Poorly controlled NOD spontaneously diabetic mice were proven to have significantly less plasma and testicular testosterone than well-controlled diabetic mice (489 +/- 15 ng/dl and 3.89 +/- 0.79 micrograms/100 g tissue, vs. 176 +/- 24 and 9.00 +/- 1.24, respectively), and these in turn had significantly less than NOD non-diabetic control mice. These data were consistent with our previous observation of a decrease in total plasma and testicular testosterone levels in streptozotocin diabetic rats. A greater difference between total plasma testosterone levels and free testosterone levels was found in streptozotocin diabetic rats (17 +/- 4 ng/dl vs. 91 +/- 7 ng/dl) than in control rats (660 +/- 141 vs. 352 +/- 77). Fat droplets, depicting blocked testosterone synthesis, were found in the testicular Leydig cells of streptozotocin diabetic rats and disappeared with insulin treatment. No difference was found among plasma total testosterone concentrations in people in different stages of diabetes, as had been previously reported. However, human diabetic males, free of complications but poorly controlled, had less free testosterone than those without complications but well controlled (18.0 +/- 2.0 pg/ml vs. 22.8 +/- 1.3), who in turn had significantly less than age-matched controls (25.3 +/- 1.1 pg/ml). These data suggest gonadal dysfunction in diabetes mellitus.