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.

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