Studies on Protection Against the Diabetogenic Effect of Alloxan by Glucose.

Abstract

Although alloxan is widely used to produce experimental diabetes, the mechanisms of its toxic action on the beta-cells are not known. A promising approach to study this mechanism is the use of protective agents in vivo. A biochemically heterogenous group of compounds was found to protect the rat against the diabetogenic effect of alloxan ( 1,2). However, many of these substances did not prove very valuable since they seem to protect by a nonspecific adrenergic type of mechanism (3) , or by reacting nonenzymatically with alloxan, e.g., glutathione( 4). Glucose ( 5 ) on the other hand seems to be among the few specific protecting agents which do not act by these mechanisms. The following hypotheses were suggested to explain the protection by glucose: (a) the reversal of the inhibitory effect of alloxan on hexokinase(5) ; (b) substrate and energy production from glucose through the glycolytic and oxidative pathways( 6,7) ; and (c) enhancement of the release of epinephrine by the hexose (3). The present communication deals with testing of some of the metabolic products of glucose and 2 of its analogues for their protective effect against alloxan in vivo. Materials and methods.Sprague-Dawley albino rats of both sexes weighing 100-150 g were used. They were fasted 24-48 hours before injection of alloxan. Unless otherwise stated, the substances to be tested were dissolved in water and injected into the tail vein 5 minutes prior to injection of alloxan through the same route. Routinely a dose of 40 mg of alloxan (Eastman) per kilogram body weight was used. Solutions of pyruvic, fumaric, L-malic and DL-lactic acids were neutralized to pH 7.4 with sodium hydroxide before injection. 3 -Methyl-D-glucose t and wD-methylglucoside ( Eastman) were crys------* Supported by U.S.P.H.S. Grant. t Kindly provided by 1)r. John B. Jewel1 of Ayerst Iaboratorics.tallized once from methanol before use.Blood sugar was determined by the Somogyi-Nelson procedure (8,s). Animals were considered diabetic if the non-fasting blood sugar values exceed 150 mg % 48 hours following injection of alloxan. 'Invariably blood sugar levels of the protected animals were lower than this arbitrary value and those of the unprotected animals were much higher (Tables I and 11).Results. The results summarized in Table I indicate that while I.V. injection of D-glucose at 0.006 Mole/kg of body weight gave full protection none of the citric acid cycle intermediates protected the animals under the same conditions. It should be mentioned, however, that in the case of L-malate and pyruvate it was not possible to use a dose equivalent to the glucose dose (i.e., molar ratio 2

Effect of methylxanthines on alloxan inhibition of insulin release

“…The concurrent presence of a high concentration of either D-glucose, D-mannose, or 3-0-methyl-D-glucose with alloxan during this brief exposure interval provided almost complete protection of the B-cells from the inhibitory effect of alloxan on glucose-induced insulin release [17]. These same hexoses had been reported previously to block the diabetogenic action of alloxan in rats when administered prior to the injection of alloxan in vivo [1,4,15,22]. This in vitro perifusion system now makes it feasible to obtain quantitative information on the protective action of other agents against alloxan and to determine whether alloxan may prove to be a useful probe in studying the mechanism of induction of glucose-induced insulin release.…”

Alloxan-induced alteration of insulin release, rubidium efflux and glucose metabolism in rat islets stimulated by various secretagogues

“…It does not appear possible to explain these observations by an action of alloxan restricted to a putative membrane glucoreceptor. The possibility should be considered that alloxan enters B-cells [33,34] via the hexose carrier system where antagonists of glucose transport (3-0-methylglucose, cytochalasin B, phlorizin) exert their protective action [4,17,21,[34][35][36]. Alloxan would then interfere with cellular events crucial for the response to glucose and subsequently lead to a more general dysfunctioning of the releasing machinery.…”

Alloxan: history and mechanism of action

“…But the hexokinases, a group of glucose phosphorylating isoenzymes with high affinity for glucose, which are present in all cells of the organism, could not be the target for expression of the selective effects of alloxan on the pancreatic B cells. Some years later, Carter and Younathan reported that the non-metabolisable sugar 3-O-methylglucose also protected against the diabetogenic action of alloxan [40].…”