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

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• Fibroblast growth factor (FGF) 21 is known for its metabolic benefits in obesity, type 2 diabetes mellitus (T2D), and fatty liver disease.
• FGF21's ability to induce insulin-independent glucose uptake in adipocytes via GLUT1 and promote fatty acid oxidation in the liver has been previously established.
• This study revisits the insulin-independent glucose uptake mechanism of FGF21.

Purpose of the Study:

• To investigate the insulin-independent glucose uptake mechanism of FGF21 in adipocytes.
• To evaluate the therapeutic potential of a PEGylated, half-life extended form of FGF21 (FGF21-PEG) in mouse models of type 1 diabetes (T1D) and insulin resistance.

Main Methods:

• In vitro experiments confirmed insulin-independent glucose uptake in adipocytes, even with an insulin receptor antagonist.
• In vivo studies utilized streptozotocin-induced T1D mice and mice with chronic insulin receptor antagonist treatment.
• A 40-kDa PEGylated and half-life extended form of FGF21 (FGF21-PEG) was administered to diabetic mouse models.

Main Results:

• FGF21-PEG normalized plasma glucose in T1D mice without affecting pancreatic β-cell function.
• In mice with chronic insulin receptor antagonist treatment, FGF21-PEG normalized plasma glucose and improved glucose tolerance.
• These findings confirm and extend the insulin-independent glucose-lowering effects of FGF21.

Conclusions:

• FGF21-PEG demonstrates efficacy in normalizing glucose levels in models of both type 1 diabetes and severe insulin resistance.
• The therapeutic applications of FGF21 can be extended to conditions beyond T2D, fatty liver disease, and obesity.
• FGF21 represents a promising pharmacological agent for a broader range of metabolic disorders.