# Engineered fibroblast growth factor 1 variants uncouple glucose-lowering effects from mitogenic activity with therapeutic potential for type 2 diabetes

## TL;DR

Scientists engineered variants of FGF1 that lower blood glucose without causing cell overgrowth, offering a safer treatment for type 2 diabetes.

## Contribution

Engineered FGF1 variants that separate glucose-lowering effects from mitogenic activity, enhancing therapeutic safety.

## Key findings

- Two FGF1 variants showed significantly reduced mitogenic potential in various cell types.
- Both variants maintained potent glucose-lowering effects in db/db mice without hypoglycemia or weight changes.
- Engineered FGF1 variants demonstrated improved thermodynamic stability and pharmacokinetic profiles.

## Abstract

Fibroblast growth factor 1 (FGF1), a well-characterized member of the FGF family, effectively lowers blood glucose levels in animal models of type 2 diabetes by stimulating glucose uptake. However, its significant mitogenic potential poses a major challenge for clinical application. Here, we present engineered variants of FGF1 designed to dissociate its potent glucose-lowering effects from its undesired proliferative activity, aiming for a future therapeutic agent for type 2 diabetes. Through a series of rational mutations focused on modulating receptor binding and heparan interactions, coupled with enhanced thermodynamic stability, we developed two lead FGF1 variants. Comprehensive in vitro studies confirmed that these variants exhibit significantly reduced mitogenic potential across various cell types compared to wild-type FGF1. Specifically, one variant showed profound loss of proliferation due to disrupted FGFR binding, while the other displayed attenuated mitogenicity linked to decreased heparin affinity. Critically, both fully maintained potent glucose-lowering properties in db/db mice without inducing hypoglycemia or changes in body weight. Furthermore, these engineered proteins demonstrate superior thermodynamic stability and markedly improved pharmacokinetic profile, critical attributes for drug development. Our findings highlight a successful strategy to uncouple the therapeutic benefits of FGF1 from its mitogenic side effects, offering promising, stable, and safe protein-based drug candidates for type 2 diabetes treatment.

The online version contains supplementary material available at 10.1186/s43556-025-00398-w.