Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced postnatal -cell proliferation and an inability to expand islet cell mass with aging. We therefore examined the effects of sex-steroid manipulation on diabetes development in pttg / male mice. Surgical gonadectomy was followed by implantation of 90-day slow-release pellets releasing 17 -estradiol (0·36 mg/pellet), placebo or dihydrotestosterone (DHT; 12·5 mg/pellet). Mean fasting blood sugars at the end of the study were 414 54 mg/dl for pttg . Gonadectomy with and without estradiol treatment did not increase the very low circulating insulin levels in pttg-null males (fasting insulin 0·44 0·04 ng/ml in pttg / controls, 0·47 0·07 and 0·4 ng/ml in pttg / gonadectomized males treated with placebo or estradiol, respectively). Gonadectomy increased serum adiponectin levels (4·9 008 µg/ml in pttg / controls versus 13 0·08 and 7·5 0·6 µg/ml in pttg / gonadectomized males treated with placebo or estradiol, respectively; P<0·001 and P<0·05), accompanied by increased insulin sensitivity. The results show that gonadectomy delayed, and gonadectomy with additional estradiol treatment prevented, diabetes development in pttg / males, possibly through increased insulin sensitivity mediated by elevated serum adiponectin levels. Male-selective effects of disrupted -cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.