Endocrinology, Vol 116, 2450-2455, Copyright © 1985 by Endocrine Society

ARTICLES

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

PH Le, EH Leiter and JR Leyendecker

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.