DIABETOGENIC ACTION 391 



Even though the hexokinase studied was from pancreas, it it likely that 

 it is not primarily /?-cell hexokinase, which might be more sensitive to 

 alloxan. Nevertheless, this hexokinase appears to be quite significantly 

 inhibited in the absence of glucose by 0.1-0.5 mM alloxan.* Carter and 

 Younathan (1962) found that 3-methyl-D-glucose also protects, but a-D- 

 methylglucoside, malate, lactate, and a fumarate-pyruvate mixture do 

 not. Release of epinephrine seems doubtful on various grounds, but they 

 showed that phentolamine, which blocks the vasoconstrictive action of 

 epinephrine, does not alter the protective ability of glucose. The results 

 with 3-methyl-D-glucose are difficult to explain since it is not metabolized 

 (at least not by most tissues, although possibly by /?-cells), and hence 

 the theory that glucose provides energy in some form to protect is invali- 

 dated. Further discussion of these points will be found in the section sum- 

 marizing the possible mechanisms by which alloxan acts. 



Effect of Alloxan on Islet Cell Tumors 



Once the selective destructive action of alloxan on /?-cells was discovered, 

 it was obvious that alloxan might be clinically useful in islet cell tumors. 

 Brunschwig et al. (1944) and Brunschwig and Allen (1944) reported the 

 treatment of an insulin-producing carcinoma and could not produce necrosis 

 of the malignant cells, although the attacks of hyperinsulinism were abol- 

 ished for some time. Conn et al. (1947) intravenously injected 50 mg/kg 

 alloxan each day for 9 days and then 100 mg/kg/day for a while, 15 days 

 after which the insuloma was removed. There had been no demonstrable 

 effect of alloxan on the /5-cells and insulin continued to be secreted during 

 the time of treatment and presurgery. They noted that normal islet tissue 

 was damaged by the alloxan. Bottger et al. (1952) also treated a patient 

 with an islet cell adenoma with increasing intravenous doses of 8-71 mg/kg 

 over 2 months, but no effect was noticed and the patient died in hyperin- 

 sulin coma. Normal /?-cells were again found to be damaged. Unfortunately, 

 it appears that tumorous /?-cells are quite resistant to alloxan, which prob- 

 ably indicates that the systems primarily responsible for insulin synthesis 

 and release are not involved in the immediate action of alloxan, but the 

 resistance could be explained if the /?-cell plasma membranes are altered 

 by malignancy. 



Natural Occurrence of Alloxan 



The hypoglycemia following administration of alloxan was attributed by 

 Dunn et al. (1943 a) to stimulation of the islets to release insulin, and they 



* These experiments were unfortunately not reported, but 4 mM alloxan inhibits 

 this hexokinase 93% in the absence of glucose and 58% in the presence of 5 iwM 

 glucose. Since 0.5 mM alloxan inhibits 25% in the presence of glucose, it is likely 

 that a good deal more depression would be noted without glucose. 



