Nutr 1983;37:740-748.

Reiser S, Powell AS, Scholfield DJ, et al: Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylase cornstarch. Am J Clin Nutr 1989;49: 832-839.

Bantle JP, Raatz SK, Thomas W, Georgopoulos A: Effects of dietary fructose on plasma lipids in healthy subjects. Am J Clin Nutr 2000;72:1128-1134.

Elliott SS, Keim NL, Stern JS, et al: Fructose, weight gain and the insulin resistance syndrome. Am J Clin Nutr 2002;76:911-922.

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;79:537-543. Saad MF, Khan A, Sharma A, et al: Physiological insulinemia acutely modulates plasma leptin. Diabetes 1998;47:544-549.

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;89:2963-2972.

Ludwig DS, Peterson KE, Gortmaker SL: Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001;357:505-508. Raben A, Vasilaras TH, Moller AC, Astrup A: Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects. Am J Clin Nutr 2002;76:721-729.

Waxman A: The WHO global strategy on diet, physical activity and health: the controversy on sugar. Development 2004;47:75-82.

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Discussion

Dr. Katsilambros: A long time ago I learned personally from Prof. Alexander Margot that when patients come in at the beginning in a state of uncontrolled diabetes, it is quite undesirable and contraindicated to provide fructose because it is much more readily converted to glucose in uncontrolled diabetes. Is this also your opinion? The second comment refers to personal studies done many years ago when I was an assistant. Patients with hepatitis B were given fructose orally, once in the acute stage and again in the recovery stage. Glucose and fructose were measured separately. In the first acute phase there was fructose intolerance; the curve was high and delayed. Then in the recovery phase a considerable improvement in this curve was observed. This means that fructose intolerance was due to the diminished capacity of the liver to transform fructose to glucose. The related question now refers to your observation that men and women have large differences with regard to the triglyceride increase; that in men triglycerides were much higher than in women. Are you sure that these men were not drinkers?

Dr. Bantle: Let me answer the first question which is about the effect of fructose in poorly controlled diabetes. I think you are absolutely correct. If fructose is fed to someone with poorly controlled diabetes, there is a greater rise in plasma glucose than in people who have well-controlled diabetes. But I think if you look at the response of such a person to ingested glucose, it is also greatly increased and in fact the glycemic response to fructose is somewhat less than glycemic response to glucose in that situation. It is true, however, that more fructose is converted to glucose in poorly controlled diabetes. Your second point about the use of fructose as a test for liver disease, I cannot answer. I don't have experience with that. Please, what was the last question?

Dr. Katsilambros: The fact that triglycerides were higher in men. Usually these men are volunteers and in many countries including yours these volunteers are paid, and certainly some of them are drinkers. With women this is not the case and it might possibly make a difference.

Dr. Bantle: This might make a difference but we screened subjects carefully for a history of alcohol consumption. They were to avoid alcohol during the period of study but I cannot guarantee they did. We were quite certain they ate what we asked them to eat, but whether or not they used alcohol I can't say for certain. They were solid Minnesotan citizens who pretty much do what you ask them to if they say they will. I will tell you a story about our study. One day I was called by one of the nurses to come and talk to one of the subjects. When I came into the room, the woman was crying. She said she had to tell me that she had eaten something that wasn't in the study diet. She confessed to have eaten 2 Cherios, and then she started crying again. I was fairly confident the data from that woman were reliable. But I can't verify that some of our subjects didn't consume alcohol. One would hope that any effect of alcohol was evenly distributed between both treatments so that the randomization process would have reduced or eliminated any effect.

Dr. T. Wilkin: If I recall a review I read some months ago now, the average American child is consuming something between 60 and 80 g of fructose from soda drinks alone in the course of the day, whereas if left to the natural sources of fruit and vegetables it might be between 10 and 15 g. Even if your evidence is such that you observe nothing special about the action of fructose, there was a huge increase in the number of calories that have been consumed as a result of fructose ingestion and the link between obesity and fructose can surely be argued still to be there.

Dr. Bantle: Yes, and perhaps the problem with fructose is it tastes good and is pleasant to consume. The overall problem may be that we are victims of our own success with abundant food that tastes good and is inexpensive. Several years ago

McDonalds was implicated in the outbreak of obesity and they may have a similar sort of problem. They make food that tastes good and is inexpensive. That may be as much the problem as the specific food type. I would not implicate fructose until we have better evidence. For instance, sucrose might do the same thing, and if we decided to sweeten drinks with glucose, it would potentially do the same thing.

Dr. T. Wilkin: In your data of the 42-day study you showed us I think 14, 28 and 42 days, but I don't think you showed us the time zero, and I wondered if the levels of time zero or levels of day 42 had returned to what they were at time zero.

Dr. Bantle: The lipid values?

Dr. T. Wilkin: Cholesterol values.

Dr. Bantle: There were baseline values obtained. The main thing that happened was that lipids got better on the glucose diet which would suggest that the baseline diet was high in fructose.

Dr. Golay: Do you have more details concerning the group of women: age, hormone replacement, etc.?

Dr Bantle: The women were picked so that 6 were under 40 and 6 were over 40. We looked at age in both men and women and could find no effect, although the subject sample size was small. Both in younger men and older men, the triglyceride values were higher on the fructose diet. In older and younger women there was no effect of the fructose diet on triglycerides. I don't recall the hormonal status but I think most of the older women were postmenopausal. We did not stop any replacement therapy they were receiving so we cannot speak much on the effect of estrogens based on this study.

Dr. Metzger: I am also interested in the differences between the men and women. Is there any difference in the handling of fructose between men and women?

Dr. Bantle: Not that I know of and I am not sure there was a real difference in our study. In the study from Elliott et al. [1] that I showed, the women did have a rise in triglycerides when given a high fructose diet. However, there was more fructose, 30% of energy for 1 day, and I think that is an important issue.

Dr. Slama: I had a similar experience as you many years ago and I came to the same conclusion. But for women I have not looked at that carefully; perhaps I missed something but I could go back to my data. Having a large experience with animal models I can say that when you feed rats large amounts of sucrose or fructose then a massive infiltration of fat is seen everywhere. What is striking is that the liver is twice the size of that of the control rat, and this liver is half fat and half glycogen. The same but less striking observation can be made in the muscle; there is a lot of fat in the muscle and a lot of glycogen which could be utilized by sportsmen. This is so true that not only we but also others are routinely using an insulin-resistant rat model: fructose fat rats.

Dr Bantle: I think you made a good point. Fructose is very lipogenic in animal models although many of the animal studies have employed very high fructose intakes, between 30 and 70% of energy. I think a key point that is not commonly reported is the energy balance of the animals. That is, with excess energy, fructose is much more lipogenic and there are more adverse effects on lipids than with an energy-deficient diet where most of the fructose is burned as it is consumed. But that hasn't been studied.

Dr. Slama: I can add that we observed this even pair-fed rats; they have the same body weight but much more fat and glycogen in the liver than control rats. So it is not only a question of energy and free access to palatable food, it is a question of metabolism and you have shown that the fructose is prone to conduct rather to glycogen and/or to lipids rather than going back to glucose.

Dr. Bantle: I don't doubt the observation but I have difficulty to explain how, if they are truly pair-fed and getting isocaloric diets, they would produce and store more fat on one diet than on the other, no matter what the source of energy. Perhaps there is something about fructose that affects metabolism.

Dr. Hill: I have a comment and a question. First I think it is very dangerous to correlate specific things in the environment with changes in obesity rates. There are so many things that correlate. Along those lines, it is disturbing to hear everybody blaming the obesity epidemic on fructose with such little data. My question relates to Dr. Slama's question. One of the concerns is that fructose may be producing insulin resistance in the liver and that could lead to weight gain and obesity. Are there data available that this may be a pathway to link fructose with obesity?

Dr. Bantle: This is a good question and I am afraid I am not aware of any data. Perhaps someone in the audience is. Is anyone aware of such data?

Dr. Slama: No, because really in animals you can feed them with 70% calories coming from fructose.

Dr. Bantle: Regarding your comment Dr. Hill, I think that the liquid sweeteners may in fact be more a problem than solid sweeteners. That is, all the calories that we get through soft drinks may in fact be highly undesirable.

Dr. Chiasson: I remember that Dr. Reaven was using that specific animal model to create hypertension and also insulin resistance. I was just wondering whether in your experience the subjects did develop any change in the blood pressure?

Dr. Bantle: We did monitor blood pressure carefully and could not demonstrate any difference between the two diets in blood pressure. I too read Dr. Reaven's studies with interest. I think he used 70% fructose in his rat models.

Dr. Halimi: As Dr. Slama's group with the same animal model, we found the same things: a huge amount of visceral fat, a large liver with steatosis, and hypertension. Fructose increases plasma triglycerides in men but not in women, and not to the same extent in all populations, more subjects with metabolic syndrome. When plasma triglyceride increases, what happens to the low-density lipoprotein particle size in the studies mentioned?

Dr. Bantle: We did not measure the particle size in our studies and I am not aware of anyone who has. So again, I am afraid I can't answer the question based on any experience or data.

Dr. Slama: I find Dr. Halimi's comment very interesting. Could you not apply the definition of metabolic syndrome to both populations in your population and see if there is a trend towards more frequent metabolic syndrome in men than in women?

Dr. Bantle: You mean retrospectively go back and look at the data and define those in the groups who had metabolic syndrome. This is an interesting idea. I think we did have a range of body mass indexes. So it may be possible for us to do that and see if it was those with higher body mass indexes and metabolic syndrome who had the more significant response to fructose. It is a good idea, thank you.

Dr. T. Wilkin: Given the data on hepatic infiltration in the animals, did you have the opportunity to look at inflammatory markers?

Dr. Bantle: We had the opportunity but we didn't take it. In retrospect, I wish we had.

Dr. Mooradian: Just a caution to those of us who do a lot of cell culture studies: fructose is a very nasty substance and it has a lot of cell toxicity. I have concerns about this fructose intake even though the effect on glycemia and lipids seems to be modest within the range of fructose consumed day to day. But at least in the cell culture field fructose is by far a much more toxic substrate than glucose is. I wonder if we are missing some additional effects of fructose when we just focus on glucose and the lipid effect of this sugar.

Dr. Bantle: That is a good point and there may be other effects of fructose, as yet not defined, that are adverse. I would use the opportunity to point out that we were looking at 17% of energy as fructose which is something like the 90th percentile of intakes in the United States. It was quite a high fructose intake but 10% of the people in the United States consume that much or more. I am of the opinion that putting this much fructose into the energy stream is perhaps not a good idea. We suggested glucose would be a suitable replacement but it turns out that glucose is much less sweet than fructose. The amount you have to put in to make a soft drink taste like it does now would give 50% more calories. Recipes that employ sucrose or high fructose corn syrup would have to be changed in terms of preparation, amounts, baking time, caramelization and all sorts of factors. These would become problems that would need to be solved.

Dr. Halimi: Just another comment about the high fructose diet in rats. It is not confirmed in human studies but in rats there is also a huge increase in many oxidative stress parameters and this parallels insulin resistance [2, 3]. It would be very interesting to examine the situation in humans, with a high fructose intake as the current intake in the US, to measure the oxidative stress in these populations.

Dr. Bantle: I agree, more study in fructose is clearly needed to see if what happens in animals also happens in humans.

Dr. Mooradian: Just to follow up on Dr. Halimi's point: tomorrow I am going to show data specifically on the effect of fructose in oxidation. Fructose is 7- to 8-fold more pro-oxidant compared to glucose.

Dr. Slama: Have you seen convincing data that 50:50% mixing of glucose and fructose is the same as sucrose in terms of the metabolic effect?

Dr. Bantle: No, I don't know of any such data. My assumption is that, since 55% fructose corn syrup contains nearly equal amounts of glucose and fructose, it would have the same effect as sucrose.

Dr. Slama: I am not sure really but there might be some data proving the reverse. I think that the problem comes from your country because you are not producing sucrose or only very small amounts, and so you are producing your natural sweeteners, corn syrup, whereas in other countries sucrose is widely used.

Dr. Bantle: I agree, we are part of the problem. Where I come from, as soon as you leave the city, there is corn as far as the eye can see in all directions.

Dr. Slama: So you may have some trouble in your country to pick up all.

Dr. Bantle: Corn is a good thing in most respects.

Dr. Halimi: Just some information, very interesting in my opinion. In cooperation with a center specialized in animal feeding, we have confirmed that a high fructose diet is able to induce insulin resistance in male rats. But this diet does not induce insulin resistance in females [4]. Second, when the same diet, very rich in fructose, is reproduced using honey, then there is no insulin resistance. This could be due to antioxidative substances in the honey [5].

References

1 Elliott SS, Keim NL, Stern JS, et al: Fructose, weight gain and the insulin resistance syndrome. Am J Clin Nutr 2002;76:911-922.

2 Faure P, Rossini E, Wiernsperger N, et al: An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes 1999;48:353-357.

3 Faure P, Roussel A, Coudray C, et al: Zinc and insulin sensitivity. Biol Trace Elem Res 1992;32:305-310.

4 Busserolles J, Mazur A, Gueux E, et al: Metabolic syndrome in the rat: females are protected against the pro-oxidant effect of a high sucrose diet. Exp Biol Med (Maywood) 2002;227: 837-842.

5 Busserolles J, Gueux E, Rock E, et al: Substituting honey for refined carbohydrates protects rats from hypertriglyceridemic and prooxidative effects of fructose. J Nutr 2002;132: 3379-3382.

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