Contrasting modes of action of d-glucose and 3-O-methyl-d-glucose as protectors of the rat pancreatic B-cell against alloxan (original) (raw)
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PHYSIOLOGICAL AND HISTOLOGICAL STUDY OF EXPERIMENTAL DIABETES MELLITUS BY ALLOXAN.
Study included using exogenous alloxan (100 mg for every 1 kg of animal weight) for inducing experimental diabetes mellitus in rats. 46 rats divided for two groups, during the time of study glucose, glycogen levels estimated every week extend for 3 weeks. Also the study included histo-pathological effect on liver and pancreas. The experiment showed an increase in blood glucose, after 7 days, 14 days, 21 days of alloxan injection, values were (11,92), (15,89), (17,31) mmol/Lrespectively, glucose level of control group was (5.84-7.44 mmol/L). while glycogen level in liverat the same period was (0,72), (018), (0.075) mg/g. Control group glycogen was (3,18 – 3.65mg/g) during 3 weeks of experiment. Histological examination of liver samples of ratswere traced pronounced signs of toxic hepatitis as a violation of the beam structure of the lobules, necrosis of hepatocytes, fat and protein dystrophy, the presence of infiltration of hematogenous cell clusters. In the control group was characterized by a uniform distribution with respect to the same hepatocytes for liver slices, hepatocytes and the structure of the test cells corresponded to the ratio of the classical histological characteristics of the active functioning of the liver. The number of β-cells in the islets of sharply reduced, in most of them marked vacuolization of the cytoplasm, reducing the size of the nuclei, chromatin condensation, in some cells-kariopik¬noz. Presence of a lymphocytic infiltrate along the periphery of the islets, interlobular connective tissue edema, congestion of the capillaries; vascular stasis traced.
On the mechanism of glucose protection against alloxan toxicity
Diabetologia, 1971
The modifying effects of some sugars and amino acids on the diabetogenie action of alloxan were studied in mice. The severity of diabetes was assessed by measuring the blood glucose level 48 h after the alloxan injection. In accordance with earlier reports, D-glucose and D-mannose, but not D-galactose, protected s~gainst alloxan diabetes. No such effect was observed with D-mannoheptulose, L-alanine, or L-leucine. The protective action of glucose was abolished by prior treatment with mannoheptulose. It is concluded that alloxan and glucose do not compete for a common biochemical site in the #-cell membrane. Protection against alloxan toxicity may, however, result from a conformational change in the fl-cell membrane induced by glucose, glucose transport, or glucose metabolism. Mdcanisme de protection du glucose centre la toxicitd de l' allo~ane Rdsumd. On a 6tudi6 chez la scurfs les effets modifiants de certains sucres et acides amin6s sur Faction diab6tog6ne de l'alloxane. La gravit6 du diab~te est d6finie grace & la mesure du taux de glucose dans le sang 48 h apr~s l'injection d'alloxane. Selon les rapports ant6rieurs, le D-glucose et le D-mannose, mais pus le D-galactose, prot~gent centre ]e diab~te provoqu6 par l'alloxane. Le re@me effet n'a pus dr6 observ6 avee le D-mannoheptu]ose, la L-alanine ou la L-leucine. L'action proteetrice du glucose a 6t6 annul6e par un traitement pr6alable au mannoheptulose. En conclusion, l'alloxane et le glucose ne sent pus en compdtition pour le m@me site biochimique duns la membrane de la cellule ft. La protection centre la toxicit6 de l'alloxane peut rdsulter, cependant, d'un changement de conformation sur la membrane de la cellule fl provoqu6 par le glucose, le transport du glucose, ou le In6tabolisme du glucose. Uber den Mechanismus der Glulcoseprotektion gegen die Alloxantoxizitat Zusammenfassung. Es wurde an M~usen der modifizierende Effekt yon einigen Zuckern und Aminos~uren auf die diabetogene Wirkung yon Alloxan studiert. Die Sehwere des Diabetes wurde an Hand yon Blutzuckermess.ungen 48 Std. nach der Alloxaninjektion beurteflt. In Uberinstimmung mit friiheren Berichten schiitzen D-Glukose und D-Mannose, jedoch nicht D-Galaktose gegen den Alloxandiabetes. Kein Effekt wurde mit D-Mannoheptulose, L-Alanin und L-Leuzin festgestellt. Der Schutzeffekt von Glukose wurde dureh vorherige Behandlung mit Mannoheptulose aufgehoben. Daraus wurde geschlossen, da2 Alloxan und Glukose nicht an der gleiehen Stelle der 1Yiembran der fl-Zelle angreifen. Jedoch kann der Schutz g.e.gen die Alloxantoxizit~it auf einer konformationellen Anderung der Membran der fl-Zelle, welche durch Glukose, den Glukosetransport oder den Glukosemetabolismus herbeigefiihrt wurde, beruhen.
Journal of Diabetes Mellitus, 2015
Background: Catalase deficiency (acatalasemia) is sensitive to alloxan, and the administration to acatalasemic mice develops hyperglycemia under mild conditions. However, the mechanism is still poorly understood. Methods: Alloxan was used to induce the oxidative stress and intraperitoneally administered to acatalasemic and normal mice. The blood samples of these mice after 1, 3, 5 and 7 days were examined. The pancreatic islets 7 days after alloxan administration were isolated, and the insulin released under 3 mM and 20 mM glucose was examined. Results: After alloxan administration, increase of oxidative markers in blood and pancreatic apoptosis in acatalasemic mice were observed immediately. Insulin in blood was lowered after 3 days, and the insulin in acatalasemic mice was lower than that in normal mice. Hyperglycemia in the acatalasemic mice was observed after 3 days. The pancreatic islets after 7 days were isolated. A reduction of the insulin released from the islets under glucose stimulation was observed. The stimulation indexes of the normal and acatalasemic mice were 1.4 ± 0.6 and 0.7 ± 0.3, respectively. Conclusions: Alloxan induced a deterioration of glucose-dependent insulin secretion ability from the islets, and the deterioration mostly contributed to hyperglycemia, rather than apoptosis.
Stimulation by 2-deoxy-d-glucose tetraacetates of hormonal secretion from the perfused rat pancreas
American Journal of Physiology-endocrinology and Metabolism, 1999
Stimulation by 2-deoxy-D-glucose tetraacetates of hormonal secretion from the perfused rat pancreas. Am. J. Physiol. 276 (Endocrinol. Metab. 39): E689-E696, 1999.-The effects of ␣and -2-deoxy-D-glucose tetraacetate (1.7 and 8.5 mM) on insulin, somatostatin, and glucagon secretion from isolated rat pancreases perfused in the presence of 8.3 mM D-glucose were compared with those of unesterified 2-deoxy-D-glucose tested at the same two concentrations. The unesterified glucose analog caused, in a concentration-related manner, inhibition of glucose-induced insulin and somatostatin release and augmentation of glucagon secretion. The two anomers of 2-deoxy-D-glucose tetraacetate, however, increased the secretion rate of all three hormones; this effect was also related to the concentration of the esters. No obvious anomeric specificity of the secretory response to 2-deoxy-D-glucose tetraacetate was observed. These findings indicate that the insulinotropic action of hexose esters cannot be accounted for solely by the metabolic effect of their glucidic moieties. They suggest that the A, B, and D cells of the endocrine pancreas are each equipped with a receptor system responsible for the direct recognition of monosaccharide esters as secretagogues. They further support the view that a paracrine effect of insulin on glucagon-producing cells does not represent a major component in the regulation of their secretory activity.
Cationic and secretory effects of 6-O-acetyl-D-glucose in rat pancreatic islets
IUBMB Life, 1997
Selected esters of D-glucose were recently proposed as tools to supply the sugar to cells affected by a defect in the carrier-mediated process of hexose transport across the plasma membrane. The present study extends this knowledge to 6-O-acetyt-D-glucose. At a 2.0 mM concentration, the ester was indeed found to stimulate insulin release from perifused rat pancreatic islets. This coincided with stimulation of calcium influx into the islet cells, as judged from comparison of the ester effects on 45Ca outflow from prelabelled islets perifused in either the absence or presence of extracellulm" Ca ~+. The facilitated inflow of Ca z~ did not appear attributable to a decrease in K + conductance, 6-O-acetyl-D-glucose augmenting 86Rb efflux from islets prelabelled with this radioactive cation. Both the latter phenomenon and the insulinotropic action of 6-O-acetyl-D-glucose failed to be antagonized by Dmarmoheptulose. These findings indicate that the cationic events coupling the recognition of D-glucose to the stimulation of insulin release are not identical in islets exposed to the hexose or its ester.
Perturbation of pancreatic islet function in glucose-infused rats
Metabolism, 1990
Likewise, in isolated islets prepared from the glucose-infused rats, L-erginine or theophylline stimulated insulin release et a low ambient concentration of o-glucose, et variance with the situation found in islets removed from normal rats. These secretory perturbations could not be attributed to eny obvious defect in either the transport of o-glucose into islet cells or its further utilization end oxidation. but coincided with the abnormal accumulation of glycogen in the B-cell. It is proposed that the letter anomaly may play a role in the altered dynamics of insulin release found in animals or patients with l&giterm hyperglycemia.
Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan
Diabetologia, 2002
Aims/hypothesis. We investigated the importance of the low affinity GLUT2 glucose transporter in the diabetogenic action of alloxan in bioengineered RINm5F insulin-producing cells with different expressions of the transporter. Methods. GLUT2 glucose transporter expressing RINm5F cells were generated through stable transfection of the rat GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Results. Cells expressing the GLUT2 transporter were susceptible to alloxan toxicity due to the uptake of alloxan by this specific glucose transporter isoform. The extent of the toxicity of alloxan was dependent upon the GLUT2 protein expression in the cells. The lipophilic alloxan derivative, butylalloxan, was toxic also to non-transfected control cells. Expression of the GLUT2 glucose transporter caused only a marginal increase in the toxicity of this substance. Butylalloxan, unlike alloxan itself, is not diabetogenic in vivo although, like the latter substance, it is beta-cell toxic in vitro through its ability to generate free radicals during redox cycling with glutathione. Conclusion/interpretation. Our results are consistent with the central importance of selective uptake of alloxan through the low affinity GLUT2 glucose transporter for the pancreatic beta-cell toxicity and diabetogenicity of this substance. Redox cycling and the subsequent generation of oxygen free radicals leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as alloxan diabetes in experimental diabetes research.
Journal of Clinical Investigation, 1975
hyperglucagonemia that occurs in vivo in animals made diabetic with alloxan or streptozotocin is not suppressed by high glucose but is suppressed by exogenous insulin. These observations together with other studies suggested that insulin-dependent glucose transport and metabolism by the a-cells serves as the primary mechanism controlling glucagon secretion. This hypothesis was tested in the present investigation. The possible interactions between glucose, insulin, and a mixture of 20 amino acids at physiological proportions were examined in the isolated-perfused pancreas of normal, alloxan diabetic, and streptozotocin diabetic rats. Release of insulin and glucagon were used as indicators of A-cell and a-cell function. According to rigid criteria the diabetic animals entering the study were severely diabetic. It was found that in vitro: (a) basal glucagon release (measured in the absence of an a-cell stimulus or inhibitor) was extremely low, even lower (i.e. 10%) than the basal rates seen in controls; (b) the a-cells of alloxanized-and streptozotocin-treated rats responded with a biphasic glucagon release to stimulation by an amino acid mixture; (c) this a-cell response was reduced after both streptozotocin and alloxan; (d) glucose at 5 mM was a potent inhibitor of amino acid-induced glucagon secretion in both types of experimental diabetes; (e) in alloxan diabetes a-cell stimulation by amino acids can be curbed by exogenous This work was presented in part at the meetings of the
Evaluation of alloxan on induction of diabetes in albino rats
International Journal of Basic & Clinical Pharmacology, 2019
Background: Alloxan-induced diabetes model is used as a “study tool” to elucidate the pathophysiology of the disease and much more as a “search engine” for antidiabetic compounds with better therapeutic characteristics. It was the first agent used in the category of chemically induced diabetes to create a model of insulin dependent diabetes mellitus. Other chemicals being streptozocin, dexamethasone, insulin antibodies-induced diabetes.Methods: Albino rats were divided into four groups with ten rats in each group. Alloxan monohydrate 2%, solution which was dissolved in 0.9% of sodium chloride (normal saline) as a diluent and given intraperitoneally to rats and blood glucose estimation made by using glucometer. Total 40 albino rats were taken and divided into 4 groups. 10 rats receiving normal saline were grouped as Group A, 10 rats received alloxan at a dose of 150 mg/kg as Group B, 10 rats received alloxan at a dose of 160 mg/kg as Group C and 10 rats received alloxan at a dose of ...