Fetal androgen signaling defects affect pancreatic β-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats
Fetal androgen signaling defects affect pancreatic β-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats
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DOI：
10.1152/ajpendo.00173.2019
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发表时间：
2019-11-01
影响因子：
5.1
通讯作者：
Yamaji, Ryoichi
中科院分区：
文献类型：
--
作者：
Harada, Naoki;Yotsumoto, Yusuke;Yamaji, Ryoichi
我们之前证明了雄激素信号在性成熟期扩大胰腺β细胞群（Am J Physiol Endocrinol Metab 314：E274-E286，2018）。本研究的目的是阐明胎儿雄激素信号传导是否在成年后β细胞群发育和β细胞功能中起重要作用，这些缺陷与2型糖尿病相关。在雄性胎儿胰腺中，雄激素受体（AR）在Nkx6.1阳性β细胞前体细胞的细胞质和细胞膜中强烈表达，但在胰岛素阳性β细胞中显著降低。在妊娠晚期对妊娠母鼠给予抗雄激素氟替卡松，以雄性特异性方式降低了出生时的β细胞质量和Ki 67阳性增殖β细胞，而不影响体重。在6周龄和12周龄时，当大鼠喂食标准饮食时，暴露于氟他胺的雄性大鼠中β细胞质量的减少未恢复，而当大鼠喂食高脂饮食（HFD）时，β细胞质量的减少完全恢复。子宫内氟暴露导致雄性大鼠发生葡萄糖耐受不良，原因是喂食HFD而非标准饮食时胰岛素分泌减少。无论饮食如何，两组之间的胰岛素敏感性没有差异。这些结果表明，胎儿雄激素的作用有助于β-细胞的质量扩张，在出生时的性别特异性的方式和葡萄糖耐受不良的发展，通过减少胰岛素分泌的HFD喂养的雄性大鼠。我们的数据表明，胎儿雄激素信号通过影响胰腺β细胞功能参与了健康和疾病的发育起源中的假设性别差异。
We previously demonstrated that androgen signaling expands pancreatic beta-cell mass in the sexual maturation period (Am J Physiol Endocrinol Metab 314: E274-E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in beta-cell mass development and beta-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive beta-cell precursor cells but was markedly reduced in insulin-positive beta-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced beta-cell mass and Ki67-positive proliferating beta-cells at birth in a male-specific manner without affecting body weight. The decrease of beta-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to beta-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic beta-cell function.