Genetic control of susceptibility to streptozotocin diabetes in inbred mice: effect of testosterone and H-2 haplotype.

Males of certain mouse strains are more susceptible than females to the diabetogenic effect of multiple low doses of streptozotocin (MSZ, 40 mg/kg BW.day X 5). Several investigators linked sensitivity to the potentiating action of androgens and genes of the major histocompatibility (H-2) complex. Our studies were designed to investigate the role of testosterone in MSZ-diabetes induction in males of three C3H stocks: C3H X SW/SnJ (H-2b), C3HeB/FeJ (H-2k), and C3H/OuJ (H-2k). Serum testosterone levels in gonad-intact animals correlated inversely with SZ sensitivity, the more resistant C3HeB/FeJ males having a higher mean level than the other two stocks. Males from each group were castrated at 4 weeks of age and implanted with either testosterone or cholesterol; 4 weeks later they were given MSZ. C3H.SW/SnJ and C3H/OuJ castrates implanted with either testosterone or cholesterol were as sensitive to the hyperglycemic effect of MSZ as the intact controls, whereas C3HeB/FeJ castrates implanted with cholesterol lost sensitivity; this sensitivity could be fully restored by testosterone implants. Surprisingly, there was no difference in the residual pancreatic insulin content (90% reduced) between the SZ-resistant cholesterol-implanted vs. the SZ-sensitive testosterone-implanted C3HeB/FeJ castrates. This demonstrated that the androgen was not potentiating SZ destruction of the beta-cells, but rather was antagonizing the ability of the residual insulin to maintain glycemic control. The present study also indicated that the H-2 complex was not a significant factor predisposing to SZ sensitivity as reflected by marked sensitivity of the C3H/OuJ and C3H.SW/SnJ males vs. the relative resistance of C3HeB/FeJ males sharing the same H-2 haplotype as C3H/OuJ.