408 4. ALLOXAN 



the hypoglycemic response to alloxan and so these tissues are not involved 

 (Goldner and Gomori, 1944; Kirschbaum et al., 1945). These results point 

 rather strongly to insulin release being the primary factor in the hypogly- 

 cemia. 



There are some results which indicate that this may not be the entire 

 story. The rise in liver glycogen during the hypoglycemic phase is not 

 typical of an insulin effect, since insulin does not promote glycogen storage 

 in the liver; indeed, hepatic glycogen usually falls secondary to the hypo- 

 glycemia (Cullimore et al., 1953). Wrenshall et al. (1950) did not find a 

 decrease in pancreatic insulin at 9 hr, but postulated that insulin synthesis 

 might be accelerated to compensate for the loss. The recent results of Dixit 

 et al. (1962) also do not indicate a fall in pancreatic insulin before 24 hr, 

 although after that it disappears rapidly. Determinations were made only 

 at 2 hr and 24 hr and not during the hypoglycemic phase, but it would 

 be surprising if a significant fall occurs between these times. Increased 

 synthesis of insulin might occur but it seems unlikely in view of the state 

 of the cells during this period. We have seen that alloxan rather readily 

 inhibits glycogenolysis in the liver (Goldner and Jauregui, 1953), but 

 whether the concentrations used are comparable to those occurring in vivo 

 is not known. Furthermore, this effect is immediate and the hypoglycemia 

 occurs several hours later. The degree of liver damage was thought to 

 parallel the degree of hypoglycemia (Ramfjord, 1952), but the doses were 

 quite high and the work was done in monkeys, which are not so specifically 

 responsive to alloxan as other species. Houssay et al. (1945) concluded that 

 the hypoglycemia cannot be due to insulin release because it occurs in 

 acutely depancreatized dogs; if the alloxan is given 24-48 hr after pancrea- 

 tectomy, no hypoglycemia is seen. The explanation for these results is not 

 evident. Another surprising observation is that 23-58 days after ligation 

 of the pancreatic duct the total blood glucose response to alloxan is reduced 

 and, inasmuch as such ligation produces parenchymal atrophy with little 

 obvious changes in the islets, it might indicate that the parenchyma is 

 somehow involved (Walpole and Innes, 1946). It was thought that the 

 ligation might also cause some ischemia of the islets so that the alloxan 

 could not reach them, but this does not sound very convincing. Most of 

 this evidence is rather circumstantial and probably does not invalidate the 

 theory of insulin release, but taken all in all it indicates that the situation 

 is more complex and that some additional factors may be involved. 



MECHANISM OF THE DIABETOGENIC ACTION 



The problem here is not to explain the late and permanent hyperglycemia, 

 since this is unquestionably due to a deficiency of insulin, but to inquire 

 into the mechanisms by which alloxan causes a selective /5-cell necrosis. 



