Faculty of Health and Medical Science, Myeloma Research Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
J Cell Physiol. 2018 May;233(5):3769-3783. doi: 10.1002/jcp.26163. Epub 2017 Sep 18.
The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new regulatory axes remains in its infancy, the bone-specific protein, osteocalcin, has been shown to be centrally involved. Undercarboxylated osteocalcin acts as a secretagogue in a feed-forward loop to stimulate pancreatic β-cell proliferation and insulin secretion, improve insulin sensitivity, and promote testosterone production. Importantly, dysregulation of insulin signaling in bone causes a reduction in serum osteocalcin levels that is associated with elevated blood glucose and reduced serum insulin levels, suggesting that the skeleton may play a significant role in the development of diet-induced insulin resistance. Insulin signaling is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) which becomes hyper-activated in response to nutrient overload. Loss- and gain-of function models suggest that mTORC1 function in bone is essential for normal skeletal development; however, the role of this complex in the regulation of glucose metabolism remains to be determined. This review highlights our current understanding of the role played by osteocalcin in the skeletal regulation of glucose metabolism and fertility. In particular, it examines data emerging from transgenic mouse models which have revealed a pancreas-bone-testis regulatory axis and discusses recent human studies which seek to corroborate findings from mouse models with clinical observations. Moreover, we review recent studies which suggest dysregulation of insulin signaling in bone leads to the development of insulin resistance and discuss the potential role of mTORC1 signaling in this process.
骨骼最近已成为调节全身葡萄糖代谢和男性生殖功能的关键胰岛素靶组织。尽管我们对这些新的调节轴的理解还处于起步阶段，但骨特异性蛋白骨钙素已被证明是其中的核心部分。未羧化的骨钙素作为一种促分泌物质，在一个正反馈循环中刺激胰岛β细胞增殖和胰岛素分泌，提高胰岛素敏感性，并促进睾酮生成。重要的是，骨骼中胰岛素信号的失调会导致血清骨钙素水平降低，这与血糖升高和血清胰岛素水平降低有关，这表明骨骼可能在饮食引起的胰岛素抵抗的发展中发挥重要作用。胰岛素信号受到雷帕霉素复合物 1 (mTORC1)的负调控，mTORC1 会对营养过剩产生过度激活。失活和获得功能模型表明，mTORC1 在骨骼中的功能对于正常的骨骼发育是必不可少的；然而，该复合物在调节葡萄糖代谢中的作用仍有待确定。这篇综述强调了我们目前对骨钙素在骨骼调节葡萄糖代谢和生育能力方面所起作用的理解。特别是，它研究了从转基因小鼠模型中得出的数据，这些数据揭示了胰腺-骨骼-睾丸调节轴，并讨论了最近的人类研究，这些研究试图用临床观察来证实小鼠模型的发现。此外，我们还回顾了最近的研究，这些研究表明骨骼中胰岛素信号的失调会导致胰岛素抵抗的发展，并讨论了 mTORC1 信号在这一过程中的潜在作用。
