Further Observations Concerning the Hyperglycemic Activity of Benzothiadiazines

Abstract

Hyperglycemia has been produced by a series of BZD in the normal rat. Diazoxide is the most potent hyperglycemic agent examined in this series and its action is complemented by combination with several other BZD. Examination in pregnant rats showed a complementary activity between diazoxide and trichlormethiazide, which had not been obtained in the normal rat. Hyperglycemic action is obtained in hypophysectomized, and demedullated rats, thus excluding these endocrine organs as necessary for production of hyperglycemia. The results in adrenalectomized rats are inconclusive. Histological sections showed evidence of degranulation in the beta cells of the islets of Langerhans in rats treated chronically with trichlormethiazide and diazoxide, an effect which was not shown during an acute experiment. The hyperglycemic action of these BZD could be overcome by oral tolbutamide. The hyperglycemic action of hydrochlorothiazide, a potassium losing BZD, as well as of diazoxide, which is not known to cause potassium loss, was overcome by concomitant administration of potassium salts. Although the etiology of BZD hyperglycemia remains obscure, its production in the normal rat by many substances of similar chemical structure, lends support to the recently made clinical observations concerning the long term diabetogenic action of BZD in man.4