Sex-steroid milieu determines diabetes rescue in pttg-null mice

M. Fraenkel, J. Caloyeras, S. G. Ren, S. Melmed

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Male mice that are pttg-null develop sexually dimorphic diabetes with hypoinsulinemia secondary to reduced postnatal β-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 17β-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 m /dl for ptt -/- controls and 371 ± 14 mg/dl for pttg-/- mice gonadectomized 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 β-cell proliferation in the absence of pttg are restored by sex-steroid effects on peripheral insulin sensitivity.

Original languageEnglish
Pages (from-to)519-528
Number of pages10
JournalJournal of Endocrinology
Volume189
Issue number3
DOIs
StatePublished - 1 Jun 2006
Externally publishedYes

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