406 4. ALLOXAN 



of epinephrine, and this was supported by several reports that adrenalec- 

 tomy abolishes the hyperglycemic response (Goldner and Gomori, 1944; 

 Kirschbaum et al., 1945; Gaarenstroom and Siderius, 1954) and that sym- 

 pathetic blockade with ergotoxin does likewise (Corkill et al., 1944). It 

 was also supported by the fact that an epinephrine-like rise in blood pres- 

 sure occurs after injection of alloxan (Hard and Carr, 1944). Histological 

 changes in the adrenal medulla, including fragmentation and shrinkage of 

 the cells, were observed. The glucose seems to come mainly from the liver 

 since hepatectomy abolishes the hyperglycemia (Houssay et at., 1945), 

 and during the development of diabetes the liver glycogen varies inversely 

 with the blood glucose, being low during the initial hyperglycemia (Culli- 

 more et al., 1953). 



Despite the simplicity of this theory and the apparently good evidence 

 for it, this mechanism has been questioned and several experimental results 

 are incompatible with it. (1) Hypophysectomy abolishes the hyperglycemic 

 response and the presence of adrenal cortex seems to be necessary (Kirsch- 

 baum et al., 1945). A pituitary-corticoadrenal activation antagonizing the 

 action of insulin was postulated. (2) Administration of DDD* produces 

 atrophy of the adrenal cortex and loss of the hyperglycemic response to 

 alloxan (Nichols and Sheehan, 1952), again pointing to some participation 

 of the adrenal cortex. (3) In rabbits whose /5-cells have been destroyed by 

 alloxan, the hyperglycemic response to alloxan is much reduced (Brun- 

 feldt and Iversen, 1950). This points to a pancreatic site of action. (4) 

 Injection of alloxan into the portal vein produces a more marked hyper- 

 glycemia than injection into the saphenous vein (Houssay et al., 1945). 

 Furthermore, the authors claimed that adrenalectomy does not abolish 

 the hyperglycemic response, and that the effect is more likely on the liver. 

 The discrepancy in the effects of adrenalectomy is not easy to explain. 

 Lukens (1948) believes that Houssay's data indicate an effect to reduce 

 the hyperglycemia, and, on the other hand, the animals were under chloro- 

 lose anesthesia, which might have decreased the magnitude of any adrenal 

 discharge. We have discussed the effects of alloxan on the glucose and 

 glycogen metabolism of liver (page 402), and there is very little evidence 

 that alloxan directly causes a release of glucose; indeed, spontaneous and 

 epinephrine-induced glycogenolysis, on the contrary, is usually inhibited. 



The hyperglycemia could be due in part to a sudden and complete ces- 

 sation of insulin secretion and Dixit et al. (1962) found that the insulin level 

 in the pancreas is elevated some 12% 2 hr after alloxan. The observation 

 by Kurita (1955) that Zn++ prevents the early hyperglycemic response with- 

 out altering the eventual diabetic state is very interesting but difficult 

 to understand. It seems impossible to formulate a mechanism which is 



* 2,2-Bis(p-chlorophenyl)-l,l-dichloroethane. 



