Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.
Diabetes. 2010 Sep;59(9):2209-18. doi: 10.2337/db09-1552. Epub 2010 Jun 21.
Pancreatic-derived factor (PANDER, FAM3B) is a pancreatic islet-specific cytokine-like protein that is secreted from beta-cells upon glucose stimulation. The biological function of PANDER is unknown, and to address this we generated and characterized a PANDER knockout mouse.
To generate the PANDER knockout mouse, the PANDER gene was disrupted and its expression was inhibited by homologous recombination via replacement of the first two exons, secretion signal peptide and transcriptional start site, with the neomycin gene. PANDER(-/-) mice were then phenotyped by a number of in vitro and in vivo tests to evaluate potential effects on glucose regulation, insulin sensitivity, and beta-cell morphology and function.
Glucose tolerance tests demonstrated significantly higher blood glucose levels in PANDER(-/-) versus wild-type male mice. To identify the mechanism of the glucose intolerance, insulin sensitivity and pancreatic beta-cell function were examined. Hyperinsulinemic-euglycemic clamps and insulin tolerance testing showed similar insulin sensitivity for both the PANDER(-/-) and wild-type mice. The in vivo insulin response following intraperitoneal glucose injection surprisingly produced significantly higher insulin levels in the PANDER(-/-) mice, whereas insulin release was blunted with arginine administration. Islet perifusion and calcium imaging studies showed abnormal responses of the PANDER(-/-) islets to glucose stimulation. In contrast, neither islet architecture nor insulin content was impacted by the loss of PANDER. Interestingly, the elevated insulin levels identified in vivo were attributed to decreased hepatic insulin clearance in the PANDER(-/-) islets. Taken together, these results demonstrated decreased pancreatic beta-cell function in the PANDER(-/-) mouse.
These results support a potential role of PANDER in the pancreatic beta-cell for regulation or facilitation of insulin secretion.
胰腺衍生因子（PANDER，FAM3B）是一种胰岛特异性细胞因子样蛋白，在葡萄糖刺激下从β细胞分泌。PANDER 的生物学功能尚不清楚，为了解决这个问题，我们生成并表征了 PANDER 敲除小鼠。
为了生成 PANDER 敲除小鼠，通过同源重组，用新霉素基因替换 PANDER 基因的前两个外显子、分泌信号肽和转录起始位点，从而破坏 PANDER 基因并抑制其表达。然后通过多项体外和体内试验对 PANDER(-/-) 小鼠进行表型分析，以评估其对葡萄糖调节、胰岛素敏感性以及β细胞形态和功能的潜在影响。
葡萄糖耐量试验表明，PANDER(-/-) 雄性小鼠的血糖水平明显高于野生型小鼠。为了确定葡萄糖不耐受的机制，检查了胰岛素敏感性和胰腺β细胞功能。高胰岛素-正常血糖钳夹和胰岛素耐量试验表明，PANDER(-/-)和野生型小鼠的胰岛素敏感性相似。令人惊讶的是，腹腔内注射葡萄糖后，体内胰岛素反应在 PANDER(-/-) 小鼠中产生了明显更高的胰岛素水平，而用精氨酸给药则减弱了胰岛素释放。胰岛灌注和钙成像研究显示，PANDER(-/-) 胰岛对葡萄糖刺激的反应异常。相比之下，PANDER 的缺失对胰岛结构或胰岛素含量没有影响。有趣的是，体内鉴定出的升高的胰岛素水平归因于 PANDER(-/-) 胰岛中肝胰岛素清除率降低。综上所述，这些结果表明 PANDER(-/-) 小鼠的胰腺β细胞功能下降。
这些结果支持 PANDER 在胰腺β细胞中对胰岛素分泌的调节或促进作用的潜在作用。
