Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3′,5′-cyclic monophosphate (cAMP)–cAMP-dependent protein kinase (PKA)–cAMP response element–binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

组织间的交流是代谢调节的基本特征，肝脏是这一过程的核心。我们已经确定sparc相关的模块化钙结合蛋白1（SMOC1）作为葡萄糖反应性肝素和葡萄糖稳态的调节剂。急性腹膜内给予SMOC1可改善小鼠的血糖控制和胰岛素敏感性，而胰岛素分泌不会改变。SMOC1通过抑制肝脏中的腺苷3'，5'-环一磷酸（cAMP）–cAMP依赖性蛋白激酶（PKA）–cAMP反应元件结合蛋白（CREB）信号传导发挥良好的降糖作用，从而导致糖原异生性基因表达降低和抑制肝葡萄糖输出。db / db小鼠，对肥胖，肝组织病理学或炎症无不良影响。此外，循环中的SMOC1与肝脏和全身胰岛素敏感性相关，并且在肥胖，胰岛素抵抗的人中减少。在一起，这些发现确定SMOC1作为2型糖尿病的血糖控制管理的潜在药理学目标。