D-fructose Metabolism Research Articles

Growth inhibitory effect of D-arabinose against the nematode Caenorhabditis elegans: Discovery of a novel bioactive monosaccharide.

Biological activities of unusual monosaccharides (rare sugars) have largely remained unstudied until recently. We compared the growth inhibitory effects of aldohexose stereoisomers against the animal model Caenorhabditis elegans cultured in monoxenic conditions with Escherichia coli as food. Among these stereoisomers, the rare sugar D-arabinose (D-Ara) showed particularly strong growth inhibition. The IC50 value for D-Ara was estimated to be 7.5 mM, which surpassed that of the potent glycolytic inhibitor 2-deoxy-D-glucose (19.5 mM) used as a positive control. The inhibitory effect of D-Ara was also observed in animals cultured in axenic conditions using a chemically defined medium; this excluded the possible influence of E. coli. To our knowledge, this is the first report of biological activity of D-Ara. The D-Ara-induced inhibition was recovered by adding either D-ribose or D-fructose, but not D-glucose. These findings suggest that the inhibition could be induced by multiple mechanisms, for example, disturbance of D-ribose and D-fructose metabolism.

Anomeric Specificity of the Stimulatory Effect ofd-Glucose on d-Fructose Phosphorylation by Human Liver Glucokinase

D-Glucose was recently reported to stimulate d-fructose phosphorylation by human B-cell glucokinase. The present study aims at investigating the anomeric specificity of such a positive cooperativity. The alpha-anomer of D-glucose was found to increase much more markedly than beta-D-glucose the phosphorylation of D-fructose by human liver glucokinase. Such an anomeric preference diminished at high concentrations of the D-glucose anomers, i.e. when the effect of the aldohexose upon d-fructose phosphorylation became progressively less marked. A comparison between the effects of the two anomers of D-glucose and those of equilibrated D-glucose upon D-fructose phosphorylation by human liver glucokinase indicated that the results obtained with the equilibrated aldohexose were not significantly different from those expected from the combined effects of each anomers of D-glucose. In isolated rat islets incubated for 60 min at 4 degrees C, alpha-D-glucose (5.6 mm), but not beta-D-glucose (also 5.6 mm), augmented significantly the conversion of D-[U-(14)C]fructose (5.0 mm) to acidic radioactive metabolites. Likewise, in islets prelabeled with (45)Ca and perifused at 37 degrees C, D-fructose (20.0 mm) augmented (45)Ca efflux and provoked a biphasic stimulation of insulin release from islets exposed to alpha-D-glucose (5.6 mm), while inhibiting (45)Ca efflux and causing only a sluggish and modest increase in insulin output from islets exposed to beta-D-glucose (also 5.6 mm). The enhancing action of D-glucose upon D-fructose phosphorylation by glucokinase thus displays an obvious anomeric preference for alpha-D-glucose, and such an anomeric specificity remains operative in intact pancreatic islets.

Metabolism of [formula omitted]-[1-13C]Fructose, [formula omitted]-[2-13C]Fructose, and [formula omitted]-[6-13C]Fructose in Rat Hepatocytes Incubated in the Presence of H2O or D2O

Isolated hepatocytes from fed rats were exposed for 120 min to d-[1-13C]fructose, d-[2-13C]fructose, or d-[6-13C]fructose in the presence of H2O or D2O. The identification and quantification of 13C-enriched metabolites (d-glucose, l-lactate) in the incubation medium and the measurement of their deuterated isotopomers indicated that the ketohexose was phosphorylated predominantly at the intervention of fructokinase and that the majority of the d-glyceraldehyde molecules generated from d-fructose 1-phosphate were further metabolized, e.g., after phosphorylation to d-glyceraldehyde 3-phosphate. It is proposed that the present procedure may help to further characterize the regulation of d-fructose metabolism in both hepatocytes and other cell types.

Effects of D-glucose upon D-fructose metabolism in rat hepatocytes: A 13C NMR study.

Isolated hepatocytes from fed rats were exposed for 120 min to D-glucose (10 mM) and either D-[1-13C]fructose, D-[2-13C]fructose or D-[6-13C]fructose (also 10 mM) in the presence of D2O. The identification and quantification of 13C-enriched D-fructose and its metabolites (D-glucose, L-lactate, L-alanine) in the incubation medium and the measurement of their deuterated isotopomers indicated, by comparison with a prior study conducted in the absence of exogenous D-glucose, that the major effects of the aldohexose were to increase the recovery of 13C-enriched D-fructose, decrease the production of 13C-enriched D-glucose, restrict the deuteration of the 13C-enriched isotopomers of D-glucose to those generated by cells exposed to D-[2-13C]fructose, and to accentuate the lesser deuteration of the C, (as compared to C5) of 13C-enriched D-glucose derived from D-[2-13C]fructose. The ratio between C2-deuterated and C2-hydrogenated L-lactate, as well as the relative amounts of the CH3-, CH2D-, CHD, and CD3- isotopomers of 13C-enriched L-lactate were not significantly different, however, in the absence or presence of exogenous D-glucose. These findings indicate that exogenous D-glucose suppressed the deuteration of the C1 of D-[I-13C]glucose generated by hepatocytes exposed to D-[1-13C]fructose or D-[6-13C]fructose, as otherwise attributable, in part at least, to gluconeogenesis from fructose-derived [3-13C]pyruvate, and apparently favoured the phosphorylation of D-fructose by hexokinase isoenzymes, probably through stimulation of D-fructose phosphorylation by glucokinase.

Metabolic and secretory interactions between D-glucose and D-fructose in islets from GK rats.

The metabolism of D-glucose and/or D-fructose was investigated in both pancreatic islets and parotid cells of control and hereditarily diabetic Goto-Kakizaki (GK) rats. In the islets from GK rats, a preferential alteration of the oxidative response to D-glucose coincided with an impaired secretory response to the aldohexose. Such a metabolic alteration was not found in the parotid cells of GK rats. Whether in islet or parotid cells, D-fructose little affected the catabolism of glucose in either control or GK rats. The metabolism of D-fructose and the effect of D-glucose thereupon were essentially comparable in control and GK rats in both pancreatic islets and parotid cells. In both cell types, the comparison between the metabolism of D-glucose and D-fructose in cells simultaneously exposed to the two hexoses suggested a far from negligible contribution of fructokinase to the phosphorylation of D-fructose. Although the catabolism of the ketohexose and its modulation by D-glucose were closely comparable in islets from control and GK rats, the insulinotropic action of the ketohexose, relative to that of the aldohexose, was severely impaired in the GK rats. The present work thus emphasizes the specificity of the alteration in D-glucose metabolism in islets, as opposed to extrapancreatic cells, of GK rats. It also reveals in the islets of GK rats a further secretory anomaly apparently not attributable to the impairment of nutrient catabolism in the islet cells of these diabetic animals.

Metabolic and Secretory Interactions between D-Glucose and D-Fructose in Islets from GK Rats

The metabolism of d-glucose and/or d-fructose was investigated in both pancreatic islets and parotid cells of control and hereditarily diabetic Goto-Kakizaki (GK) rats. In the islets from GK rats, a preferential alteration of the oxidative response to d-glucose coincided with an impaired secretory response to the aldohexose. Such a metabolic alteration was not found in the parotid cells of GK rats. Whether in islet or parotid cells, d-fructose little affected the catabolism of glucose in either control or GK rats. The metabolism of d-fructose and the effect of d-glucose thereupon were essentially comparable in control and GK rats in both pancreatic islets and parotid cells. In both cell types, the comparison between the metabolism of d-glucose and d-fructose in cells simultaneously exposed to the two hexoses suggested a far from negligible contribution of fructokinase to the phosphorylation of d-fructose. Although the catabolism of the ketohexose and its modulation by d-glucose were closely comparable in islets from control and GK rats, the insulinotropic action of the ketohexose, relative to that of the aldohexose, was severely impaired in the GK rats. The present work thus emphasizes the specificity of the alteration in d-glucose metabolism in islets, as opposed to extrapancreatic cells, of GK rats. It also reveals in the islets of GK rats a further secretory anomaly apparently not attributable to the impairment of nutrient catabolism in the islet cells of these diabetic animals.

Double purification of radiolabelled d-fructose by high-performance liquid chromatography for tracing its metabolism

This paper describes the microsynthesis and the purification of various 14C- or 3H-labelled tracers of d-fructose. These tracers were prepared from the corresponding 14C- or 3H-tracers of d-glucose by interconversion in alkaline media, and then purified by HPLC using a carbohydrate column constituted of a calcium-loaded sulfonated polymer. This work also documents that the purification step is essential to investigate in a reliable manner the metabolism of d-fructose in isolated rat pancreatic islets.

Hexose metabolism in pancreatic islets: effect of D-glucose upon D-fructose metabolism.

In the light of recent findings on the effect of D-glucose upon D-fructose phosphorylation by human B-cell glucokinase, the influence of the aldohexose upon the metabolism of the ketohexose was investigated in rat pancreatic islets. D-glucose, although slightly decreasing D-[5-(3)H]fructose utilization, augmented the oxidation of the ketohexose, indicating that the aldohexose stimulates preferentially the oxidative, as distinct from anaerobic, modality of glycolysis. Such was not the case in parotid cells, taken as representative of functionally nonglucose-responsive cells. In the islets exposed to D-fructose, D-glucose also decreased the fractional contribution of the pentose shunt to the generation of CO2 and D-glyceraldehyde 3-phosphate from the ketohexose, and increased the inflow into the Krebs cycle of dicarboxylic metabolites relative to that of fructose-derived acetyl-CoA. This glucose-induced remodeling of D-fructose metabolism may optimize the insulin secretory response of islet cells to these hexoses, e.g. after food intake.

Radiosynthesis, rodent biodistribution, and metabolism of 1-deoxy-1-[ 18F]fluoro- d-fructose

Fluorine-18 labeled analog of d-fructose, 1-deoxy-1-[ 18F]fluoro- d-fructose (1-[ 18F]FDFrc), was synthesized by nucleophilic substitution of [ 18F]fluoride ion and the effect of the fluorine substitution on its in vivo metabolism was investigated. The tissue distributions of 1-[ 18F]FDFrc in rats and tumor bearing mice showed initial high uptake and subsequent rapid washout of the radioactivity in the principal sites of d-fructose metabolism (kidneys, liver and small intestine). The uptakes in the brain and tumor (fibrosarcoma) were the lowest and moderate, respectively, but tended to increase with time. The in vivo metabolic studies of 1-[ 18F]FDFrc and nonradioactive 1-FDFrc in mouse brain and tumor showed that the fluorinated analog remained unmetabolized in these tissues, indicating that the substitution of fluorine at the C-1 position produces a nonmetabolizable analog of d-fructose. Thus, 1-[ 18F]FDFrc had no features of a metabolic trapping tracer without showing any appreciable organ or tumor specific localization.

Unusual fructose utilization by Pichia stipitis and its potential application

The pentose-fermenting yeast Pichia stipitis was recently found to metabolize d-fructose poorly in the presence of d-xylose. In a survey of strains from 17 other Pichia species growing in a xylose/fructose mixture, only P. abadieae displayed a pattern of sugar utilization similar to P. stipitis in that the pentose was consumed preferentially over d-fructose. However, poor or incomplete d-fructose utilization was found with several species. The question was raised whether such a property may be useful for d-fructose enrichment in a glucose/fructose mixture. Among the species which utilized d-fructose incompletely, P. stipitis strains showed the best potential in this regard, as it rapidly consumed d-glucose with the production of ethanol, while d-fructose remained unused. Cell extracts of P. stipitis possessed d-fructose-phosphorylating activity. Therefore, the site responsible for poor d-fructose metabolism was postulated to be d-fructose transport.

Differential fructose effect in Pachysolen tannophilus and Pichia stipitis

The yeasts Pachysolen tannophilus and Pichia stipitis differed in their ability to utilize D-xylose in the presence of D-fructose. When P. tannophilus was grown aerobically in fructose-xylose mixture, the ketohexose was utilized preferentially over the pentose. However, in P. stipitis cultures, the converse was observed. The effect was associated with the ability of D-fructose to repress the induction of xylose reductase and xylitol dehydrogenase activities in P. tannophilus but not in P. stipitis. Both yeasts grew on D-fructose and fermented it to ethanol when it was supplied as the sole carbon source. The results suggest that there may exist some fundamental difference in the regulation of D-fructose metabolism between P. tannophilus and P. stipitis.

Hexose metabolism in pancreatic islets: Metabolic and secretory responses to d-fructose

d-Fructose (3.3 to 33.0 mmol/liter) caused a concentration-related increase in insulin output from rat islets exposed to d-glucose (3.3 to 7.0 mmol/liter), such an increase not being more marked in mouse islets. The fructose-induced increment in insulin release, relative to that evoked by d-glucose, was two times higher in islets exposed to d-glucose than in islets stimulated by d-mannose, 2-ketoisocaproate, or nonnutrient secretagogs. Likewise, the metabolism of d-fructose in islet cells was significantly different in the absence or presence of d-glucose. Thus, the ketose was largely channeled into the pentose phosphate pathway in glucose-deprived, but not so in glucose-stimulated, islets. In both glucose-deprived and glucose-stimulated islets, however, the magnitude of the secretory response to d-fructose was commensurate with the increase in ATP production attributable to its catabolism. These findings indicate that the metabolic fate of hexoses—and, hence, their insulinotropic capacity—is not ruled solely at the level of their phosphorylation.

Nutritional significance of fructose and sugar alcohols.

Human metabolism of D-fructose, D-sorbitol, D-mannitol, and xylitol has been documented. In humans, sorbitol and xylitol at a single oral dose of 20 g or less and fructose at 70 g or less most likely can be fully absorbed. These there sugars can maintain, either independently or nearly independently, the integrity or the carbohydrate requirement for the growth of cells and animals. The absorption of D-mannitol is no more than 80% and is more laxative. In general, there is no adverse effect other than osmotic diarrhea after oral administration of these sugars. Transient hyperuricemia was seen in some humans. The chronic toxicity of life-long usage of these sugars in humans or other primates is not known. However, a 2-year Turku sugar studies suggested the safety of fructose and xylitol. Two-year feeding experiments in mice and rats indicated possible carcinogenicity of a high-percentage xylitol diet. Abnormalities of cellular growth were also documented in animals fed high percentages of sorbitol and sucrose. Long-term mannitol feeding experiments also revealed an increased incidence of benign thymic tumors in rats. Intravenous feeding of fructose, xylitol, and sorbitol causes major concern. The toxicity is total-dose and infusion-rate dependent. The physical toxicity induced by hyperosmolar effect of the concentrated infusion solutions can be lethal. The primary metabolic toxicities, mainly lactic acidosis and hypruricemia, are reversible. The suggested safe infusion rate of these sugars is 0.25 g/kg/h; sporadic toxic observations have been reported at this or lower doses (0.125 g/kg/h). The combination of glucose, fructose, xylitol, and sorbitol mixture intravenously is in use in Europe due to the critical threshold of each element. There are positive findings from the use of the combination in human illness (114). The beneficial effect of xylitol, mannitol, sorbitol, and fructose in decreasing order has been well documented in the prevention of dental caries in animals and in humans. Oral organisms do not appear to metabolically adapt to xylitol even after 4 years of in vivo exposure. This was based on the quantitation of xylitol dehydrogenase activity in saliva and oral organisms. In addition, a therapeutic and preventive effect for xylitol in human and animal dental caries has been demonstrated. There appears to be at least a theoretical edge in the dietary use of fructose, xylitol, and sorbitol in diabetics.(ABSTRACT TRUNCATED AT 400 WORDS)

ChemInform Abstract: METABOLISM OF D‐FRUCTOSE

Chemischer InformationsdienstVolume 9, Issue 37 Reviews ChemInform Abstract: METABOLISM OF D-FRUCTOSE M. CHEN, M. CHENSearch for more papers by this authorR. L. WHISTLER, R. L. WHISTLERSearch for more papers by this author M. CHEN, M. CHENSearch for more papers by this authorR. L. WHISTLER, R. L. WHISTLERSearch for more papers by this author First published: September 12, 1978 https://doi.org/10.1002/chin.197837374Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume9, Issue37September 12, 1978 RelatedInformation

Metabolism of D-fructose by Arthrobacter pyridinolis.

Previous studies showed that Arthrobacter pyridinolis can transport and utilize d-glucose only after prior growth on certain Krebs cycle intermediates. In contrast, we found that d-fructose was taken up and metabolized by A. pyridinolis without special prior conditions of growth. d-Fructose was first converted to d-fructose-1-phosphate by a phosphoenolpyruvate (PEP):D-fructose phosphotransferase. This activity required both supernatant and pellet fractions from d-fructose-grown cells centrifuged at 150,000 x g. The d-fructose-1-phosphate formed was converted to d-fructose-1, 6-diphosphate. Mutants deficient in PEP:d-fructose phosphotransferase and d-fructose-1-phosphate kinase, or d-fructose-1, 6-diphosphatase (FDPase) were unable to grow on d-fructose but retained the normal ability to use d-glucose. Mutants forming reduced amounts of FDPase were completely unable to grow on d-fructose but were still capable of limited growth on Krebs cycle intermediates. A requirement for higher levels of FDPase for growth on d-fructose than for growth on Krebs cycle intermediates was also indicated by the higher specific activities of FDPase in d-fructose-grown cells than in cells grown on l-malate or amino acids.

D-Fructose 1-Phosphate Kinase, a New Enzyme Instrumental in the Metabolism of d-Fructose

Abstract An inducible enzyme which phosphorylates d-fructose 1-phosphate with adenosine triphosphate to yield d-fructose 1,6-diphosphate has been identified and partially purified from extracts of d-fructose-grown Aerobacter aerogenes PRL-R3. Evidence is cited which supports the participation of this enzyme in d-fructose metabolism in this organism.

Some Aspects of d-Fructose Metabolism in Rat Liver

Some Aspects of d-Fructose Metabolism in Rat Liver