412 4. ALLOXAN 



but the degree of dependence of the tissue on that substance. Until we know 

 more of the nature of such a critical component in the /?-ceUs, it is difficult 

 to evaluate this theory of selectivity. 



It is thus clear that despite the many postulates which have been made, 

 we do not understand at all the reason for the greater susceptibility of 

 the /5-cells. It is difficult to explain satisfactorily why no other SH reagents 

 act in this way if SH components of the /?-cells are the targets for alloxan 

 action. Perhaps insufficient attention has been paid to the one definite 

 characteristic of ^-cells, their special function of synthesizing and releasing 

 insulin, especially in response to an elevated glucose concentration. Unfor- 

 tunately, very little is known of the mechanisms and controls for the se- 

 cretion of insulin. 



Possible Mechanisms by Which Alloxan Damages the /?-Cells 



One can only speculate as to how alloxan acts on the /?-cells. With respect 

 to the possible sites of the action, most of the theories can be classified as 

 follows: (1) an SH enzyme, (2) a thiol cofactor (e. g., glutathione or coen- 

 zyme A), (3) a metal ion or metalloenzyme, (4) an enzyme catalyzing some 

 reaction in pyridmidine or purine metabolism, or (5) a nonenzymic mem- 

 brane component. One general difficulty is understanding how the reaction 

 of alloxan with these sites so rapidly and extensively damages the /?-cells. 

 A simple inhibition of some metabolic pathway seldom evokes such im- 

 mediate cytological changes in tissue, and many inhibitors capable of block- 

 ing the major pathways do not produce alloxan-like effects in the /5-cells. 

 Even anoxia for several minutes does not harm these cells. This, taken 

 in conjunction with the selectivity, must mean that some component 

 intimately related to the maintenance of cell structure is attacked, or some 

 component involved in the particular functions of the /?-cells. The various 

 theories will be briefly mentioned and discussed. 



(A) Inhibition of hexokinase. Griffiths (1949) thought that previous 

 indirect evidence might point to an inhibition of hexokinase, and this 

 received some support from the observation by Bhattacharya (1954) that 

 glucose can protect the /?-cells against alloxan. The main difficulty is 

 that the protective potencies do not run parallel with the affinities of 

 the known hexokinases for various sugars (Villar-Palasi et al., 1957), but 

 one must admit that the properties of /5-cell hexokinase are unknown. 

 The sensitivities of the examined hexokinases to alloxan are not enough 

 to allow one to predict a very significant inhibition at the concentrations 

 reached in vivo, and unless a very marked block occurs it is difficult to 

 understand how rapid structural changes would be produced. Finally, 

 unless the B-cell hexokinase is much different from that of other tissues. 



