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
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