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FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction

Diener, John and Mowbray, Sarah and Huang, WaanJeng and Yowe, David and Xu, Jian and Caplan, Shari and Misra, Abhay and Kapur, Ankur and Shapiro, Jeffrey and Ke, Xiaoling and Wu, Xiaoping and Bose, Avirup and Panza, Darrell and Chen, Min and Beaulieu, Valerie and Gao, Jiaping (2021) FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction. bioRxiv. pp. 1-19. ISSN https://doi.org/10.1101/2021.01.04.425295

Abstract

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 the 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.

Item Type: Article
Date Deposited: 23 Feb 2021 00:45
Last Modified: 23 Feb 2021 00:45
URI: https://oak.novartis.com/id/eprint/44026

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