RT Journal Article
SR Electronic
T1 FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.04.425295
DO 10.1101/2021.01.04.425295
A1 John L Diener
A1 Sarah Mowbray
A1 Waan-Jeng Huang
A1 David Yowe
A1 Jian Xu
A1 Shari Caplan
A1 Abhay Misra
A1 Ankur Kapur
A1 Jeffrey Shapiro
A1 Xiaoling Ke
A1 Xiaoping Wu
A1 Avirup Bose
A1 Darrell Panza
A1 Min Chen
A1 Valerie Beaulieu
A1 Jiaping Gao
YR 2021
UL http://biorxiv.org/content/early/2021/02/01/2021.01.04.425295.abstract
AB Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor (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 two 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.Competing Interest StatementAll authors were employees of Novartis Institutes for BioMedical Research during the time period when the research was conducted.