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At least 19 recordsLinked to original sources
PubMed2001

Uptake of D-mannoheptulose by normal and tumoral pancreatic islet cells.

D-mannoheptulose was recently proposed as a possible tool to label preferentially insulin-producing cells in the pancreatic gland. In the present study, D-[3H]-mannoheptulose uptake by rat pancreatic islets or dispersed islet cells was found to represent a time-related and temperature-sensitive process inhibited by cytochalasin B. This mould metabolite also inhibited the efflux of D-[3H]-mannoheptulose from prelabelled islets. After 60 min incubation at 37 degrees C, the apparent intracellular distribution space of the tritiated heptose was close to or somewhat higher than that of D-[5-3H]glucose and close to 50% of the intracellular 3HOH space. It was further enhanced by D-glucose and a high concentration of 10 mM of D-mannoheptulose. The uptake of D-[3H]mannoheptulose was much lower however than that of D-[3H]mannoheptulose hexaacetate. As judged from the fate of D-mannoheptulose hexa[2-14C]acetate, the latter ester was efficiently hydrolyzed in the islet cells. The internalization of D-[3H]mannoheptulose (or its ester) coincided with the generation of tritiated acidic metabolites, reflecting phosphorylation of the heptose. The situation found in normal islet cells sharply differed from that found in tumoral islet cells of either the RINm5F or INS-1 line, in which the apparent distribution space of D-[3H]mannoheptulose represented only about 3 and 9%, respectively, of the intracellular 3HOH space. These results indicate that the entry of D-mannoheptulose into islet cells represents a carrier-mediated process, possibly mediated at the intervention of GLUT2 and, hence, provide further support to the possible use of a suitable D-mannoheptulose analog as a tool for the preferential labelling of insulin-producing cells in the pancreatic gland.

Animals↗
PubMed2000

Effects of D-mannoheptulose and its hexaacetate ester on hormonal secretion from the perfused pancreas.

D-mannoheptulose was recently proposed to be transported into cells by GLUT2, whereas its hexaacetate ester may cross the plasma membrane without requiring the intervention of a specific carrier system. In the light of these proposals, the effects of unesterified D-mannoheptulose and D-mannoheptulose hexaacetate upon hormonal secretion by the perfused rat pancreas were now investigated. Unesterified D-mannoheptulose (1.7 mM) inhibited insulin release and, in most cases, somatostatin output, whereas it augmented glucagon secretion by pancreases exposed to D-glucose (3.3 mM) in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM). The heptose failed, however, to affect hormonal secretion in the sole presence of SAD. D-mannoheptulose hexaacetate (also 1.7 mM) reproduced, within limits, the effects of unesterified D-mannoheptulose in pancreases exposed to both D-glucose and SAD. In addition, however, the ester displayed a positive effect upon the secretion of the three hormones, even in the sole presence of SAD. These findings support the view that monosaccharide esters may affect the secretion of pancreatic hormones in a dual manner, linked to both the metabolic response to their glucidic moiety and a direct effect of the ester itself. Moreover, they reveal that unesterified D-mannoheptulose is able to antagonize the effect of D-glucose upon hormonal secretion even in cells claimed not to contain GLUT2. The modality by which D-mannoheptulose apparently gains access to the cytosol of these cells remains to be elucidated.

Analysis of Variance↗
PubMed1999

Environmental modulation of the inhibitory action of D-mannoheptulose upon D-glucose metabolism in isolated rat pancreatic islets.

In pancreatic islets prepared from fed rats and incubated at a low concentration (1.7 mM) of D-glucose, D-mannoheptulose (10.0 mM) virtually fails to affect the metabolism of the hexose. Likewise, in islets from starved rats, the relative extent of the inhibitory action of D-mannoheptulose upon D-glucose metabolism is much more marked at high (16.7 mM) than low (1.7 mM) hexose concentration. Nevertheless, despite decreasing the metabolism of D-glucose, starvation augments the sensitivity to D-mannoheptulose in the islets incubated at a low concentration of the hexose, D-galactose, but not D-fructose, also augments the inhibitory action of D-mannoheptulose upon D-glucose metabolism in islets prepared from fed rats and exposed to the low concentration of D-glucose. A comparable situation prevails in islets exposed to 2-ketoisocaproate. Forskolin, however, which decreases D-glucose catabolism in the islets from fed rats exposed to 1.7 mM D-glucose, fails to affect significantly the inhibitory action of D-mannoheptulose on D-glucose metabolism. It is proposed that hexoses transported by the same carrier as D-glucose and non-glucidic nutrient secretagogues somehow increase D-mannoheptulose uptake by the islet cells. The latter two conditions may be operative in islets exposed to a high concentration of D-glucose, this accounting for the exquisite sensitivity to D-mannoheptulose of glucose-stimulated islets.

Animals↗
PubMed1998

Comparison of the effects of D-mannoheptulose and its hexaacetate ester on D-glucose metabolism and insulinotropic action in rat pancreatic islets.

It was recently, and surprisingly, found that D-mannoheptulose did not affect D-glucose metabolism and insulinotropic action in pancreatic islets incubated at a low concentration of D-glucose. To explain this finding, the metabolism and secretory response to the hexose were investigated in rat islets exposed to D-mannoheptulose hexaacetate, which was recently found to inhibit D-glucose catabolism in cells that are otherwise fully resistant to the heptose. At a high concentration of D-glucose (16.7 mmol/l), the utilisation of D-[5-(3)H]glucose and oxidation of D-[U-14C]glucose, as well as the insulinotropic action of the hexose, were affected less by D-mannoheptulose tetraacetate than by unesterified D-mannoheptulose. This coincided with a reduced uptake of the ester by intact islets and a lower rate of hydrolysis of the ester in islet homogenates compared with findings in other monosaccharide esters such as D-glucose pentaacetate. At a low concentration of D-glucose (2.8 mmol/l), D-mannoheptulose hexaacetate was slightly more efficient than the unesterified heptose in reducing D-glucose catabolism, but still failed to suppress the secretory response to the hexose. These findings do not necessarily mean that unesterified D-mannoheptulose enters beta-cells more efficiently at high than at low extracellular D-glucose concentrations, especially if possible differences in the respective contributions of distinct islet cell types to the overall catabolism of D-glucose by whole islets is allowed for. These data do not rule out the possibility that D-glucose phosphorylation is more resistant to D-mannoheptulose in beta cells incubated at a low than a high concentration, independently of any difference in the intracellular concentration of the heptose. However, the mechanism of this resistance is still not explained.

Animals↗
PubMed2001

Effects of D-mannoheptulose upon D-glucose metabolism in tumoral pancreatic islet cells.

D-[3H]mannoheptulose was recently reported to be poorly taken up by tumoral pancreatic islet cells of the RINm5F and INS-1 lines. We have now investigated the effects of D-mannoheptulose upon D-glucose metabolism in these two cell lines. D-mannoheptulose (1.0-10.0 mM) only caused a minor decrease of D-glucose metabolism in RINm5F cells, whether at low (1.1 mM) or higher (8.3 mM) D-glucose concentration. A comparable situation was found in INS-1 cells examined after more than 20 passages. In both cases, however, the hexaacetate ester of D-mannoheptulose (5.0 mM) efficiently inhibited D-glucose metabolism. In the INS-1 cells, the relative extent of the inhibitory action of D-mannoheptulose upon D-glucose metabolism increased from 12.4 +/- 2.6 to 38.3 +/- 3.8% as the number of passages was decreased from more than 20 to 13-15 passages, the latter percentage remaining lower, however, than that recorded in INS-I cells also examined after 13-15 passages but exposed to D-mannoheptulose hexaacetate (66.9 +/- 2.2%). These findings when compared to our recent measurements of D-[3H]mannoheptulose uptake, reinforce the view that the entry of the heptose into cells and, hence, its inhibitory action on D-glucose metabolism are dictated by expression of the GLUT2 gene.

Animals↗
PubMed2000

Impairment by cytochalasin B of the inhibitory action of D-mannoheptulose upon D-glucose metabolism in rat pancreatic islets.

D-mannoheptulose was recently found to inhibit D-glucose metabolism in hepatocytes and pancreatic islets, whilst failing to do so in parotid cells, erythrocytes and the exocrine pancreas. In the latter three systems, however, the hexaacetate ester of D-mannoheptulose efficiently inhibits D-glucose metabolism. It was proposed, therefore, that the transport of unesterified D-mannoheptulose into cells may be mediated by GLUT2. Since cytochalasin B is known to inhibit D-glucose transport into pancreatic islet cells, it was now investigated whether the mould metabolite (0.02 mM) also impairs the inhibitory action of D-mannoheptulose (1.0 mM) upon D-glucose metabolism in rat pancreatic islets. The relative extent of D-mannoheptulose inhibitory action on D-[5-3H]glucose utilization and D-[U-14C]glucose conversion to 14CO2, as well as radioactive amino acids and acidic metabolites, was indeed much less marked in the presence of cytochalasin B (13+/-4% inhibition) than in its absence (40+/-3% inhibition). A comparable situation was not observed, however, in the case of glucose-stimulated insulin secretion, cytochalasin B augmenting insulin output to the same relative extent in the absence or presence of D-mannoheptulose. These findings support the view that the entry of D-mannoheptulose into cells may be mediated by a cytochalasin B-sensitive transport system, such as the GLUT2 carrier.

Animals↗
PubMed2001

Uptake of D-mannoheptulose by rat erythrocytes, hepatocytes and parotid cells.

D-[3H]mannoheptulose (or D-[1-14C] mannoheptulose) net uptake was measured in rat erythrocytes, parotid cells and hepatocytes. In the erythrocytes and parotid cells, the intracellular distribution space of the heptose (0.1 mM) represented only about 1 and 13%, respectively, of the intracellular 3HOH space. In hepatocytes, however, it amounted to approximately 45% of the intracellular 3HOH space. In all cases, the apparent distribution space of D-[3H]mannoheptulose hexaacetate largely exceeded that of unesterified D-[3H]mannoheptulose. Relative to the intracellular water space, the generation of acidic metabolites (expressed as an apparent distribution space) from radioactive D-mannoheptulose was one order of magnitude lower in parotid cells (< or = 3%) than in hepatocytes (> or = 20%). These findings are compatible with the hypothesis that D-mannoheptulose is transported into cells mainly, if not exclusively, at the intervention of GLUT2.

Animals↗
PubMed2002

Effects of D-mannoheptulose upon D-glucose metabolism in pancreatic B and non-B islet cells.

D-mannoheptulose was recently proposed to be transported into cells mainly at the intervention of GLUT2. In the present study, the heptose (10 mM) decreased the steady state content of dispersed rat pancreatic islet cells in D-[U-(14)C]glucose, and inhibited to a greater relative extent the utilization of D-[5-(3)H]glucose, the oxidation of D-[U-(14)C]-glucose and its conversion to radioactive amino acid when the dispersed islet cells were incubated at 16.7 mM rather than 2.8 mM D-glucose. A comparable situation was found in purified islet B-cells, whereas D-mannoheptulose only exerted minor to negligible effects upon the metabolism of D-glucose in non-B islet cells. This coincided with a much higher uptake of D-[(3)H]mannoheptulose by B, as distinct from non-B, islet cells. These findings indicate that the unexpectedly greater relative inhibitory action of D-mannoheptulose upon D-glucose metabolism by isolated islets (or dispersed islet cells) observed at high rather than low hexose concentration cannot be accounted for solely by differences in the relative contribution of non-B cells to total D-glucose metabolism by islets incubated at increasing concentrations of D-glucose. A comparable metabolic response to D-mannoheptulose is indeed observed in purified B cells. It could be attributable, in part at least, to D-glucose and D-mannoheptulose countertransport, resulting inter alia in a greater net uptake of the heptose by B cells exposed to a high concentration of the hexose.

Animals↗
PubMed2001

Pancreatic fate of D-[3H] mannoheptulose.

D-Mannoheptulose was recently postulated to be transported into cells by GLUT2. The validity of such an hypothesis was assessed by comparing the uptake of tritiated D-mannoheptulose by pancreatic islets versus pieces of pancreas and, in the latter case, by comparing results obtained in control rats versus animals injected with streptozotocin (STZ). The uptake of D-[3H] mannoheptulose by islets represents a time-related and temperature-sensitive process, inhibited by cytochalasin B and enhanced by D-glucose. The uptake of the tritiated heptose was much lower in pieces of pancreatic tissue and inhibited by D-glucose, at least in the STZ rats. Whether in pieces of pancreas exposed in vitro to D-[3H] mannoheptulose or after intravenous injection of the tritiated heptose, the radioactive content of the pancreatic tissue was lower in STZ rats than in control animals. This contrasted with an unaltered radioactive content of liver and muscle in the STZ rats, at least when treated with insulin. Suitably radiolabelled D-mannoheptulose or an analogue of the heptose could thus conceivably be used for quantification of the endocrine pancreatic mass.

Animals↗
PubMed2000

D-mannoheptulose uptake and its metabolic and secretory effects in human pancreatic islets.

D-mannoheptulose was recently proposed to be transported into cells at the intervention of GLUT2. Since GLUT1, rather than GLUT2, represents the major carrier system for the transport of monosaccharides across the islet B-cell plasma membrane in human subjects, the uptake of D-mannoheptulose and its metabolic and secretory effects were investigated in human islets. The uptake of D-glucose reached much more rapidly a close-to-equilibrium value in isolated islets than in pieces of pancreas obtained from the same donor. The distribution space of D-[3H]mannoheptulose in the human islets largely exceeded that of [U-14C]sucrose, considered as an extracellular marker, and did not differ significantly from that of 3HOH. In the human islets, the heptose (10.0 mM) inhibited both D-[5-3H]glucose utilization and D-[U-14C] glucose oxidation, and decreased glucose-stimulated insulin release to the same extent as D-mannoheptulose hexaacetate. These findings indicate that a suitable radioactive analog of D-mannoheptulose could be used, in human like in rat islets, for preferential labelling of the endocrine moiety of the pancreatic gland.

Carbon Radioisotopes↗
PubMed2001

D-mannoheptulose phosphorylation by hexokinase isoenzymes.

D-mannoheptulose is a specific inhibitor of D-glucose phosphorylation by hexokinase isoenzymes. In the present study, the phosphorylation of this heptose was investigated by either a spectrophotometric or radioisotopic procedure. Using yeast hexokinase, the phosphorylation of 25 mM D-mannoheptulose only represented 0.02% of that of 5 mM D-glucose. Such a percentage was increased to 3.93% in the case of bovine heart hexokinase. In the latter case, the Km for D-mannoheptulose was close to 0.2 mM and both D-glucose (0.1-1.0 mM) and D-glucose 6-phosphate (also 0.1-1.0 mM) inhibited the phosphorylation of the heptose (0.03-0.60 mM). Human B-cell glucokinase also catalyzed the phosphorylation of D-mannoheptulose (0.1 mM), which was now increased in a bell-shaped manner by D-glucose (1.0-20 mM). Likewise, rat parotid gland, liver and pancreatic islet homogenates catalyzed the phosphorylation of D-[3H]mannoheptulose. The results obtained in these three tissues differed from one another by their absolute values (per mg wet wt.), relative values (by reference to the phosphorylation rate of 10 mM D-glucose), and sensitivity to inhibition by D-glucose (10 mM).

Amino Acid Substitution↗
PubMed1995

High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose.

Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not catalyse the rate-controlling step. Instead, hexokinase activity may assume a more important regulatory role. Hexokinase activities are consistently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., Biochem. J. 265: 503-509, 1990). The present work has focused on the glucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cell lines were found to have an additional glucose-phosphorylating activity, with properties similar to hepatic glucokinase. Maximal activities range from 1.1-20 nmol/min/mg cell protein, and the activity is consistently absent from any untransformed cell line or tissue tested, except rat liver tissue (18 nmol/min/mg cell protein). Tumor cell glucokinase activity has been characterized by its high Km for glucose (8-11.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptulose (I50, 12.5 mM); and lack of inhibition by 10 mM glucose-6-phosphate. Mannoheptulose also causes inhibition of glucose uptake by tumor cells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growth of cultured tumor cell lines (I50, 21.4 mM). Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified from avocados and is assumed to be of low toxicity), as a cancer treatment is discussed.

Animals↗
PubMed1986

Increased adenine nucleotides in liver mitochondria after mannoheptulose injection in vivo.

In adult rats, mannoheptulose injection causes a transient decrease in the serum insulin-to-glucagon ratio and a concomitant increase in serum glucose concentration. These effects attain a maximum 1 h after the injection and then decline toward normal. Correlated with the hormone changes is a dramatic increase in the adenine nucleotide content (ATP + ADP + AMP) of liver mitochondria, which peaks to over 50% of control values at 1 h. The increase in mitochondrial adenine nucleotides must occur by uptake from the cytosol, because the adenine nucleotide content of the whole tissue remains constant. The accumulation of adenine nucleotides by the mitochondria probably occurs over the recently characterized carboxyatractyloside-insensitive transport pathway that allows exchange of ATP-Mg for Pi. The actual mechanism by which net uptake is regulated after mannoheptulose injection has not yet been elucidated; however, changes in the Km or Vmax of the carrier and an increase in the tissue ATP/ADP ratio were eliminated as possibilities. The increase in matrix adenine nucleotide content in response to hormone changes brought about by mannoheptulose was much greater and more reproducible than what is achieved with glucagon injection. Mannoheptulose treatment may therefore be preferable as a model for further study of hormone effects on mitochondrial function.

Adenine Nucleotides↗
PubMed1998

Interference of D-mannoheptulose with D-glucose phosphorylation, metabolism and functional effects: comparison between liver, parotid cells and pancreatic islets.

D-mannoheptulose is currently used as a tool to inhibit, in a competitive manner, D-glucose phosphorylation, metabolism and functional effects in the pancreatic islet B-cell. In order to better understand the mode of action of the heptose, we have explored its effect upon D-glucose phosphorylation in liver, parotid cells and islet homogenates, this allowing to characterize the interference of the heptose with glucokinase and/or hexokinase. The effect of D-mannoheptulose upon the metabolism of D-glucose was also examined in both intact parotid cells and pancreatic islets. Last, the effect of D-mannoheptulose upon glucose-stimulated insulin release was reinvestigated over large concentration ranges of both the heptose and hexose. The experimental data revealed a mixed type of D-mannoheptulose inhibitory action upon D-glucose phosphorylation, predominantly of the non-competitive and competitive type, in liver and parotid homogenates, respectively. Despite efficient inhibition of hexose phosphorylation in both parotid cell and islet homogenates, the heptose suppressed the metabolic and functional responses to D-glucose only in pancreatic islets, whilst failing to affect adversely D-glucose catabolism in parotid cells. These findings suggest that factors such as the intracellular transport and availability of the heptose may interfere with the expression of its antagonistic action upon D-glucose metabolism.

Animals↗
PubMed1998

Esterification of D-mannoheptulose confers to the heptose inhibitory action on D-glucose metabolism in parotid cells.

D-mannoheptulose, but not its hexaacetate ester, inhibits, in a competitive manner, D-glucose phosphorylation by either purified beef heart hexokinase or crude parotid gland homogenates. Yet, D-mannoheptulose hexaacetate, but neither the unesterified heptose nor acetate or its methyl ester, inhibits D-[5-3H]glucose utilization and D-[U-14C]glucose conversion to 14CO2 and 14C-labelled acidic metabolites and amino acids in intact isolated parotid cells. It is proposed, therefore, that D-mannoheptulose hexaacetate crosses efficiently the plasma membrane of parotid cells and, after intracellular hydrolysis, allows inhibition of D-glucose phosphorylation by the unesterified heptose. The ester of D-mannoheptulose could thus represent a useful tool to inhibit hexose phosphorylation and interfere with cell growth in cells otherwise resistant to the heptose.

Acetates↗
PubMed1976

Gluconeogenic response to mannoheptulose in the rat.

Since administration of mannoheptulose induces temporary hyperglycemia, the present study was conducted to elucidate this phenomenon. The results indicate that mannoheptulose stimulates the activity of hepatic fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase, and enhances incorporation of alanine into blood glucose and hepatic glycogen. In addition, mannoheptulose increases plasma levels of glucagon and hepatic cyclic AMP concentration. Gluconeogenic effects of mannoheptulose appear to be mediated by glucagon.

Alanine↗
PubMed1976

Effects of mannoheptulose and DL-glyceraldehyde on glucose induced insulin release and adenosine 3',5'-monophosphate levels in isoalted islets of rat pancreas.

The effects of mannoheptulose and DL-glyceraldehyde on glucose-induced insulin release and cycli AMP levels in islets isolated from rat pancreas were investigated. Mannoheptulose inhibition on glucose-induced insulin release was observed after only 5-min incubation period, indicating an inhibitory effect on the early phase of insulin release. This inhibition on insulin release was accompanied with the simultaneous depression of cyclic AMP levels in islets. By the addition of DL-glyceraldehyde to the medium in which glucose and mannoheptulose were present, the depressed cyclic AMP levels in islets were recovered to the control level completely but the restoration of insulin release in the early phase was not complete. In the absence of glucose, DL-glyceraldehyde did not demonstrate a significant increase of insulin release during 5 min incubation, though a marked stimulation was observed after 30-min incubation. Cyclic AMP levels in islets were not affected by DL-glyceraldehyde. When DL-glyceraldehyde was added to the medium with glucose, significant inhibition of glucos-induced insulin release in its early phase was observed without the reduction of cyclic AMP levels in islets. From these findings, the following possibilities are suggested and discussed. 1. Maintenance of the cyclic AMP levels in islets is a necessary but insufficient condition for glucose-induced insulin release particularly for its early phase. 2. Glucose-induced insulin release seems to depend on both the binding of glucose with glucoreceptor and the supply of some metabolites. Mannoheptulose inhibits both mechanisms. DL-glyceraldehyde may supply metabolites but competitively inhibit the binding of glucose to the glucoreceptor.

Animals↗
PubMed2000

Effects of D-mannoheptose and D-glycero-D-gulo-heptose upon D-glucose metabolism and insulinotropic action in rat pancreatic islets and D-glucose phosphorylation by hexokinase isoenzymes: comparison with D-mannoheptulose.

The possible use of D-mannoheptose or D-glycero-D-gulo-heptose as substitute of D-mannoheptulose for specific inhibition of D-glucose phosphorylation, metabolism and insulinotropic action was investigated in the present study. The two aldoheptoses failed to duplicate the effect of D-mannoheptulose upon the phosphorylation of D-glucose by yeast hexokinase, bovine heart hexokinase or human B-cell glucokinase. They were poorly phosphorylated by the low-Km hexokinase isoenzymes or liver B-cell glucokinase. D-mannoheptose failed to reproduce the inhibitory action of D-mannoheptulose upon D-glucose metabolism by isolated rat pancreatic islets. Whilst D-glycero-D-gulo-heptose failed to affect glucose-induced insulin release, D-mannoheptose slightly enhanced glucose-induced insulin release when tested at low concentrations (0.75-1.5 mM) and progressively decreased insulin output at higher concentration (3. 0-20.0 mM) in islets exposed to a high (16.7 mM), but not physiological (8.3 mM), concentration of D-glucose. D-mannoheptose, however, also caused a modest inhibition of insulin release evoked by 2-ketoisocaproate. It is concluded, therefore, that neither D-mannoheptose nor D-glycero-D-guloheptose can be considered as suitable substitutes of D-mannoheptulose.

Animals↗