MECHANISMS IN HYPERGLYCEMIA AND HYPOGLYCEMIA 407 



not contradicted by some experiments. Increased adrenal and sympathetic 

 activity is probably involved, at least in part, but we do not know the 

 site of alloxan action; it could be a nonspecific stress reaction or directly 

 on the adrenals, the latter being favored by the marked histological changes 

 and the severe fall in adrenal SH groups (page 387). Contributions could 

 be made from suppression of insulin release of a general minor depression 

 of hexokinase activity. If it is true that the degree of initial hyperglycemia 

 is correlated with the severity of the final diabetic state, it seems more 

 likely that the primary action is on the /5-cells. 



Hypoglycemia 



Hypoglycemia usually results from (1) increased utilization of glucose 

 by the tissues, (2) increased renal excretion of glucose, or (3) a suppres- 

 sion of the release of glucose from the tissues into the blood. The renal 

 mechanism can be immediately eliminated for alloxan since there is no eleva- 

 tion of glucose excretion (Wrenshall et al., 1950). It is not so easy to decide 

 definitely between the other two possibilities. 



The most commonly accepted mechanism for the hypoglycemia is that 

 insulin, preformed and stored in the /5-cells, is released during the damage 

 to these cells by alloxan (Hughes et at., 1944; Kadota, 1950). The original 

 suggestion by Jacobs (1937) that alloxan itself might have an insulin-like 

 action has been adequately shown to be incorrect, as has the early theory 

 of Dunn et al. (1943 a) that there is a transitory stimulation of the /5-cells 

 by alloxan, since at the time of hypoglycemia these cells are usually quite 

 severely damaged. A very early stimulation, however, may occur and ac- 

 count for the occasional hypoglycemia noted during the first hour but is 

 usually masked by the hyperglycemia (Gaarenstroom and Siderius, 1954). 

 The following evidence for the release of insulin from the degenerating 

 /5-cells as the origin of the hypoglycemia can be cited. (1 ) Pancreatectomy or 

 previous destruction of the /?-cells with alloxan abolishes the hypoglycemia, 

 so that pancreatic tissue seems to be necessary for this response (Goldner 

 and Gomori, 1944; Kennedy and Lukens, 1944; Eidout et al., 1944). (2) The 

 hypoglycemic response can be simulated by the injection of insulin in the 

 amount occurring within the pancreas (Hughes et al., 1944). (3) The in- 

 sulin content of the pancreas appears to fall during ^-cell necrosis and at 

 the beginning of the hypoglycemia, but unfortunately no values were 

 obtained during the hypoglycemic stage (Ridout et al., 1944). (4) Alloxan 

 does not alter the utilization of glucose in the eviscerated cat (Corkill 

 et al., 1944). (5) Sulfonylureas stimulate the release of insulin from the 

 pancreas so that pretreatment with these drugs should reduce the hypo- 

 glycemic response to alloxan if it is mediated through insulin release, and 

 this has been found to be the case (Klimas and Searle, 1958; Volk and 

 Lazarus, 1961). (6) Neither adrenalectomy nor hypophysectomy prevents 



