DIABETOGENIC ACTION 381 



a-cells and the acinar tissue are normal. Usually there is no accompanying 

 inflammatory reaction, fibrosis, or hyalinization. The general picture is 

 one of a selective progressive necrosis of the /5-cells leading to their com- 

 plete obliteration. The mitotic phase distribution of islet cells is shifted, 

 showing a retardation of metaphases and an increase in anaphases (Faller, 

 1953). Chromosomes may be clumped on the equatorial plate and chromatin 

 bridges are visible. Electron microscopy studies show essentially the same 

 changes but the early vacuolization is even more apparent, especially in 

 the mitochondria, and evidences of karyolysis are seen at an earlier stage 

 (Lacy and Cardeza, 1958; Williamson and Lacy, 1958). In certain fish, 

 e. g. the sculpin {Cottus scorpivs), there is segregation of the ^-cells making 

 them more easily visualized, and here similar ultrastructural changes have 

 been observed (Falkmer and Olsson, 1962). It is very interesting that rats 

 given several small daily doses of alloxan exhibit islet dysfunction without 

 observable changes in the /^-cells (Molander and Kirschbaum, 1949). The 

 animals are not made totally diabetic by this procedure but it demonstrates 

 that functional disturbance can be induced without gross cell damage. 



Alterations of Blood Glucose 



Administration of alloxan leads to a characteristic triphasic variation 

 of the blood glucose in mammals, birds, reptiles, and certain fish. There 

 is a rapid initial hyperglycemia lasting for 3-4 hr, followed by a temporary 

 hypoglycemia usually of 6-12 hr duration, and finally a rise to a permanent 

 diabetic hyperglycemia. The exact time relations vary with the species 

 and to some extent the dose. There is an unexplainable variation in response 

 among individuals and a certain fraction in a population seems to be quite 

 resistant. The degree of the initial hyperglycemia can be correlated with 

 the eventual appearance of the diabetic state, and thus it was concluded 

 that the final fate of the animal is determined within a few minutes of the 

 injection (Lisewski and Mohnike, 1959 b). The hypoglycemia, however, 

 is greater in those animals showing a small initial hyperglycemia and failure 

 to develop diabetes. A typical blood glucose curve is shown in Fig. 4-3. 

 Gaarenstroom and Siderius (1954) believe there is initially both a hypo- 

 and a hyperglycemic effect of alloxan, the latter usually masking the former. 



Early death from alloxan is usually due to the severe hypoglycemia which 

 is often produced. Jacobs (1937) was the first to show that convulsions 

 during this period can be readily prevented by the administration of 

 glucose, and it is now common practice in the production of alloxan diabetes 

 to protect the animals during the first day by injecting glucose as needed, 

 since this procedure does not affect the development of diabetes, as shown 

 by Bailey and Bailey (1943). 



An unexpected response to alloxan has recently been observed in heredi- 

 tarily obese hyperglycemic mice (Solomon and Mayer, 1962 a, b). These 



