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Cedars-Sinai Research Institute, David Geffen School of Medicine at UCLA, 8700 Beverly Blvd, Los Angeles, California 90048, USA

(Requests for offprints should be addressed to S Melmed, Academic Affairs, Room 2015, Cedars-Sinai Medical Center; Email: melmed{at}csmc.edu)

Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced post-natal -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 17ß-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^–/– controls and 371 ± 14 mg/dl for pttg^–/– mice gonad-ectomized and treated with DHT compared with 124 ± 40 and 85 ± 12 mg/dl in gonadectomized pttg^–/– males treated with placebo or estradiol, respectively (P < 0.01 compared with control 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 ß-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.

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