416 4. ALLOXAN 



a pentose-P pathway exists, glucose is readily oxidized and incorporated 

 into lipid, and leucine is incorporated into insulin. Studies of changes 

 induced by subdiabetogenic doses of alloxan might also be valuable. Mo- 

 lander and Kirschbaum (1949) reported, for example, that rats given 20 

 mg/kg alloxan intravenously every other day demonstrate a functional im- 

 pairment of the /5-cells without visible changes. One would like to know 

 how alloxan affects the synthesis and release of insulin, and especially if 

 it modifies the response to elevated glucose. Increasing the glucose con- 

 centration in the perfusate of both intact and isolated pancreas evokes 

 an augmented output of insulin, and also protects against alloxan. It will 

 be recalled that /?-cell tumors are resistant to alloxan, and that obese 

 hyperglycemic mice, with hyperplastic and hypersecreting islets, exhibit 

 only a fall in blood glucose when alloxan is administered (page 391). 

 The /?-cells of treated obese mice are heavily granulated while those of 

 treated normal mice are degranulated, as if some effect on insulin synthesis 

 or release has occurred. If the /5-cells of rabbits are stimulated by giving 

 cortisone, the response to alloxan is altered, some resistance being mani- 

 fest and the degeneration of the /5-cells assuming a different course (Volk 

 and Lazarus, 1961). All of these results point vaguely to a relationship 

 between the action of alloxan and the controlling factors in insulin synthesis 

 or release. Since the /?-cells are specialized to provide insulin, possibly 

 anything which sufficiently disturbs this process could readily and rapidly 

 damage the cells. 



Glucose may accelerate insulin liberation from the /?-cells by reacting 

 with some receptor in the membrane and alloxan might also attack this 

 site, which would account for the protection afforded by glucose. The 

 protection is presumably not related to the metabolism of glucose since 

 3-methyl-D-glucose is also effective. The protection observed with barbi- 

 turate might also indicate a competition for some site having affinity 

 for structures of this type. Could alloxan by reacting with this site stimulate 

 the formation of insulin to such a degree that the /?-cells are damaged, as 

 gastric parietal cells can be damaged by overstimulation of acid secretion? 

 One recalls that the insulin content of the pancreas rises initially after 

 alloxan, and at 24 hr when the diabetic state is developing, the insulin 

 level is not significantly different from normal values (Dixit et al., 1962), 

 and yet there is evidence that during the first 24 hr there is at times a marked 

 release of insulin. Effects of alloxan on the release mechanisms or the glucose 

 control of release might also be invoked. Glucose infused into rats for 

 several hours stimulates the /5-cells and depletes them of granules and 

 Zn++; alloxan is now ineffective in inducing the diabetic state, but the 

 susceptibility returns after 1 hr (Kaneko and Logothetopoulos, 1963). 

 The granulation, Zn++ content, and insuhn-secreting activity are not the 

 important factors here since /?-cells depleted of granules and Zn++ by pro- 



