University of Pennsylvania School of Medicine, 803B Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399, USA.
Endocrinology. 2010 Nov;151(11):5174-84. doi: 10.1210/en.2010-0379. Epub 2010 Sep 15.
The pancreas-derived hormones, insulin and glucagon, are the two main regulators of glucose homeostasis. However, their actions can be modulated by the presence of other circulating factors including cytokines. Pancreatic-derived factor (PANDER) is a novel cytokine-like molecule secreted from the endocrine pancreas, but its biological function is currently unknown. To address this, we employed adenoviral gene delivery to develop a novel murine model of PANDER overexpression, which we used to study PANDER's effect on glucose homeostasis. Although serum metabolites in fed mice were unaffected by PANDER overexpression, fasting glucose, insulin, and corticosterone levels were significantly elevated. Additionally, PANDER-overexpressing mice displayed elevated glucose and insulin levels during a glucose tolerance test, indicating that glucose tolerance was impaired. However, there were no defects in glucose-stimulated insulin secretion or peripheral insulin sensitivity. Elevated transcription of hepatic gluconeogenic genes, PEPCK and G6Pase accompanied the fasting hyperglycemia observed in PANDER-overexpressing animals. Similarly, treatment of primary hepatocytes with PANDER-expressing adenovirus or PANDER-enriched conditioned medium elevated gluconeogenic gene expression and glucose output. PANDER treatment also resulted in higher levels of Ser133-phosphorylated cAMP-response element-binding protein in hepatocytes stimulated with 8-bromo-cAMP and dexamethasone and higher levels of intracellular cAMP upon stimulation with forskolin. In summary, we provide the first report that identifies PANDER as a regulator of hepatic glucose metabolism, where it serves as a novel factor that amplifies hepatic cAMP and cAMP-response element-binding protein signaling to induce gluconeogenic gene expression and glucose output.
胰腺衍生的激素胰岛素和胰高血糖素是葡萄糖稳态的两个主要调节剂。然而，它们的作用可以通过其他循环因子（包括细胞因子）的存在来调节。胰腺衍生因子（PANDER）是一种从内分泌胰腺分泌的新型细胞因子样分子，但它的生物学功能目前尚不清楚。为了解决这个问题，我们采用腺病毒基因传递来开发一种新型的 PANDER 过表达小鼠模型，我们用它来研究 PANDER 对葡萄糖稳态的影响。虽然喂食小鼠的血清代谢物不受 PANDER 过表达的影响，但空腹血糖、胰岛素和皮质酮水平显著升高。此外，PANDER 过表达小鼠在葡萄糖耐量试验中表现出升高的葡萄糖和胰岛素水平，表明葡萄糖耐量受损。然而，葡萄糖刺激的胰岛素分泌或外周胰岛素敏感性没有缺陷。肝糖异生基因（PEPCK 和 G6Pase）的转录升高伴随着 PANDER 过表达动物观察到的空腹高血糖。同样，用表达 PANDER 的腺病毒或富含 PANDER 的条件培养基处理原代肝细胞会升高糖异生基因的表达和葡萄糖的产生。PANDER 处理还导致用 8-溴-cAMP 和地塞米松刺激的肝细胞中 Ser133 磷酸化 cAMP 反应元件结合蛋白水平升高，以及用 forskolin 刺激时细胞内 cAMP 水平升高。总之，我们首次报道了 PANDER 是肝葡萄糖代谢的调节剂，它作为一种新型因子，可放大肝 cAMP 和 cAMP 反应元件结合蛋白信号，诱导糖异生基因的表达和葡萄糖的产生。
