Androgen Sensitization of Streptozotocin-induced Diabetes in Mice

Abstract

Male mice are more sensitive to the diabetogenic effect of streptozotocin (SZ) than female mice. These studies were designed to determine whether sex hormones could be responsible. A single intraperitoneal (i.p.) dose of 80 mg SZ/kg regularly induced acute severe diabetes in 45 day old male CD-1 mice beginning after 1 day, whereas females of the same age and strain remained euglyce-mic for 75 days after the same SZ dose. With 120 mg SZ/kg, similar female mice developed a mild, delayed hyperglycemia 41 days after injection. Inbred strains (DB A/2 J) demonstrated a similar sex relationship. In 45 day old male CD-1 mice, pretreatments with antiandrogen (SCH.13521) reduced the hyperglycemie effect of SZ when compared with control male mice given the same SZ dose (P < 0.001). Castration of male CD-1 mice before SZ also caused a milder hyperglycemia than in sham-operated control mice (P < 0.001). Pretreatment with estrogens before SZ in male CD-1 mice had little effect. Female CD-1 mice, given 10 mg testosterone twice before the 120 mg SZ/kg injection, showed an increased sensitivity to SZ-induced diabetes when compared with female control mice or with female mice pretreated with only 1 mg testosterone (P < 0.001). Examination of the pancreases of these animals showed that the testosterone effect was accompanied by enhanced β cell destruction and increased and more centrally placed α cells within islets. Phenobarbital when given daily for 7 days before the SZ injection potentiated the diabetogenic effect of SZ in male CD-1 mice and in female mice. These studies are consistent with an important action of testosterone in potentiating the pancreatic /3 cell toxicity of SZ. The similar synergistic effect of phénobarbital may help to clarify the biochemical mechanism of SZ-induced pancreatic β cell destruction.