Where is fructose metabolism

Taylor, M. Trenell, E. Stevenson, and L. Sucrose ingestion after exhaustive exercise accelerates liver, but not muscle glycogen repletion compared with glucoe ingestion in trained athletes. Gonzalez, J. Fuchs, J. A, Betts, and L. Glucose plus fructose ingestion for post-exercise recovery - greater than the sum of its parts? Nutrients 9:E Haidari, M.

Leung, F. Mahbub, K. Uffelman, R. Kohen-Avramoglu, G. Lewis, and K. Adeli Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoBcontaining lipoprotein overproduction. Hawley, J. Dennis, and T. Noakes Oxidation of carbohydrate ingested during prolonged endurance exercise.

Sports Med. Jandrain, B. Pallikarakis, S. Normand, F. Pirnay, M. Lacroix, F. Mosora, C. Pachiaudi, J. Gautier, A. Scheen, J. Riou, and P. Lefebvre Fructose utilization during exercise in men: rapid conversion of ingested fructose to circulating glucose.

Jeukendrup, A. Carbohydrate and exercise performance: the role of multiple transportable carbohydrates. Care Latulippe, M. Skoog Fructose malabsorption and intolerance: effects of fructose with and without simultaneous glucose ingestion. Food Sci. Le, K. Ith, R. Kreis, D. Faeh, M. Bortolotti, C. Tran, C. Boesch, and L. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes.

Lenoir, M. Serre, L. Cantin, and S. Ahmed Intense sweetness surpasses cocaine reward. PLoS One 2:e Marriott, B. Cole, and E. Lee National estimates of dietary fructose intake increased from to in the United States. Olsho, L. Hadden, and P. Connor Mayes, P. Control of hepatic triacylglycerol metabolism. Moore, M. Chong, et al. DNL is relatively small for either glucose or fructose.

Figure 5 shows typical results from Stanhope, et al. The figure shows superimposed fructose and glucose curves from reference [ 34 ]. The error bars in the figure, in fact, represent the standard error of the mean SEM.

SEM can provide a statistical measure of the difference in the populations, but in terms of presentation of data, it does not communicate very well a sense of the true variability of the individual data. With such large variation, a couple of outliers would change the character of the curve.

In other words, whereas there is a unique effect of fructose, it is not large and appears to be highly variable. Superposition of Figures 2 A and 2 B, redrawn from Stanhope, et al. Similarly, Teff, et al. Dividing subjects in both groups into sub-populations on the basis of insulin sensitivity showed that, in fact, differences due to insulin sensitivity within each sugar were as great as the differences between the two sugars.

As shown 0in Figure 6 , insulin-resistant subjects in the glucose arm had higher TAG than insulin-sensitive subjects in the fructose arm. Because of the importance of insulin resistance, it is reasonable to think that insulin will be the true variable of interest. Comparative effects of fructose-sweetened red and glucose-sweetened beverages blue. Data from Teff, et al. The association between levels of dietary carbohydrate and plasma TAG may be the single most predictable effect of nutrients on lipid metabolism reviews: [ 11 , 13 , 14 ].

That increases in plasma TAG are not always seen in high fructose feeding [ 36 ] suggests that it is not the major, or at least, not the only player. The proper control, again, is substitution of total carbohydrate with something else, sensibly fat. Although no such explicit comparison has been done, replacing total carbohydrate with fat always shows much greater changes than experiments in which sugars are exchanged.

For example, Volek, et al. Figure 7 from Volek, et al. Changes in TAG from replacing total carbohydrate are larger and more reliable than studies in which glucose replaces fructose. Hollenbeck [ 36 ] reviewed studies through on the effect of fructose on lipid metabolism. Of 18 relevant studies, she considered that only 8 met the criteria of 1 sufficient dietary and experimental control, 2 glucose or starch for comparison; and 3 had limited heterogeneity present in the study population.

Of these 8, half showed no change in plasma TAG while one found no change in a normal group but an increase in subjects with hypertriglyceridemia, and one study similarly found no change in the normal population with increases in subjects with hyperinsulinemia. Only two studies found increases in TAG. Effect of diet on postprandial lipemic responses in subjects with atherogenic dyslipidemia. Redrawn from Volek, et al. Differential effects of glucose and fructose reviewed in reference [ 37 ] follow the pattern described here.

For example, Hudgins, et al. Consistent with the idea that fructose ingestion may change total availability of sugars in the liver, they found that fructose has a much greater effect than glucose when administered alone; an oral glucose tolerance test OGTT had little effect.

However, adding glucose to a dose of fructose increased DNL, and as total carbohydrate becomes high, exceeding the K m of glucokinase, there is little difference between sugars Figure 8 , absolute changes, however, are small and, again, there is great variability. Redrawn from reference [ 38 ]. That this was due to a decrease in DNL was shown by a corresponding reduction in palmitoleic acid n-7 , the product of the desaturase.

Palmitoleic acid is present in only low concentrations in the diet and is generally taken as an indication of DNL. Because of its limited effect on insulin secretion, it was originally thought that fructose might be a desirable sugar for people with diabetes.

However, this proved to be not only ineffective but led to the risk of lactic acidosis. Similar effects of pure fructose are observed in parenteral nutrition [ 39 ] or administering fructose during exercise [ 40 ]. This response has traditionally been explained as a kinetic effect due to the rapid phosphorylation of fructose and a depletion of ATP. One of the consequences is increased glycolysis and increased lactic acid production. Under conditions where both fructose and glucose are available, there is somewhat greater lactic acid production from higher fructose although there is no threat of acidosis and lactic acid is one of the ways that fructose supplies energy to extrahepatic cells.

While speculative, a reasonable deduction is that hepatic metabolism has evolved so as to require glucose for fructose metabolism. In addition, there are reported digestive effects of fructose alone which indicate the involvement of problems in absorption.

It may be that results with fructose alone cannot be compared to results where both sugars are present and such interventions may not be a good model for human consumption which almost never includes pure fructose. It is widely reported that fructose depletes ATP due to the fructokinase reaction [ 1 ] although this has generally been observed in isolated hepatocyte cultures and with addition of pure fructose. The major focus of current interest are studies done under conditions of high energy charge and the reactions characteristic of fructose — glycogen and triglyceride formation — require ATP.

Veech, et al. Oddly, Abdelmalek, et al. The effects on ATP may be dependent on particular conditions. The effects of different conditions of substrate source and particularly exercise are beyond the scope of this review but there is, again, a good deal of variability as seen even in the effects on rates of oxidation of different sugars Review: [ 8 ].

As noted above, the presence of fructose tends to increase the levels of plasma lactate but, generally, differences between dietary glucose vs. There are clearly specific effects of fructose but we emphasize that these must be rationalized in the face of the continuum between fructose and glucose metabolism.

Control of fructose metabolism is primarily at the level of substrate regulation, the more favorable K m of fructokinase compared to glucokinase. Because downstream metabolism of fructose from the triose-phosphates is the same as that for glucose, there is an expectation that there will be variability among studies.

This expectation is borne out and even those that have clear-cut outcomes, show significant statistical error. Finally, nobody is suggesting that continued high consumption of sugar is good but there there is a logical problem and a practical problem. Logically, you cannot say that we will look at the effect of fructose but not the effect of carbohydrates.

Removing sugar without replacement is obviously good for weight loss but practically speaking, if we want to reduce sugar consumption isocalorically, we must consider whether to replace sugar with starch or with another nutrient, usually fat.

There are numerous studies showing the benefit of the latter approach but few demonstrating the value of the former. Showing that fructose is worse than glucose under some conditions is not the same thing as showing that specifically removing fructose is beneficial. Until these comparisons are made, it seems like a good idea to keep some perspective. While studies with combinations of fructose and glucose are consistent with a general effect of carbohydrate, fructose alone appears to have aberrant behavior and one might speculate that the system evolved to deal with the two sugars together, consistent with the general absence of pure fructose outside of experimental trials.

From the perspective of ideas in the popular media, however, there is little relation between fructose metabolism and ethanol metabolism and it is unreasonable to refer to fructose as a toxin. The strongest argument for caution in a strategy of specifically removing fructose as sucrose or HFCS from the food supply is the absence of significant prospective trials.

In terms of basic metabolism, fructose is incorporated into general carbohydrate metabolism which may have specifically evolved to deal with the sudden appearance of desirable food. Persistence in a state of over-consumption has serious consequences and there is a clear benefits in restricting sugar, especially for children. However, suggesting that fructose is somehow a foreign substance is not consistent with the science and, therefore, should not be the basis of policy.

There is a continuum from scientific studies to popular media that suggests a circumspect approach is unlikely and, in our opinion, there is a clear sense of a rush to judgement on sugar, entirely analogous to that in the diet-heart-cholesterol phenomenon. Perhaps the most important similarity is that both official agencies and individual doctors and researchers are recommending, even demanding, reduction in sugar, despite the absence of any experimental test of the idea.

The message to reduce fat and cholesterol was, similarly, made before any test of what the outcomes might be. Given increasing evidence of risk from high total carbohydrate intake, the likelihood of unintended consequences from reducing fructose alone starch replacing sugar is strong.

Emphasizing fructose outside of general carbohydrate metabolism has the serious limitation of substantially ignoring the hormonal effects of glucose the major secretagogue of insulin.

In people with type 2 diabetes, removing starch is more beneficial than removing sugar [ 44 ] and effective treatment has been demonstrated in several studies from Nuttall and Gannon where the controlling variable is reduction of what the authors call bioavailable glucose [ 17 , 18 , 45 ].

In this area, at least, it would be good to proceed carefully. A virtue of the current emphasis on the dangers of fructose is the appeal to an analysis based on basic metabolism [ 3 , 4 ]. The points made in the current review should be included in that analysis. Google Scholar. Lustig RH: Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. Bray GA: Fructose: pure, white, and deadly?

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F1P may also enhance glycogen synthesis by allosterically inhibiting glycogen phosphorylase 67 , Lastly, F1P also allosterically activates pyruvate kinase, the terminal step in glycolysis, contributing to increased circulating lactate levels following fructose ingestion In rodent liver, hepatic F1P levels increase fold to approximately 1 mM within 10 minutes after fructose ingestion and remain elevated for several hours Thus, fructose ingestion is likely to have rapid, robust, and sustained effects on hepatic glucose uptake and intermediary metabolism.

Fructose-induced gene expression programs. These metabolic pathways contribute to steatosis, VLDL packaging and secretion, as well as glucose production and the generation of lipid intermediates that may affect hepatic insulin sensitivity and other biological processes. While the efficiency and rapidity with which the liver can extract and phosphorylate ingested fructose are likely important for its role in integrating nutritional and systemic fuel metabolism, this robust metabolism may also have deleterious consequences.

For instance, decreases in intracellular free phosphate due to rapid hepatic fructose phosphorylation can increase uric acid production through activation of AMP deaminase, which leads to catabolism of AMP to uric acid 72 , Fructose feeding may also stimulate purine synthesis, contributing to uric acid production Increased circulating uric acid levels increase the risk of gout, a condition characterized by painful inflammation due to deposition of uric acid crystals in joints.

Indeed, a growing body of evidence implicates sugar intake as a risk factor for gout Moreover, elevated serum uric acid levels and gout are associated with other cardiometabolic risk factors in diverse populations 76 — A substantial body of work suggests that increased uric acid levels may independently regulate important aspects of metabolism and contribute to cardiometabolic risk 79 — However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease The association between uric acid levels and cardiometabolic risk may be indirect and may reflect activation of distinct fructose-regulated processes that contribute both to uric acid production and cardiometabolic risk.

The liver is at a metabolic crossroads and is crucial for gauging nutrient consumption and integrating peripheral nutrient status to regulate systemic fuel storage versus provisioning. While hormones like insulin and glucagon help inform the liver of systemic fuel status, the liver is also well configured to integrate signals derived directly from fuel substrates. Robust physiological activation of hepatic GCK occurs only when fructose-containing sugars are consumed.

This activation enhances net hepatic glucose uptake and storage as glycogen and lipid. Thus, in the setting of uncontrolled diabetes, the liver may aberrantly sense hyperglycemia as a state of increased sugar consumption.

KHK exists as two alternatively spliced isoforms produced by mutual exclusion of the adjacent exons 3C and 3A within the KHK gene 87 , Mice deficient in both isoforms were fully protected from fructose-induced metabolic disease even though blood and urinary fructose levels were markedly increased Thus, elevated blood fructose itself is not deleterious; rather, fructose metabolism is essential for fructose-induced metabolic disease.

Loss-of-function mutations in KHK cause the benign human disorder essential fructosuria, characterized by impaired hepatic fructose metabolism leading to high blood and urine fructose levels after sucrose or fructose consumption Consistent with observations in mice, there are no documented adverse health effects observed in people with this condition.

Altogether, these results suggest that inhibiting KHK may be a safe therapeutic strategy to prevent fructose-induced metabolic disease.

In contrast with global KHK deletion, selective deletion of the A isoform exacerbates the adverse metabolic effects of fructose feeding These results suggest two important hypotheses: a fructose metabolism outside of tissues that express the C isoform is non-negligible and contributes to whole-body fructose clearance, and b fructose metabolism within the tissues expressing KHK-C is critical for fructose-induced metabolic disease.

This is supported by recent data showing that selective knockdown of KHK in mouse liver protects against fructose-induced steatosis Recent data also indicate that altered splicing between KHK-A and KHK-C isoforms may contribute to the development of distinct diseases like hepatocellular carcinoma and heart failure 94 , Hereditary fructose intolerance HFI is a rare autosomal recessive disease caused by a deficiency of aldolase B ALDOB , which is highly expressed in the liver, kidney, and small intestine People with HFI develop abdominal pain, vomiting, diarrhea, symptomatic hypoglycemia, hyperuricemia, and potentially liver failure and death following ingestion of foods containing fructose, sucrose, or sorbitol An Aldob- deficient mouse model mimics the human HFI condition These mice fail to thrive and die when exposed to high-fructose diets.

Interestingly, even on a fructose-free diet, Aldob- deficient mice develop steatosis 98 , possibly due to impaired metabolism of endogenously synthesized fructose While the vast majority of metabolized fructose is derived from dietary sources of sugar, animals including humans are capable of synthesizing fructose endogenously.

The sorbitol polyol pathway, which is active in a wide range of tissues, is responsible for endogenous fructose formation from glucose , In this pathway, glucose is first reduced to sorbitol by aldose reductase Sorbitol is then oxidized to fructose by sorbitol dehydrogenase Physiologically, endogenously synthesized fructose is the primary energy source for sperm and may be important for fertility — The placenta may also synthesize sorbitol that the developing fetus may use to synthesize fructose, suggesting a broader role for endogenous fructose in reproductive and developmental biology Sorbitol pathway activity increases during diabetic hyperglycemia Endogenous fructose synthesis and polyol metabolites are considered key players in the development of diabetic microvascular complications Interestingly, semen fructose concentrations are increased in type 1 diabetes and in obesity, in which it is associated with impaired sperm parameters , Whether endogenous fructose synthesis might occur at sufficient rates to contribute to other aspects of fructose-induced cardiometabolic risk has only recently been addressed.

Glucose dose-dependently induces aldolase reductase in human tissues, and chronic exposure to a high-glucose diet induces polyol pathway activation in mice 99 , This may be a mechanism by which severe hyperglycemia may exacerbate cardiometabolic risks.

Additionally, Lanaspa et al. Although sorbitol dehydrogenase is expressed at high levels in human liver , whether this pathway is sufficiently active in humans to play an adverse metabolic role will require further investigation.