Long-lasting hypoglycemic effect of modified FGF-21 analog with polyethylene glycol in type 1 diabetic mice and its systematic toxicity

• Published in: European journal of pharmacology 2016-06, Vol.781, p.198-208
• Main Authors: Ye, Xianlong, Qi, Jianying, Wu, Qiang, Yu, Dan, Li, Shujie, Wu, Yunzhou, Li, Deshan
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Drug Carriers - chemistry; Drug Stability; FGF-21; Fibroblast Growth Factors - chemistry; Fibroblast Growth Factors - pharmacology; Fibroblast Growth Factors - toxicity; Gene Expression Regulation - drug effects; Glucose - metabolism; Glucose Tolerance Test; Glycated Hemoglobin A - metabolism; Hep G2 Cells; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - toxicity; Insulin - blood; Male; Mice; PEGylation; Polyethylene Glycols - chemistry; Stability; Structure-Activity Relationship; Toxicity; Type 1 diabetes
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.04.025

Fibroblast growth factor-21 (FGF-21) is a novel metabolic regulator and has the potential to become a powerful therapy to treat diabetes mellitus. However, we found that the clinical application of wild type FGF-21 was influenced by its low intrinsic bio-stability and poor hypoglycemic potency. In this study, The N-terminus of FGF-21 analog (mFGF-21) was PEGylated in a site-specific manner by 20kD methoxy poly-ethylene glycol-propionaldehyde (mPEG-ALD). PEGylated mFGF-21 was isolated by Capto Q anion exchange chromatography. The properties of PEGylated mFGF-21 including the in vitro bio-stability and biological activity were evaluated. As well as the anti-diabetic effect of PEGylated mFGF-21 were studied in streptozotocin (STZ)-induced type 1 diabetic mice. Results demonstrated that PEGylated mFGF-21 had a similar capacity of stimulating glucose uptake in HepG2 cells with mFGF-21 and PEGylation of mFGF-21 significantly enhanced the anti-protease ability and the long acting anti-diabetic effect in type 1 diabetic mice. Furthermore, the preliminary safety of PEGylated mFGF-21 following subcutaneously injection was assessed using healthy mice by measuring the body weight, histopathology and clinical biochemical parameters, and the results showed no subacute toxicity to major organs or tissues and no significant changes in physiological and biochemical parameters in healthy mice. Taken together, under the premise of remaining the in vitro biological activity of mFGF-21, PEGylation significantly improves the long lasting hypoglycemic effect of mFGF-21 in type 1 diabetic mice. Our valuation shows that PEGylated mFGF-21 is a potential drug for the effective treatment of type 1 diabetes.