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

Abstract

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.

• Authors: John L Diener, Sarah Mowbray, Waan-Jeng Huang, David Yowe, Jian Xu, Shari Caplan, Abhay Misra, Ankur Kapur, Jeffrey Shapiro, Xiaoling Ke, Xiaoping Wu, Avirup Bose, Darrell Panza, Min Chen, Valerie Beaulieu, Jiaping Gao
• Journal: Endocrinology (Endocrinology) Vol. 162 Issue 9 (09 01 2021) ISSN: 1945-7170 [Electronic] United States
• PMID: 33951176 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Blood Glucose
• Insulin
• fibroblast growth factor 21
• Streptozocin
• Fibroblast Growth Factors
• Receptor, Insulin

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Experimental (blood, chemically induced, complications)
• Diabetes Mellitus, Type 1 (blood, metabolism, pathology)
• Fibroblast Growth Factors (pharmacology)
• HEK293 Cells
• Humans
• Hyperglycemia (blood, etiology, pathology, prevention & control)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (blood, complications, pathology)
• Receptor, Insulin (antagonists & inhibitors, drug effects, physiology)
• Streptozocin