骨钙素在糖代谢中的研究进展

杨焱平，封启明

(上海交通大学附属第六人民医院急诊医学科，上海 200233)

骨钙素在糖代谢中的研究进展

杨焱平，封启明

(上海交通大学附属第六人民医院急诊医学科，上海 200233)

骨钙素（Osteocalcin，OC）是成骨细胞分泌并沉积在骨基质中的非胶原蛋白，参与骨的矿化。糖代谢可以影响成骨细胞活性，最近研究发现羧化不全骨钙素(uncarboxylatedostecalcin，ucOC）可以促进小鼠胰岛β细胞增殖，胰岛素分泌，增强胰岛素敏感性，进而调控血糖。在糖尿病人群中也发现骨钙素含量与血糖、胰岛素抵抗等存在相关性，这将有助于在控制血糖领域的研究。

骨钙素；血糖；胰岛素；胰岛素受体

一直以来，骨骼仅仅被认为是构成机体的结构器官，但近年来人们发现骨骼也是一种内分泌器官。通过对小鼠的研究显示小鼠体内成骨细胞分泌的骨钙素增加可以调节脂肪含量、促进胰岛β细胞增殖、增加胰岛素的表达及分泌，降低血糖和改善糖耐量，进而调控机体能量代谢[1]。骨钙素作为一种由内分泌激素影响糖代谢越来越受到关注，本文主要阐述关于骨钙素对糖代谢影响的研究进展。

1 OC的基本情况

OC是一种沉积于骨基质中的非胶原蛋白，由成骨细胞、成牙质细胞、软骨细胞分泌，最近研究发现循环内皮祖细胞(circulating endothelial progenitor cells，EPCs)中亦可检测到骨钙素的存在[2]。骨钙素基因包含4个外显子和3个内含子，转录和翻译过程受维生素D3和维生素K2的影响[3]，翻译形成的前体骨钙素含98个氨基酸，该肽链在内质网转移的过程中经过两次裂解，形成含49个氨基酸，分子量约为5 800。绝大多数骨钙素[4]在受体样跨膜蛋白酪氨酸磷酸酶(osteoblast protein tyrosine phosphatase，OST-PTP)和维生素K依赖的γ-谷氨酸羧化酶(γ-glutamylcarboxylase，GGCX)的作用下形成肽链中17、21和24号位含γ-羧基谷氨酸残基的羧化骨钙素(carboxylated ostecalcin，cOC)[5]。cOC与钙离子亲和力高，有利于结合羟磷灰石沉积于骨基质中[6]，小部分骨钙素以羧化不全骨钙素(uncarboxylatedostecalcin，ucOC)的形式释放入血[3]。血浆中总OC含量依赖于成骨细胞功能，而ucOC含量依赖维生素K活性[7]。目前已经证实ucOC为骨钙素的活性形式参与能量的调节[1]。

2 OC在糖代谢中的研究进展

2.1 胰岛素-骨钙素信号前馈调节的形成 胰岛素可以通过成骨细胞膜上的胰岛素受体(insulin receptor，Insr)促进成骨细胞增殖和分化，增加骨钙素mRNA的表达和OC的分泌[8]，而血清ucOC通过作用于胰岛β细胞膜上的G蛋白耦联受体C家族6组(G-protein-coupled receptor 6a，Gprc6a)使小鼠胰岛β细胞增殖、胰岛素表达及分泌增加[1]，该过程为胰岛素-骨钙素信号前馈调节[3]。

2.1.1 增强胰岛素-骨钙素信号前馈调节的途径胰岛素不仅有促进成骨细胞分化的作用[8-9]，也可通过成骨细胞膜Insr减弱TWIST2对RUNX2的抑制作用，使链接到骨钙素启动子的RUNX2比例增加，增强骨钙素启动子的表达[8-10]；同时能使骨保护素(osteoprotegerin，OPG)的减少表达[8]，减弱OPG对核因子κB受体活化因子配体(receptor activator for nuclear factor-κB ligand，RANKL)的抑制，进而增加破骨细胞的活性，促使骨基质形成pH 4.5的微环境，该酸性环境中骨基质cOC第C17脱羧，形成ucOC进入血液[11]。以上多种途径共同使血清ucOC浓度增加，增加的ucOC不仅可以直接作用于胰岛细胞膜表面的Gprc6a，也可通过刺激肠细胞的Gprc6a使肠细胞分泌人胰高血糖素样肽1 (glucagon-like peptide-1，GLP-1)增加[12-13]，间接促进胰岛素分泌增多；另外，血清ucOC不仅可以保护高血糖环境下小鼠胰岛细胞的功能[14]，也可以刺激脂肪细胞分泌脂联素进而增强胰岛素的敏感性[1]。

2.1.2 减弱胰岛素-骨钙素信号前馈调节的途径 研究发现Esp基因敲除的小鼠血清ucOC水平升高，表明Esp基因介导OC的生成[1]。Esp基因在小鼠成骨细胞中特异性表达生成OST-PTP，在GGCX的协同作用下可以使ucOC羧化成cOC；ESP的活性受转录激活因子-4(activating transcription factor 4，ATF4)和FoxO1的调节，ATF4或FOXO1可与ESP启动子相连，促进下游ESP表达OST-PTP[15-17]，同时OST-PTP可以抑制Insr的活性[11]，阻碍ucOC的生成。除此之外，持续高血糖不仅可降低成骨细胞Insr对胰岛素的敏感性，产生胰岛素抵抗，也可直接抑制成骨细胞生长和骨钙素表达的作用[18]，Hamada等[19]还发现高血糖对成骨细胞有直接的毒害作用，这可能与高血糖刺激活性氧簇(reactive oxygen species，ROS)增多、削弱成骨细胞功能有关[20]。

2.2 OC与糖代谢的关系 Lee等[1]发现OC缺失小鼠表现出胰岛体积和胰岛β细胞数目下降，血浆中胰岛素浓度及胰岛素敏感性降低，而血糖浓度升高，出现胰岛素抵抗，而外源性OC能改善该现象，这暗示OC与糖代谢可能呈负相关关系。临床研究发现糖尿病患者血清OC呈低水平，同时大部分横断面研究均显示血清骨钙素与糖代谢指标存在负相关关系，即血清骨钙素水平越低，血糖越高，这种负相关关系同样存在于血清骨钙素水平与糖化血红蛋白及胰岛素抵抗指数之间[21-25]。血清骨钙素水平越高，稳态模型评估的胰岛β细胞功能越好，这种相关关系同样存在于不同糖耐量状态及不同性别的人群中[26-28]。骨钙素与上述指标的负相关关系在糖耐量正常人群、Ⅰ型糖尿病及Ⅱ型糖尿病患者中均存在[29-31]。而且在不同性别、年龄、体重指数、种族以及是否绝经等状态下，骨钙素与糖代谢指标之间的变化趋势似乎都不受影响[32]。

3 展望

动物实验表明不同浓度的外源性ucOC能调节血糖代谢[1]，口服骨钙素能通过GLP-1途径促进胰岛素分泌，胰岛细胞增殖，降低血糖等[13]。骨钙素对机体能量代谢平衡起着重要的调控作用。在人群中对包括骨钙素在内的骨转换血清指标及其功能的进一步研究，有可能为糖尿病的发生发展及治疗提供新的理论依据和思路。近些年的研究多集中于骨钙素与胰岛β细胞的信号交流，ucOC的受体Gprc6a在胰岛素靶组织如骨骼肌、肝脏、脂肪组织内都有分布，关于其作用机制的研究目前很少，而且人的内分泌系统错综复杂，骨、胰岛、胰岛素靶器官等之间的各种信号通路、各种因素互相影响，难以确定骨钙素在机体中调节糖代谢和能量代谢中的独立性作用，因此，也应结合大量临床、流行病学证据进行综合评价。同时，骨钙素能否开辟为降血糖药物也需要得到进一步研究证实。可见，随着骨钙素对糖代谢的影响及其机制进一步阐明，将开辟糖尿病预防和治疗全新的领域。

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Research progress of osteocalcin in glucose metabolism.

YANG Yan-ping,FENG Qi-ming.Department of Emergency Medicine,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,CHINA

Osteocalcin(OC),secreted by osteoblasts,is a non-collagen protein and deposits in bone matrix,affecting bone mineralization.Glucose metabolism can affect osteoblast function.Recent studies have shown that uncarboxylatedostecalcin(ucOC)can promote mouse islet beta cells proliferation and insulin secretion,increase insulin sensitivity and control blood glucose.The findings of the correlations between osteocalcin content and glucose,insulin resistance in patients with type 2 diabetes mellitus(T2DM)would contribute to the control of blood glucose.

Osteocalcin;Blood glucose;Insulin;Insulin receptor

R589.1

A

1003—6350（2016）19—3204—03

10.3969/j.issn.1003-6350.2016.19.036

2015-11-13)

封启明。E-mail：fengqiming04@126.com