The overall effect is increased gluconeogenesis from the triose-phosphates, light blue pathway in Figure 1 , net conversion of fructose to glucose and, as described below, a high potential for glycogen synthesis. FructoseP exerts positive allosteric control on glucokinase.

It is now understood that the high K m of glucokinase, and its apparent allosteric properties, are due to binding of an inhibitory glucokinase-regulatory protein RP; Figure 2 that reduces its affinity for substrate.

Fructosephosphate relieves inhibition by binding to RP thereby stabilizing the dissociated proteins. Inhibition is a consequence of translocation of the glucokinase-RP complex to the nucleus [ 27 ].

Dissociation of RP and transport from the nucleus is enhanced by postprandial glucose and insulin [ 28 ]. Additional regulation is provided by fructoseP from glycolysis which acts as a feedback inhibitor of glucokinase, changing the affinity for RP, re-establishing binding and returning the enzyme to the nucleus, thereby creating an apparent higher K m state.

Control of glucokinase. Binding of glucokinase-regulatory protein RP reduces the activity of glucokinase GK. FructoseP relieves the inhibition by stabilizing the dissociated RP, while FP furthers inhibition by stabilizing the complex.

Not shown in the figure: the GK-RP complex is transported to the nucleus [ 27 ]. Dissociation leads to transport from the nucleus.

Fructose might be thought of as a metabolic signal for affluence, calling for additional glucose via relief of inhibition of glucokinase. This response, an apparent equalizing of added fructose and glucose, may be of general importance. Administration of fructose alone may be a distinctly abnormal state for the human liver which evolved in an environment where the sugars were always presented together.

Thus fructose, directly and indirectly increases the effective level of glycolytic intermediates. Hepatic carbohydrate metabolisms responds to lower plasma levels of fructose than of glucose but the combination of fructose and glucose is expected to be stronger than fructose alone.

A further prediction is that under conditions of high plasma glucose, conditions where the K m of glucokinase is exceeded, differences between the two sugars should cancel out. Again, DNL, under conditions of overfeeding, conform to this prediction [ 21 ]. A large fraction of ingested fructose is converted to glucose [ 8 ].

Delarue, et al. After a 6 hour period, addition of 0. Similar results, reviewed by Sun [ 8 ], have been found by others. Gluconeogenesis from fructose is generally assumed to proceed as shown by the light blue arrows in Figure 1 [ 8 ]. The process will also be sensitive to the varying energy charge and presence of other macronutrients.

As expected for a response to times of plenty, high fructose enhances glycogen storage Figure 1 either directly from glucose or via gluconeogenesis. The interacting effects of glucose and fructose were studied in primary cultures of hepatocytes from rats deprived of food for 24 hours.

Parniak and Kalant [ 19 ] measured the incorporation into glycogen of [ 14 C]-glucose in the presence of cold fructose and incorporation of [ 14 C]-fructose in the presence of cold glucose.

The results, shown in Figure 3 indicate that label from either sugar in the form of glucose is incorporated into glycogen in a dose-dependent manner. Each sugar enhanced the incorporation of the other red symbols and, in both cases, high insulin heavy line increased the total yield compared to its absence gray line.

Fructose leads to greater incorporation presumably due, again, to relative higher uptake and phosphorylation but most notable is the similarity of the patterns and the extent of conversion of fructose to glucose. Incorporation of labeled glucose or fructose as a function of concentration of the labeled sugar and effect of presence of other cold sugar.

Incorporation of labeled sugar in the absence of the other is shown by the blue symbol and the unbroken gray line. When the other unlabeled sugar is added there is a shift in the incorporation as shown by the red symbol and the gray broken line.

All the effects are enhanced upon addition of insulin heavy black lines. This stimulating effect of fructose was demonstrated in humans by Petersen, et al. Infusions of 13 C-labeled glucose in the presence or absence of fructose were followed by a cold chase to determine rates of synthesis and breakdown.

In distinction to the results with hepatocytes, increased flux was due to the glycogen synthase reaction 2. High fructose is frequently described as causing insulin resistance and metabolic syndrome MetS and there are several observations supporting the idea e. Most such experiments, however, are done under conditions of high total carbohydrate where, again, separate effects of the sugars and their interactions are inadequately addressed.

Also, not all tests show a clear fructose effect. Most recently, Lecoultre, et al. However, as seen in Figure 4 , there was great variation and overfeeding glucose had a similar effect.

Male subjects consumed weight maintenance diets for 6—7 days and then the indicated amount of sugar was added to the same diet. Data from reference [ 30 ]. An important question is the operational definition of insulin resistance.

Dirlewanger, et al. The fructose addition caused an increase of insulin demand by 2. Using radio-labeled glucose, they showed that there was no effect of fructose on endogenous glucose production or total output compared to control. When measurements were made under a hyperinsulinemic hyperglycemic clamp protocol, fructose addition caused an The results were described as hepatic insulin resistance, that is, more insulin was needed to maintain the level of blood glucose in the presence of fructose and, conversely, high insulin did not repress production of glucose.

Although the results conformed to an operational definition of insulin resistance, Dirlewanger, et a l. This will lead to enhanced total glucose output despite the high insulin concentration, an insulin concentration that was able to repress output in the glucose-alone controls.

At the same time, fructoseP, by causing an increased glucokinase activity, would lead to enhanced re-uptake of glucose and increased glucose cycling. Thus, apparent insulin resistance is the effect of higher levels of glucose intermediates in a fructose-stimulated cell and does not represent any basic detrimental change in hepatic physiology.

The concept of insulin sensitivity or resistance is thus strongly dependent on the method of measurement and the operational definition. Insulin resistance may be a characteristic of type 2 diabetes and the sine qua non of metabolic syndrome but, depending on what is measured, need not be associated with maladaptive responses to food or other stimulation and my represent productive adaptation to different conditions.

Again looking at the influence of total dietary carbohydrate as a control, it is known that carbohydrate restriction across the board will improve all of the features of MetS. It was suggested, in fact, that the response of all of the individual markers of MetS to reduced carbohydrate might serve as an operational definition [ 13 ], given that there is some question as to whether the syndrome even exists [ 32 ].

This is important in that it is reasonable that at least some part of insulin resistance is down-regulation of response due to chronic high insulin as in many hormonal systems. Reduction in glucose, rather than fructose, will reduce this high insulin. A critical prospective test was carried out by Volek and coworkers who assigned 40 overweight men and women with the atherogenic dyslipidemia characteristic of MetS high TAG, low HDL-C, high concentration of small dense LDL to a very low carbohydrate ketogenic diet VLCKD in [ 12 , 14 , 24 ].

An isocaloric fat-restricted diet served as control. Compared to these controls, the VLCKD group showed greater improvement in body mass, in glycemic control, and in many of the features of MetS: TAG, HDL-C, apo B, apo A-1 and LDL particle size distribution as well as a greater anti-inflammatory effect.

The extent to which these effects of carbohydrate restriction were specifically due to removing fructose or sucrose is unknown but the magnitude of the effect although in the direction of improvement are generally larger than those seen in glucose-fructose comparisons.

The point here is that we know that restricting carbohydrates is effective in reducing the features of metabolic syndrome. Until there is evidence that it is specifically sugar that was removed, logic dictates that carbohydrate restriction is the preferred approach.

Carbohydrate-induced hypertriglyceridemia and its flip-side, reduction in triglycerides by dietary carbohydrate restriction, are well established phenomena. The effect is generally attributed to the increased flux of insulin which inhibits lipolysis and the reduction in glycerolP to provide substrate for synthesis.

It is unknown whether and to what extent there is a unique effect of fructose but several papers have indicated a high potential for fructose to increase plasma TAG compared to the effect of glucose [ 22 , 33 — 35 ]. There are, however, conflicting reports [ 11 ] and, again, most of the recent studies have been done against a baseline of high total carbohydrate or unusually high fructose, or both, meaning that baseline may already be very high.

Chong, et al. showed that, under acute postprandial conditions, little activity from radio-labeled fructose showed up in the fatty acid portion of TAG, that is, fatty acids are primarily from endogenous fat [ 35 ].

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. is representative. 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. Absolute TAG values in subjects who consumed a very low carbohydrate ketogenic diet VLCKD or a low-fat diet LF for 12 weeks.

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.

Effect of sugar on percentage of palmitate in VLDL TG before and after OGTT glucose, 75 g; average, 0. 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. The cytosol is much more oxidizing than the mitochondrion and conversion of DHAP to glycerolP requires NADH.

At low NADH, glyceraldehydeP will be oxidized to provide ATP and NADH, resulting in conversion to pyruvate and to lactate production.

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. showed that high ATP accompanied a high sucrose diet [ 41 ]. 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.

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Swarbrick MM, Stanhope KL, Elliott SS, Graham JL, Krauss RM, Christiansen MP, Griffen SC, Keim NL, Havel PJ: Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women. This is in line with literature describing that fructose is almost completely extracted by the liver, whereas glucose is also consumed by other tissues Tappy and Le, ; Hannou et al.

These observations can be reconciled with the high turnover of fructose in the liver Tappy and Le, ; Hannou et al. After uptake in the liver, fructose is instantly phosphorylated into fructosephosphate, which is then metabolized into triose phosphates.

In contrast to glucose, the hepatic uptake of fructose and its metabolism into triose phosphates is not regulated by the hepatic energy status Tappy and Le, ; Hannou et al.

The consequent higher turnover of fructose in the liver as compared to glucose could explain the faster decay of its 2 H signal in the bolus measurement, the lower signal maximum in the slow infusion measurements, and the faster increases in tissue concentration of deuterated water with both protocols.

However, the deuterated water is not necessarily produced in the liver itself, but likely originates also from other tissues, such as the skeletal muscles, heart and brain, especially for the later time points. Fructose-derived triose phosphates in the liver are routed toward glucose and glycogen production, lactate production, or de novo lipogenesis, depending on the hepatic energy status Tappy and Le, ; Hannou et al.

However, signals from deuterated lactate or lipids with overlapping resonance frequencies were not detected. The decrease of the 3. A limitation of our method is that part of the signal that we observe in the liver could also originate from blood.

Therefore, the higher 3. While it was commonly believed that the liver is the main site of fructose metabolism Tappy and Le, ; Hannou et al.

recently showed that in mice the small intestine clears most dietary fructose when consumed at low doses, whereas high fructose doses spill over to the liver Jang et al.

For the experiments with IV bolus injection, we used one animal per condition i. However, the inter-individual variabilities after slow IV infusion of either glucose or fructose Figure 4 were small compared to the group differences, signifying that the more than two-fold higher initial uptake of fructose versus glucose upon IV bolus injection will likely also be representative for larger group sizes.

Deuterated glycogen is 2 H MRS invisible in vivo , because of its large size and consequent short T 2 relaxation time, but in isolated liver glycogen in solution the deuterium enrichment can be determined by 2 H NMR upon addition of the glucose-releasing enzyme amyloglucosidase De Feyter et al.

Another important aspect of this study is that the DMI measurements were performed under isoflurane anesthesia. Isoflurane increases blood glucose concentrations in mice, without significantly affecting insulin secretion Windelov et al.

In contrast, hepatic fructose metabolism will likely be less affected by anesthesia. Therefore, the observed two-fold higher initial uptake of fructose versus glucose upon IV bolus injection in mice under isoflurane anesthesia may be an underestimation of what is expected in awake mice and humans.

Similarly, the results obtained with slow IV infusion may have been affected by the isoflurane anesthesia, in particular for glucose infusion. In the future, this method could potentially contribute to a better understanding of human liver metabolism, both in the healthy state and in diseases like diabetes and non-alcoholic fatty liver disease.

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation. The animal study was reviewed and approved by the Central Animal Experiments Committee CCD of the Netherlands and the local animal welfare body RU-DEC All authors contributed to the conception and design of the study.

AV and IV designed and constructed the deuterium surface coil. ADH and AV conducted the measurements and performed the spectral data analysis.

JP performed the statistical analysis. JP wrote the first draft of the manuscript. ADH, AV, AH, and TS wrote sections of the manuscript. All authors contributed to the article and approved the submitted version. This work was supported by the Netherlands Organisation for Health Research and Development ZonMw via the Enabling Technologies Hotels programme grant number: and the Dutch Research Council NWO grant number: HTSM We gratefully acknowledge the biotechnicians of PRIME for their assistance in mouse preparation and handling, and Drs.

Henk De Feyter and Robin de Graaf for sharing the DMI pulse sequence and analysis software DMIWizard and their assistance in setting up the DMI experiments. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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After rapid phosphorylation of fructose into fructosephosphate, it is converted to triose phosphates, which are routed toward glucose and glycogen production, lactate production, or de novo lipogenesis, depending on the energy status of the liver Tappy and Le, ; Hannou et al.

The lipogenic effect of fructose has been suggested to play a role in fructose-induced hepatic steatosis Nunes et al. Yet, high fructose loads exceeded the clearance capacity of the small intestine, resulting in spillover of fructose to the liver Jang et al.

Currently, the contribution of intestinal versus hepatic fructose clearance in humans is not clear Herman and Birnbaum, Direct measurement of hepatic glucose or fructose uptake is complicated by the fact that the portal vein is difficult to access DeFronzo, ; Moore et al.

However, considering the recent finding that the small intestine may play an important role in fructose metabolism, a more direct assessment of hepatic metabolism is warranted.

Using 13 C magnetic resonance spectroscopy MRS , hepatic glucose uptake can be studied directly and non-invasively after intravenous or oral administration of [1— 13 C]glucose Beckmann et al. Because of the large chemical shift range, signals in 13 C MR spectra are usually very well resolved.

However, 13 C MRS has a low intrinsic sensitivity and 13 C-enriched substrates are very costly Gursan and Prompers, Recently, deuterium metabolic imaging DMI has emerged as a new technique to measure metabolism in vivo De Feyter et al.

Deuterium 2 H nuclei have much shorter T 1 and T 2 relaxation times compared to 13 C nuclei De Feyter et al. The shorter T 2 relaxation times result in broader resonance lines and thus a lower spectral resolution of 2 H compared with 13 C MR spectra.

However, in return, the shorter T 1 relaxation times of 2 H nuclei allow faster signal averaging, yielding a higher sensitivity per unit of time for DMI compared with 13 C MRS.

In addition, deuterium-labeled compounds are generally cheaper than their 13 C-labeled counterparts. This new application of DMI should provide more insight into the role of the liver in glucose versus fructose clearance. The animal experiments were approved by the Central Animal Experiments Committee CCD of the Netherlands and the local animal welfare body RU-DEC Magnetic resonance MR measurements were performed on an Anatomical MR imaging MRI and DMI were performed with a standard Bruker 1 H transmit-receive body coil diameter: 72 mm; frequency: MHz combined with a custom-built 2 H transmit-receive elliptical surface coil dimensions: 16 mm × 20 mm; frequency: Body temperature was monitored with a rectal temperature probe and maintained at 37°C with heated air flow.

Respiration of the animal was monitored using a pneumatic cushion respiratory monitoring system Small Animal Instruments Inc. In total, 8 mice were scanned. At the start of infusion, a time series of dynamic 3D DMI scans was started with a total duration of either 60 min bolus injection or 90 min slow infusion.

DMI measurements were performed with a 3D MR spectroscopic imaging sequence Brown et al. Processing of the 3D DMI datasets was done with DMIWizard v1. For each animal experiment, a single voxel, centrally located in the liver, was selected from the 3D DMI datasets for further analyses.

Signals of deuterated water HDO; 4. Statistical analyses were performed in IBM SPSS Statistics FIGURE 1. For the mouse experiments, we first obtained anatomical MR images to guide the location of a voxel in the liver for B 0 shimming, and planning of the DMI grid Figure 2.

Because the two fructose signals were not resolved and because the spectroscopic pattern changed as a function of time after bolus injection of fructose, for quantification of the spectroscopic data of the dynamic experiments Figures 3C,D only a single resonance line was fit for either fructose or glucose at 3.

The decay of the 3. The initial rise of the deuterated water signal was also faster after fructose injection than after glucose injection.

After about 20 min, the concentration curve of the 3. From that time point on, the increase in deuterated water was also similarly slow for the experiments with both glucose and fructose.

FIGURE 2. Preparation of DMI measurements. In vivo anatomical 3D MR images were acquired as a guide to perform B 0 shimming on a voxel 3 × 5 × 5 mm 3 ; orange and to position the DMI grid green.

FIGURE 3. Top A,B DMI spectra of the liver after IV bolus injection of 1. The DMI spectra were obtained after averaging over a period of: 0—3 min I, bottom , 3—12 min II, middle and 30—60 min III, top. The shoulder has disappeared after 30 min, supporting the concept of conversion of fructose to glucose.

The spectra in trace III are amplified by 5 with respect to those in I and II. Despite this large initial difference, the tissue concentration seems to return to the same value at around 30 min after bolus injection of either glucose or fructose.

FIGURE 4. The mean and standard deviation of the concentrations over 3 mice with a moving average filter is displayed, including their individual time curves thin lines. The start and stop of the 30 min infusion period is indicated dashed grey lines.

Note that, during infusion of fructose compared to glucose, the 3. This is in line with literature describing that fructose is almost completely extracted by the liver, whereas glucose is also consumed by other tissues Tappy and Le, ; Hannou et al. These observations can be reconciled with the high turnover of fructose in the liver Tappy and Le, ; Hannou et al.

After uptake in the liver, fructose is instantly phosphorylated into fructosephosphate, which is then metabolized into triose phosphates. In contrast to glucose, the hepatic uptake of fructose and its metabolism into triose phosphates is not regulated by the hepatic energy status Tappy and Le, ; Hannou et al.

The consequent higher turnover of fructose in the liver as compared to glucose could explain the faster decay of its 2 H signal in the bolus measurement, the lower signal maximum in the slow infusion measurements, and the faster increases in tissue concentration of deuterated water with both protocols.

However, the deuterated water is not necessarily produced in the liver itself, but likely originates also from other tissues, such as the skeletal muscles, heart and brain, especially for the later time points. Fructose-derived triose phosphates in the liver are routed toward glucose and glycogen production, lactate production, or de novo lipogenesis, depending on the hepatic energy status Tappy and Le, ; Hannou et al.

However, signals from deuterated lactate or lipids with overlapping resonance frequencies were not detected. The decrease of the 3. A limitation of our method is that part of the signal that we observe in the liver could also originate from blood.

Therefore, the higher 3. While it was commonly believed that the liver is the main site of fructose metabolism Tappy and Le, ; Hannou et al. recently showed that in mice the small intestine clears most dietary fructose when consumed at low doses, whereas high fructose doses spill over to the liver Jang et al.

For the experiments with IV bolus injection, we used one animal per condition i. However, the inter-individual variabilities after slow IV infusion of either glucose or fructose Figure 4 were small compared to the group differences, signifying that the more than two-fold higher initial uptake of fructose versus glucose upon IV bolus injection will likely also be representative for larger group sizes.

Deuterated glycogen is 2 H MRS invisible in vivo , because of its large size and consequent short T 2 relaxation time, but in isolated liver glycogen in solution the deuterium enrichment can be determined by 2 H NMR upon addition of the glucose-releasing enzyme amyloglucosidase De Feyter et al.

Another important aspect of this study is that the DMI measurements were performed under isoflurane anesthesia. Isoflurane increases blood glucose concentrations in mice, without significantly affecting insulin secretion Windelov et al.

In contrast, hepatic fructose metabolism will likely be less affected by anesthesia. Therefore, the observed two-fold higher initial uptake of fructose versus glucose upon IV bolus injection in mice under isoflurane anesthesia may be an underestimation of what is expected in awake mice and humans.

Similarly, the results obtained with slow IV infusion may have been affected by the isoflurane anesthesia, in particular for glucose infusion.

Exit from the epithelial cells through the basolateral membrane to the blood is facilitated by GLUT2. Fructose is absorbed at a slower rate from the lower part of duodenum and jejunum both passively and actively by the brush-border membrane transporter 5 GLUT-5 and transported into blood also by GLUT2[ 34 , 35 ].

GLUT transporters are primarily made up of 13 multiple homologous proteins GLUT 1—12 and 14 and they are located throughout the body often exhibiting tissue specificities[ 36 ]. The capacity for fructose absorption in humans is not completely clear, but early studies suggested that fructose absorption is quite efficient, though it is less efficient than that of glucose or sucrose[ 34 ].

The slower absorption and prolonged contact time with the luminal intestinal wall would be expected to result in the stimulation of regulatory and satiety signals and release of hormones from enteroendocrine cells[ 37 , 38 ].

When fructose is consumed as the sole carbohydrate source, it can be incompletely absorbed, and as a result, produces a hyperosmolar environment in the intestine.

A high concentration of solute within the gut lumen draws fluid into the intestine which can produce feelings of malaise, stomachache or diarrhea[ 39 ], and results in decreased food intake.

However, when glucose is also present, malabsorption is significantly attenuated[ 40 ]. Riby et al. Pure fructose alone produced dose-dependent evidence of malabsorption starting from12 gram ingestion loads, while glucose and sucrose individually produced no intolerance up to 50 gram ingestion loads.

Incremental amounts of added free glucose to a 50 gram fructose load dose-dependently attenuated malabsorption symptoms, and at the equimolar mixture of the two up to grams total sugars , no malabsorption was observed.

Thus, how studies are designed to deliver the various sugars can have an impact on sugar uptake and appearance in the blood. Sucrose is a valid comparison for glucose-fructose mixtures, as the disaccharide is cleaved by the enzyme sucrase into the mono sugars before being absorbed into the circulation.

Comparison of sucrose absorption rates in 32 normal subjects with an equivalent amount of monosaccharide mixture containing glucose and fructose, infused intralumenally to avoid gastric hydrolysis, resulted in the similar absorption rates for each glucose and fructose component of the test[ 41 ].

Other comparison studies in normal men and women[ 44 ] and in diabetics[ 45 , 46 ] produced no differences in intestinal uptake between sucrose and honey a glucose-fructose mixture. Thus, the body appears to handle oral free glucose-fructose mixtures or HFCS similarly as sucrose and that hydrolysis of sucrose does not appear to be rate limiting for uptake.

Once absorbed, glucose is delivered to the liver then to peripheral organs for utilization, and its entrance into muscle and fat cells is insulin dependent. Fructose is primarily delivered to and metabolized in the liver for energy and for two and three carbon precursor production without dependence on insulin.

Although little dietary fructose appears in the circulation, it can influence plasma glucose concentrations via sugar inter-conversion. In man, studies indicate fructose to glucose conversion may occur to a highly significant degree reviewed below and that this conversion occurs via the 3-carbon intermediate pathways.

The extent of inter-conversion may be species dependent. Key points: 1 Fructose is readily absorbed and its absorption is facilitated by the presence of co-ingested glucose.

Sucrose, honey, glucose-fructose mixtures and HFCS all appear to be similarly absorbed. And, 3 Plasma levels of fructose are an order of magnitude 10—50 folds lower than circulating glucose, and fructose elicits only a modest insulin response.

This lower glucose and insulin response by the body to fructose intake has been considered desirable for diabetic diets. The important point of distinction between glucose and fructose metabolism resides in two areas. Absorbed fructose is extracted by, held, and processed in the liver, with little fructose circulating in the blood stream or delivered to peripheral tissues.

Absorbed glucose or that produced in the liver from fructose or other precursors is either metabolized in the liver or exported to the blood stream and further to extrahepatic tissues. Most absorbed fructose is cleaved in the liver into glyceraldehyde and dihydroxy acetone phosphate, and these trioses further go to glycerol phosphate and pyruvate metabolic pathways, respectively.

Lactate discharge is also a means for fructose carbons to escape the liver and be transported to peripheral tissues. Fructose cleavage to glyceraldehyde can result in the production of glycerol via reduction.

It was observed that blood glycerol concentration increased after fructose ingestion in exercise subjects[ 55 , 56 ]. The noted glycerol increases after fructose ingestion are either greater or similar compared with the values after glucose ingestion, and the produced glycerol can be oxidized for energy.

However, the metabolic balance between glycerol produced from fructose and central pathway trioses has not been clearly determined. Given the complexity and interdependencies of energy metabolism and biochemical synthesis arising from sugars, consideration of the flux of carbons among these pathways is critical to understanding the health consequences of consuming these nutrients.

Single sugar distribution and fluxes between pathways are not easily studied without isotopic labels. Classically, a limited number of metabolites are characterized in a study and some disposal points can be missed.

More recently, a computational technique is being employed utilizing. Nuclear Magnetic Resonance NMR or mass spectral analyses of the 13 C isotopomer distribution of metabolites, following administration of labeled precursors.

These precursors may be uniformly labeled compounds or labeled at specific carbons, depending on the question to be answered. An empirical metabolic flux analysis profile is generated which can be mathematically modeled without being constrained by physical chemistry rigor, as reviewed by Selivanoc and Lee[ 57 , 58 ].

This technique allows one to model metabolite fluxes which may not be well characterized or understood from direct enzymatic or physical chemistry data. A second method is under development to mathematically model general metabolism and interdependencies of pathways using known thermodynamic free energy and kinetic constant parameters for each reaction in the pathway sequences[ 59 ], but there is currently insufficient data to apply to fructose metabolism questions.

Each method has advantages and disadvantages, and likely the combination of both is needed for optimal predictive power. Metabolic differences among compartments and their interactions as a whole should be included. Experimentation should account for metabolome interactions, and study results should be interpreted carefully with respect to the experimental conditions employed.

Key points: 1 Fructose is observed to enter all the pathways of disposal as found for glucose glycolysis and the TCA cycle. The following reviews the data as presented in the papers. Thus, in discussing the disposal of fructose carbons, e. through oxidation, one cannot accurately distinguish if the labeled CO 2 arose directly from the fructose itself, or from fructose which had undergone conversion to neoformed glucose, neoformed lactate, or other neoformed compounds.

Where the conversions occur, these metabolites can be readily transported out of the liver to other tissues, altering the temporal appearance of metabolites.

Further complicating the analysis, some studies used fructose labeled with 13 C at different positions of its carbon backbone, uniformly labeled fructose, or 13 C naturally enriched fructose. The different labeling may also influence the appearance of the isotope tracer in various metabolites.

Using uniformly labeled fructose would limit the potential complications from different labeling positions on isotope tracer appearance in its metabolites.

Multiple studies have been conducted to observe how much fructose and other sugars can be oxidized following ingestion. In all, 19 relevant studies were found which met the inclusion criteria of this review.

Within the study monitoring periods, the ingested fructose was oxidized from The study by Chong and colleagues[ 48 ] showed fructose was oxidized faster than glucose This effect may be due to less regulation of phosphorylation for fructose or to a wider tissue distribution of glucose.

Oxidation rates increase as the dose increases but would be attenuated by its rate of absorption when intake amounts are large. Delarue et al. However, there is a difference in oxidation rates between normal and diabetic subjects, in that normal subjects could more efficiently oxidize fructose than type-2 diabetics The oxidized amounts of ingested fructose ranged from Except in one study[ 60 ] which showed that fructose and glucose had similar oxidation rates A very interesting phenomenon noted is that when fructose and glucose are ingested together including fructose-containing sucrose , the oxidation rates of the mixed sugars were faster than that of either one of them ingested alone at the same dosage.

Adopo et al. The series of studies by Jentjens and colleagues[ 66 — 69 ] also reported that fructose plus glucose or sucrose plus glucose consumed together were oxidized faster than glucose alone.

The data of obese or diabetic subjects are not included in this figure. In non-exercise subjects, the mean of the oxidized fructose amount was Under exercise conditions, this mean was When fructose and glucose are ingested in combination, either as fructose plus glucose, as sucrose, or as sucrose plus one of the 2 mono-sugars, the mean oxidized amount of the mixed sugars increased to The oxidation data of glucose alone is Also, the produced CO 2 from labeled sugar oxidation can arise directly from sugar molecules themselves, or other compounds converted from the sugars, such as glucose, lactate, or fatty acid from fructose.

Key points: 1 A significant amount of ingested fructose is oxidized by the body to produce energy. A potential consideration with these oxidation studies is that with shorter time frames of measurement or incomplete oxidation and with only partial labeling, position of the isotope label can influence the rate of appearance of the isotope in the exhaled carbon dioxide CO 2.

Temporal isotope appearance in CO 2 can be altered if some of the fructose carbons are not completely oxidized in the time frame of measurement due to diversion to non-oxidative pathways.

The disposal pathway for fructose is not solely by direct oxidation, as some absorbed fructose will be converted to glucose.

A number of studies have determined the extent of the conversion, which can only be clearly done using tracers. Tran and colleagues[ 70 ] studied the conversion of fructose to glucose as compared between men and women. After a 3 times ingestion of a fructose-containing beverage 3x0.

This value is significantly higher than the conversion rate of Similarly, using an equal fructose dosage, Paquot et al. However, the conversion proportion appeared to be lower in obese and diabetic subjects Surmely et al.

Under exercise conditions, Lecoultre et al. With repeated administration to achieve a high dose level and under exercise, Jandrian et al. This data is similar to that observed by Delarue et al. This conversion may be lower in women compared to men, and obese and diabetic subjects may also have lower conversion capability.

For the conversion from dietary fructose to glycogen, data are very limited. Nilsson et al. Another fructose infusion study non-exercise by Dirlewanger et al. Blom and colleagues[ 74 ] reported that dietary fructose could be about half as efficient as glucose or sucrose to replenish muscle glycogen after exercise.

In that study, healthy young subjects exhaustively exercised on bicycle ergometers, and ingested 0. The rates of glycogen synthesis in muscle corresponding to each sugar treatment were observed as 0.

The data indicate that energy status plays a role in how the body handles fructose distribution and conversion to glycogen. Although it was reported that a significant amount of fructose in the circulation could be used to produce glycogen in liver via first conversion to glucose, no isotope tracer studies were found to directly quantitate 13 C-carbons from dietary fructose incorporated into glycogen in humans.

Considering that most of absorbed fructose is extracted and metabolized in liver, the data from the fructose infusion studies noted above may not be representative for orally administered fructose.

Lastly, a number of studies using labeled glucose have examined how dietary fructose loads affect glucose production and disposal[ 76 — 78 ]. Results indicated that hepatic glucose production in normal subjects did not change[ 76 ], or had no effect on whole-body insulin-mediated glucose disposal[ 78 ].

Using a 2-step hyperinsulinemic euglycemic clamp, healthy offspring of Type 2 diabetics fed a high fructose diet exhibited higher fasting hepatic glucose levels compared to controls[ 77 ]. Key points: 1 Fructose is converted to glucose to variable extents, depending on exercise condition, gender, and health status.

This interconversion occurs at the triose phosphate intersection of the glucose-fructose pathways. And, 4 Fructose may be processed differently in obese population or population with higher diabetes risk. Another significant and perhaps underappreciated metabolic pathway of dietary fructose is its conversion to lactate.

It was also observed that sucrose ingestion also caused a higher blood lactate response than did glucose[ 67 , 81 ]. However, no detailed data were reported to clarify how much of the ingested fructose was converted into the lactate in these studies. Recently, Lecoultre et al.

The non-oxidative fructose disposal was 0. The rate of appearance of glucose from fructose conversion was However, the study did not indicate conversion percentage from the labeled fructose or glucose dosages.

Key points: 1 Clearly, a significant amount of fructose can be converted to lactate, but quantitative metabolic data of dietary fructose to lactate conversion is very limited. The effects of fructose dose, administration method, physical activity, and subject characteristics on fructose-lactate metabolism remain to be further studied.

A significant number of clinical studies have been performed to investigate the influence of fructose intake on blood triglyceride TG concentrations.

However, tracer studies aimed at revealing metabolic conversion from labeled fructose carbons to TG are extremely limited. In contrast to the conversion from fructose to glucose, the metabolic pathway from fructose to TG conversion can be much more complicated due to the complex distribution and diversity of blood lipid compositions in the body.

There are currently no convenient methods to quantitate overall DNL and intrahepatic lipid deposition. The fractional contribution of sugars to de novo lipogenesis and VLDL TG are commonly determined using tracer enrichment data of blood samples. The time periods of liver de novo lipogenesis from sugars and the factors influencing it are not completely understood, and are impacted by the concentrations and tracer characteristics of the various substrates drawn from lipid precursor pools.

De novo lipogenesis may also occur in adipose tissue or muscles, but there are no adequate methods available to quantitate it. A more expansive discussion of de novo lipogenesis and methodological considerations is an appropriate subject for a separate review. Perhaps because of these difficulties, only two tracer studies were found that investigated conversion of labeled dietary fructose carbons into plasma lipids.

Chong et al. Blood lipid changes were monitored in a 6-hour period. However, the concentration increases of 13 C-enriched TG-fatty acids and TG-glycerol from the labeled fructose in the S f 20— lipid fraction including VLDL were very small within the monitoring period.

The plateau value of 13 C-palmitate concentration was about 0. The authors indicated that the lipogenic potential of fructose seems to be small, since the results showed that only 0. The reported data should be viewed in the context of the 4-hour time period and whether further conversion would be observed at extended times was not illustrated.

It was observed by Vedala and colleagues[ 83 ], using labeled fatty acids, acetate and glycerol as precursors, that a meaningful portion of de novo synthesized triglyceride would appear in blood at later times, and rates of this delayed secretion were significantly different among normal, hypertriglyceridemic, and diabetic subjects.

However, this study did not specifically measure fructose conversion using labeled sugars. In another study, Tran et al. However, compared to baselines, plasma TG and non-esterified fatty acid concentrations decreased 5. The data indicate that the conversion from fructose to fatty acid occurred, however, no blood lipid concentrations increased.

Although the authors reported that This study also noted that men processed dietary fructose differently than women, and the given fructose lowered postprandial plasma lipids. It was discussed that although fructose is a potent lipogenic substrate, the observed fat synthesis arising from fructose carbons appeared to be quantitatively minor compared with other pathways of fructose disposal, but it may nevertheless have a significant impact on plasma and tissue lipids.

This data suggest that the increase of blood TG frequently observed in men compared to women after high dose fructose ingestion could be due to fat sparing during energy utilization. There are several studies which used labeled acetate, administered by intravenous infusion as a precursor of lipid synthesis, to assess the fructose stimulation of de novo lipogenesis DNL.

This technique uses the approach of Mass Isotopomer Distribution Analysis MIDA to estimate the infused subunit acetate appearance in newly synthesized fatty acids and further predict the effect of dietary fructose on fractional DNL.

The advantages and limitations of the method were well reviewed by Hellerstein in [ 84 ]. Parks et al. Four hours after fructose ingestion, a standard lunch was consumed. Compared to glucose, more palmitate synthesis in triglyceride-rich lipoprotein TRL TG was noted after fructose-containing drinks, but not after the lunch.

No significant differences were observed for TRL-TG concentrations between glucose and fructose-containing drink arms after baseline correction.

Plasma TG concentration was decreased after glucose preload and stayed constant after fructose-containing drink preloads. Following the lunch, TG concentrations increased for all treatments. The authors reported that the after lunch TG-AUC data from fructose-containing drink treatments were significantly larger than that of glucose drink treatment.

However, this AUC data was calculated over the entire study time period. Due to the negative TG rise during the glucose preload phase, the difference between the glucose and fructose arms was accentuated.

The percent changes of fractional hepatic DNL were not significantly different from baseline following 9-week glucose consumption for both fasting and postprandial measurements.

The actual amount of the DNL was not reported. Faeh et al. conducted a shorter term crossover study using a 6-day intervention[ 78 ].

Fractional hepatic DNL was measured via 13 C-labeled acetate infusion. The authors noted that the results could not truly differentiate the effects of the high-fructose intake per se and that of the total carbohydrate energy overfeeding.

This study also found that fish oil added to the diets containing fructose attenuated this hyperlipidemic response somewhat[ 78 ]. Clearly, the 3 studies discussed above[ 78 , 85 , 86 ] assess effects of dietary fructose with or without over energy intakes on the utilization of acetate in the circulation, which is designed to feed directly into lipid synthesis.

In humans, acetate concentrations in blood are fairly low. As indicated in the Human Metablome Database[ 87 ], normal blood concentrations of acetate are For earlier data, Richards et al.

Beyond alcohol consumption, common dietary intakes have no or limited influence on blood acetate concentration[ 89 , 90 ]. In the studies of Parks, Stanhope, and Faeh, acetate was constantly infused at 0. Although the data of blood acetate concentration were not reported in those studies, it would be important to determine whether the acetate infusion significantly raised blood acetate concentrations such that this could have a meaningful impact on metabolic response to the fructose challenge.

The coexistence of the infused acetate and intermediate metabolites of fructose, including regulatory elements of citrate, malate, and lactate, could prime the pathway of DNL. Thus, the meaning of stimulation of de novo lipogenesis observed from use of infused intermediate metabolite tracer and its interaction with the sugars studied should be considered carefully, along with the study methodologies being validated for the dosage of infused tracer.

Additionally, how the infused acetate can truly represent intrahepatocellular acetyl-CoA pool is another key point to be clarified. Key points: 1 The above tracer studies indicate the complex relationship between dietary fructose and lipid synthesis.

The observed increases in plasma TG and DNL in these studies can arise from both increased lipid synthesis and decreased lipid clearance, and the relative contributions were not addressed in any detail.

And, 2 The intake levels, health status, and gender of subjects are all important factors influencing sugar-lipid relationships. The influence of fructose consumption on plasma lipids and de novo lipogenesis remains controversial and understudied.

After sugar ingestion, body utilization of energy sources will change. As exogenous carbohydrate is used as a fuel source, the oxidation rates of stored energy, typically, endogenous carbohydrates and fat, will decrease.

The extent of the decrease is usually driven by ingested sugar type, intake amount, and status of body energy need such as vigorous exercise or screen watching. Under exercise, glucose is more likely to be preferentially oxidized than fructose, and this scenario will go in the opposite direction under a resting state.

Although data are limited related to detailed shifting of energy sources under different conditions, some studies using subjects under exercise may provide a basic concept of energy source shifting after sugar ingestion.

Jentjens and colleagues conducted a series of studies[ 66 — 69 , 80 ] using exercise subjects under somewhat comparable conditions, and reported some data related to the energy source shifting.

For controls 0 gram of sugar intake , the oxidation rates of fat and endogenous carbohydrate were between 0. Compared to the control, glucose-containing drinks decreased fat oxidation rates by However, this is still a contentious issue.

Dietary fructose is not well absorbed and increased dietary intake often results in malabsorption. Whether or not sufficient amounts of dietary fructose could be absorbed to cause a significant reduction in phosphorylating potential in liver cells remains questionable and there are no clear examples of this in the literature.

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Main article: Essential fructosuria. Main article: Hereditary fructose intolerance. Carbohydrate Metabolism: synthesis and Oxidation. Missouri: Saunders, Elsevier. doi : ISSN PMC PMID Adv Nutr. Biochemistry 5th ed. ISBN OCLC ISSN X. AJP: Endocrinology and Metabolism. Skeletal Muscle Metabolism in Exercise and Diabetes.

Advances in Experimental Medicine and Biology. Biochemical Journal. Robin Subcellular Biochemistry: Biochemistry and Biochemical Cell Biology. Sugars and sweeteners.

Boca Raton: CRC Press. ISBN X. In Saudubray J, van den Berghe G, Walter JH eds. Inborn Metabolic Diseases: Diagnosis and Treatment 5th ed. New York: Springer. Retrieved 11 April National Organization for Rare Disorders. Retrieved 1 November Wikimedia Commons has media related to Fructolysis.

Metabolism , catabolism , anabolism. Metabolic pathway Metabolic network Primary nutritional groups. Purine metabolism Nucleotide salvage Pyrimidine metabolism Purine nucleotide cycle. Pentose phosphate pathway Fructolysis Polyol pathway Galactolysis Leloir pathway.