410 4. ALLOXAN 



against the vasoconstrictive theory. We may thus assume that the action 

 is on the /5-cells. 



Possible Reasons for the Selective Damage to the /?-Cells 



There are two important questions to be answered. Why are the /5-cells 

 so remarkably susceptible to alloxan, and what is the mechanism by which 

 alloxan damages the /5-cells? The first question will be considered in this 

 section. Whatever the reason for the high susceptibility of the y5-cells, 

 it is evident that this is a common property of insulin- secreting cells, 

 inasmuch as it occurs in so many types of animal. 



(A) Selective accumulation of alloxan in the /3-cells. Total analyses of the 

 pancreas and radioautography of the islets have failed to demonstrate 

 accumulation of alloxan; indeed, there seems to be generally a lower con- 

 centration than in many other tissues (page 394). There is thus sufficient 

 evidence to eliminate this unlikely hypothesis. 



(B) The intracellular pH of the fi-cells is low. Alloxan is more stable the 

 lower the pH and it has been suggested that the /?-cells may have a particu- 

 larly low pH, the alloxan level thus remaining higher for a longer period 

 (Klebanoff and Greenbaum, 1954). It is doubtful if the alkaline acinar 

 secretion would affect the intracellular pH of the /5-cells, as postulated. 

 No reliable pH determinations in these cells have been made so there is 

 at present no positive evidence for this hypothesis. 



(C) The extra- or intracellular glucose concentration of the ^-cells is low. 

 Glucose protects the /?-cells against alloxan and we have seen that Arteta 

 et al. (1954) thought the glucose concentration around these cells would 

 determine their susceptibility to alloxan. Bhattacharya (1953) believed 

 the /5-cells might contain low concentrations of glucose because of the 

 high insulin content. It seems very unlikely that the glucose concentration 

 around the /?-cells would be different from that in other tissues in view of 

 the rapid equilibration of glucose between plasma and intercellular tissue 

 fluid, and the fact that administration of glucose protects the cells. Little 

 can be said about the internal glucose until direct determinations are made. 



(D) The f^-cells contain a low concentration of glutathione. Glutathione 

 readily reacts with alloxan and exerts a protective action. Using 2,2'- 

 dihydroxy-6,6'-dinaphthyldisulfide, a reagent measuring protein SH groups, 

 Barrnett and Seligman (1952) found that islet tissue is very low in such 

 SH groups, and Lazarow (1954 a) postulated that the glutathione level 

 may also be low, due to the utilization of much of the cysteine in insulin 

 synthesis. Lazarow felt that a low concentration of glutathione might pre- 

 dispose the /5-cells to alloxan damage, other cells being more adequately 

 protected. Ina&much as alloxan is so unstable in solutions free of thiols, 



