Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Endocrinology. 2021 Sep 1;162(9). doi: 10.1210/endocr/bqab092.
Fibroblast growth factor (FGF) 21 is a member of the FGF family of proteins. The biological activity of FGF21 was first shown to induce insulin-independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin-independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40-kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to 2 different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic β-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver, and obesity.
成纤维细胞生长因子 21（FGF21）是成纤维细胞生长因子家族蛋白的一员。FGF21 的生物学活性最初被证明可通过葡萄糖转运蛋白 1（GLUT1）诱导脂肪细胞中的胰岛素非依赖性葡萄糖摄取。随后，研究表明它对肝脏有作用，可增加脂肪酸氧化。FGF21 治疗在肥胖症、2 型糖尿病（T2D）和/或脂肪肝患者的动物模型和患者中均具有有益的代谢作用。在本文中，我们重新研究了最初的发现结果，发现胰岛素受体拮抗剂存在时，脂肪细胞中的胰岛素非依赖性葡萄糖摄取得以保留。我们使用 40kDa 的聚乙二醇化（PEG）和半衰期延长的 FGF21 形式（FGF21-PEG），将这些体外结果扩展到 2 种不同的糖尿病小鼠模型中。FGF21-PEG 使链脲佐菌素（STZ）处理的 1 型糖尿病（T1D）小鼠的血浆葡萄糖正常化，而没有恢复胰腺β细胞功能。FGF21-PEG 还使慢性接受胰岛素竞争胰岛素受体拮抗剂治疗的小鼠的血浆葡萄糖水平正常化，并改善了葡萄糖耐量，该模型模拟了自身免疫性/β型胰岛素抵抗。这些数据将 FGF21 的药理学潜力扩展到了 T2D、脂肪肝和肥胖症以外的范围。
