Laboratory of Experimental Medicine, Brussels Free University, Brussels, Belgium
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1 Vol. 45, No. 3, July 1998 Pages DUAL EFFECT OF 2-DEOXY-D-GLUCOSE TETRAACETATE UPON GLUCOSE- INDUCED INSULIN RELEASE Willy J. Malaisse, Luis E. Flares and Marcel M. Kadiata Laboratory of Experimental Medicine, Brussels Free University, Brussels, Belgium Received March 4, 1998 SUMMARY: The effect of 2-deoxy-D-glucose tetraacetate upon glucose-stimulated insulin release was explored in pancreatic islets from either normal or hereditary diabetic rats. At a high concentration (1 ram), it decreased the secretory response to D-glucose, such an inhibitory effect being more marked in the case of the ~- than B-anomer of the ester. At lower concentrations (.19 to 1.7 mm), however, 2-deoxy-D-glucose tetraacetate augmented insulin secretion evoked by 8.3 mm D-glucose, with again a preference for the o~-anomer of the ester. In relative terms, such an enhancing action was more marked in Goto-Kakizaki than normal rats. Hence, it is proposed that selected esters of non-nutrient carbohydrates could be used as insulinotropic tools in the treatment of non-insulin-dependent diabetes mellitus. Key words: 2-deoxy-D-glucose tetraacetate, insulin release, pancreatic islets. INTRODUCTION Several esters of monosaccharides were recently found to display higher nutritional and/or biological efficiency than the corresponding unesterified carbohydrates [1-3]. This seems attributable to the fact that such esters are able to cross the plasma membrane without requiring the intervention of a specific carrier system and then undergo hydrolysis in esterasecatalyzed reactions, so that the unesterified monosaccharides eventually become readily available for phosphorylation and further metabolism [1, 4, 5]. For instance, D-glucose pentaacetate is more efficiently metabolized and stimulates insulin release to a greater extent than unesterified D-glucose in isolated rat pancreatic islets [4, 6]. Likewise, D- mannoheptulose hexaacetate inhibits D-glucose metabolism in cells, such as parotid cells or erythrocytes, that are otherwise resistant to the unesterified heptose [3, 7]. Last, 2-deoxy-Dglucose tetraacetate is also more efficient than unesterified 2-deoxy-D-glucose as either an inhibitor of D-glucose metabolism and "insulinotropic action in pancreatic islets [2] or as a cytostatic agent in several tumoral cells lines [8-11]. In all these cases, the metabolic and/or functional effects of the esters appear attributable to their carbohydrate rather than acetate /98/ / Copyright by Academic Press Australia. All rights of reproduction in any form reserved.
2 moiety. For instance, control experiments conducted in isolated rat pancreatic islets indicate that esters of poorly metabolized hexoses, such as D-galactose pentaacetate, fail, like unesterified D-galactose, to stimulate insulin release, despite the fact that the latter ester penetrates into islet cells and then undergoes intracellular hydrolysis as efficiently as D- glucose pentaacetate [4, 5]. The present work, however, reveals that 2-deoxy-D-glucose tetraacetate unexpectedly exerts both positive and negative insulinotropic actions in rat pancreatic islets, suggesting that the ester itself may be recognized by insulin-producing B-cells as a secretagogue. It is proposed that advantage could be taken of the stimulatory effect of 2-deoxy-D-glucose tetraacetate upon insulin release, an effect that displays anomeric specificity and is also operative in islets of hereditarily diabetic rats, in the perspective of using comparable esters as novel insulinotropic agents in the treatment of non-insulin-dependent diabetes mellitus. MATERIALS AND METHODS The oc- and B-anomers of 2-deoxy-D-glucose tetraacetate were prepared by a method reported elsewhere [2]. Pancreatic islets were isolated by the collagenase procedure [12] from female normal Wistar rats (B & K Universal Ltd., Hull, UK) and Goto-Kakizaki rats (GK rats) from our local colony, all animals being given free access to food (KM-4-kl2; Pavan Service, Oud Turnhout, Belgium) up to the time of killing by decapitation. The methods used to measure insulin release [12], as well as plasma D-glucose [13] and plasma insulin [14] concentrations, were previously described in the cited references. All results are presented as mean values (+ SEM) together with the number of individual observations (n). The statistical significance of differences between mean values was assessed by use of Student's t-test. RESULTS A first series of experiments was conducted in islets prepared from fed female Wistar rats (Table 1). In the presence of 8.3 mm D-glucose, 2-deoxy-c~-D-glucose tetraacetate (.19 to 1.7 ram) caused a concentration-related increase in insulin output. The threshold concentration for such an enhancing action was below.57 mm. Indeed, at the latter concentration, the ester-induced increment in insulin output was already highly significant (P <.5). However, when the concentration of the ester was raised to 1. ram, the secretory response to D-glucose was decreased below its control value (P <.1). Comparable, but not identical, results were recorded with the B-anomer of 2-deoxy-D-glucose tetraacetate. Thus, the B-anomer of the ester increased (P <.5) glucose-stimulated insulin output when 43
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4 BIOCHEMISTRYand MOLECULAR BIOLOGY INTERNATIONAL tested at concentrations of.57 and t.7 mm, and inhibited (P <.5) glucose-induced insulin release when used at a concentration of 1. mm. At a concentration of 1.7 mm, however, the enhancing action of the 13-anomer appeared somewhat less marked (P <.6) than that of the ~-anomer whilst, at a 1. mm concentration, the 13-anomer was definitely tess efficient (P <.1) than the ~-anomer in inhibiting glucose-stimulated insulin secretion. When the same experiments were repeated in the presence of 16.7 mm D-glucose, no significant increase of the secretory response to the hexose was any more detected at low concentrations of either the ~- or 13-anomer of 2-deoxy-D-glucose tetraacetate (Table 1). At a 1. mm concentration, the esters inhibited insulin release (P <.1), the 13-anomer being again less efficient (P <.1) than the ~-anomer in opposing the insulinotropic action of D- glucose. The second series of experiments was performed in islets prepared from fed female Goto-Kakizaki rats. The 8 animals used in this study had a body weight ( g) comparable to that of the normal female rats used in the first series of experiments, but were frankly hyperglycaemic (plasma D-glucose concentration : ram). In the sole presence of 8.3 mm D-glucose, the output of insulin averaged no more than ~tu/islet per 9 min (n = 3), as distinct (P <.1) from ~tu/islet per 9 min in normal rats (n = 51). In the diabetic animals, 2-deoxy-13-D-glucose tetraacetate (1.7 mm) augmented insulin release (P <.1) to t ~tu/islet per 9 min (n = 3). Thus, despite their impaired secretory response to D-glucose, the islets from diabetic rats displayed a greater responsiveness to the ester, the absolute value for insulin release by islets exposed to both 8.3 mm D-glucose and 1.7 mm 2-deoxy-13-D-glucose tetraacetate being comparable (P >.5) in control rats ( ~ 7.3 ~tu/islet per 9 min; n = 26) and diabetic animals ( ~tu/istet per 9 min; n = 3). DISCUSSION Three major new pieces of information emerge from these findings. First, they reveal that, at low concentrations, in the.57 to 1.7 mm range, the tetraacetate ester of 2-deoxy-D-glucose unexpectedly stimulates insulin release evoked by D- glucose at a physiological concentration of the hexose, comparable to that found in normal fed rats. This stimulant action of the ester only became masked at a much higher concentration (1. mm) of 2-deoxy-D-glucose tetraaeetate. Since the positive insulinotropic effect of 2- deoxy-d-glucose tetraacetate cannot be attributed to the metabolism of either its carbohydrate 432
5 or acetate moiety, as indicated by control experiments conducted with either unesterified 2- deoxy-d-gtucose [2] or D-galactose pentaacetate (see above), the most likely explanation is that the ester itself acts as a stimulus for insulin release, in a manner comparable to that recently documented in the case of L-glucose pentaacetate [4] and possibly involving a receptor mechanism similar to that currently implied in the recognition of bitter compounds by taste buds [15]. Second, the present results indicate that both the positive and negative insulinotropic actions of 2-deoxy-D-glucose tetraacetate display anomeric specificity, with a preference for the ot-anomer. The greater inhibitory effect of the a- than g-anomer upon glucose-stimulated insulin release is consistent with the knowledge that phosphoglucoisomerase acts as an oc- stereospecific enzyme towards D-glucose 6-phosphate [16, 17], a situation currently held responsible, in part at least, for the higher insulinotropic action of a- than g-d-glucose [18]. The fact that the ~-anomer of 2-deoxy-D-glucose tetraacetate was also more potent than the g- anomer in enhancing glucose-induced insulin secretion could suggest a comparable c~- stereospecificity of the receptor postulated to represent the target for the ester itself. Last, the experiments conducted in Goto-Kakizaki rats, considered as an animal model of inherited non-insulin-dependent diabetes mellitus [19], reveal that, in these diabetic rats, 2- deoxy-d-glucose tetraacetate restores a close-to-normal secretory rate in islets concomitantly exposed to D-glucose, despite the severe alteration of their functional responsiveness to the hexose and several other nutrients [2, 21]. In conclusion, therefore, the present findings lead us to propose that esters, acting like 2-deoxy-D-glucose tetraacetate, could be used as novel insulinotropic agents in the treatment of non-insulin-dependent diabetes. They would offer the advantages of enhancing glucose- induced insulin release at relatively low concentrations and to compensate for the impaired responsiveness to the hexose often prevailing in non-insulin-dependent diabetes [22]. Moreover, esters like L-glucose pentaacetate, which also stimulates insulin release [4], would offer the further advantage over other esters currently contemplated as potential insulin secretagogues for the treatment of type-2 diabetes [23-25] of avoiding the risks of both the untoward generation of methanol by intracellutar hydrolysis [23] and the undesirable stimulation of hepatic gluconeogenesis [26]. Acknowledgments. This study was supported by a Concerted Research Action of the French Community of Belgium. We are grateful to M. Mahy and C. R6mion for technical assistance, mad C. Demesmaeker for secretarial help. 433
6 REFERENCES 1. Mataisse, W.J., Jijakli, H., Kadiata, M.M., Sener, A., and Kirk, O. (t997) Biochem. Biophys. Res. Commun. 231, Vanhoutte, C., Kadiata, M.M., Sener, A., and Malaisse, W.J. (1997) Biochem. Mol. Biol. Int. 43, Malaisse, W.J., Kadiata, M.M., Scruet, O., and Sener, A. (1998) Biochem. Mol. Biol. Int. in press. 4. Malaisse, W.J., Sfinchez-Soto, C., Larrieta, M.E., Hiriart, M., Jijakli, H., Vifiambres, C., Villanueva-Pefiacarrillo, M.L., Valverde, I., Kirk, O., Kadiata, M.M., and Sener, A. (1997) Am. J. Physiol. 273:E19-E Vanhoutte, C., Sener, A., and Malaisse, W.J. (1998) Submitted for publication. 6. Sener, A., Welsh, N., Malaisse-Lagae, F., Kadiata, M.M., and Malaisse, W.J. (1998) Submitted for publication. 7. Ladri~re, L., Kadiata, M.M., and Malaisse, W.J.. (1998) Horm. Metab. Res. in press. 8. Malaisse, W.J., Delvaux, A., Rasschaert, J., and Kadiata, M.M. (1997) Cancer Lett. in press. 9. Delvaux, A., Kadiata, M.M., and Malaisse, W.J. (1997) Oncol. Rep. 4, Reinhold, U., and Malaisse, W.J. (1998) Int. J. Mol. Med. 1, Malaisse, W.J., and Delvaux, A. (t997) Med. Sci. Res. 25, Malaisse-Lagae, F., and Malaisse, W.J. (1984) In Methods in Diabetes Research (J. Lamer, and S.L. Pohl, Eds.) pp Wiley, New York. 13. Bergmeyer, H.U., and Berndt, E. (1974) In Methods of Enzymatic Analysis (H. Bergmeyer, Ed.) pp t5. Academic Press, New York. 14. Leclercq-Meyer, V., Marchand, J., Woussen-Colle, M.-C., Giroix, M.H., and Malaisse, W.J. (1985) Endocrinology 116, Malaisse, W.J., and Malaisse-Lagae, F. (1997) Biochem. Mol. Biol. Int. 43, Malaisse, W.J., Sener, A., Koser, M., and Herchuelz, A. (1976) J. Biol. Chem. 251, Witlem, R., Biesemans, M., Hallenga, K., Lippens, G., Malaisse-Lagae, F., and Malaisse, W.J. (1992) J. Biol. Chem. 267, Malaisse, W.J., Malaisse-Lagae, F., and Sener, A. (1983) Physiol. Rev. 63, Goto, Y., Kakizaki, M., and Masaki, N. (1975) Proc. Jap.. Acad. 51, ()stenson, C.-G., Khan, A., Abdel-Halim, S.M., Guenifi, A., Suzuki, K., Goto, Y., and Efendic, S. (1993) Diabetologia 36, Giroix, M.-H., Zhang, T.-M., Leclercq-Meyer, V., Sener, A., Portha, B., and Malaisse, W.J. (1995) Acta diabetol. 32, Malaisse, W.J. (1994) Diabetologia 37 (suppl. 2), $36-$ Malaisse, W.J. (1995) Gen. Pharmac. 26, Malaisse, W.J., Ladri6re, L., Laghmich, A., Louchami, K., Jijakli, H., Vifiambres, C., Villanueva-Pefiacarrillo, M.L., Valverde, I., and Bj6rkling, F. (1997) Biochem. Mol. Med. 62, LadriSre, L., Laghmich, A., Malaisse-Lagae, F., Dannacher, H., Bj6rkling, F., and Malaisse, W.J. (1998) Eur. J. Pharmacol. in press. 26. Zhang, T.-M., Sener, A., and Malaisse, W.J. (1994) Arch. Biochem. Biophys. 314,
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