DIABETOGENIC ACTION 383 



given alloxan, just as they are in diabetes of any other origin, and these 

 changes are undoubtedly due to the hypoinsulinemia rather than to a direct 

 effect of the alloxan (El Hawary, 1955; El Hawary and Thompson, 1954). 

 The hyperlipemia and hypercholesterolemia seen around 5-10 days after 

 the administration of alloxan to rabbits are also caused mainly by the dia- 

 betic state, since the levels can be reduced by insulin (Kendall et al., 1945). 

 However, certain other blood changes may be due to the alloxan directly. 

 Thus alloxan causes marked uricacidemia 12-36 hr after injection in pigeons 

 (Saviano and Leone, 1946) and a creatinuria, accompanied by increased 

 K+ and decreased phosphate excretion, in rabbits (Bruns and Wiist, 1952). 

 Whether these changes reflect an action of alloxan on the kidney or on 

 tissue metabolism is not known. 



Diabetogenic Doses and the Factors Determining Susceptibility to Alloxan 



The effectiveness of alloxan in producing selective /?-cell destruction and 

 .permanent diabetes in a particular species depends on several factors. 

 One of these factors must be the blood thiol level: the greater the thiol 

 concentration, the less alloxan reaches the pancreas. Swenson et al. (1959) 

 found that various strains of mice respond differently to alloxan, and that 

 the more resistant strains have higher erythrocytic GSH, so that both 

 GSH levels and alloxan susceptibility seem to be genetically controlled. 

 Another factor is the blood glucose concentration (see page 390) and this 

 may be altered by the diet or other means. Saito et al. (1959) showed that 

 the diabetic response in rats is most frequent when the animals have been 

 on a high protein, high fat, and high calory diet. It has become more and 

 more evident that, to achieve the most consistent results, it is necessary 

 to starve the animals 24-60 hr before the administration of alloxan. Kass 

 and Waisbren (1945) developed a reliable method for producing diabetic 

 rats by starving the animals for at least 48 hr prior to the injection of 

 alloxan, in which case 175 mg/kg of alloxan gives 90-95% chronically 

 diabetic animals when administered subcutaneously. If the rats are not 

 starved, only 25% become diabetic. A third factor is apparently the age 

 of the animal. Lisewski and Mohnike (1959 a) attempted to correlate the 

 diabetic response in rabbits with various factors, such as body weight, 

 plasma protein, and other variables, but the only statistically valid cor- 

 relation was with age, younger animals being less sensitive to alloxan. A 

 fourth important factor is the rate at which the alloxan is injected intra- 

 venously, as would be expected of a substance which is very unstable. 

 Pincus et al. (1954) established that lower doses (around 75 mg/kg) are 

 effective in rabbits when injected within 1 min but completely ineffective 

 if over 5 min are taken; higher doses can be injected more slowly. As al- 

 loxan is injected into the blood stream, a certain fraction is destroyed in 

 the blood and another fraction is removed by the tissues; if the rate of 



