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Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Previous studies have reported that FGF21 is expected to become a new drug for treatment of diabetes. Liraglutide and insulin glargine are the two representative anti-diabetic biological drugs. In the current study, we aim to compare the long-term pharmacological efficacy of mFGF21 (an FGF21 analogue), liraglutide and insulin glargine in type 2 diabetic db/db mice. Db/db mice were initially treated with three kinds of proteins (25nmol/kg/day) by subcutaneous injection once a day for 4weeks, then subsequently be treated with once every two days for next 4weeks. After 8weeks of treatments, the blood glucose levels, body weights, glycosylated hemoglobin levels, fasting insulin levels, serum lipid profiles, hepatic biochemical parameters, oral glucose tolerance tests and hepatic mRNA expression levels of several proteins (GK, G6P, GLUT-1 and GLUT-4) associated with glucose metabolism of the experimental mice were detected. Results demonstrated that three proteins could significantly decrease the fed blood glucose levels of db/db mice. After treatment for 1week, the fed blood glucose levels of db/db mice in liraglutide group were significantly lower than those in mFGF21 and insulin glargine groups. However, after 2weeks of administration, the long-lasting hypoglycemic effect of mFGF21 was superior to liraglutide and insulin glargine up to the end of the experiments. Compared with liraglutide and insulin glargine, mFGF21 significantly reduced the glycosylated hemoglobin levels and improved the ability on glycemic control, insulin resistance, serum lipid and liver function states in db/db mice after 8weeks treatments. In addition, mFGF21 regulated glucose metabolism through increasing the mRNA expression levels of GK and GLUT-1, and decreasing the mRNA expression level of G6P. But liraglutide and insulin glargine could only up-regulate the mRNA expression of GLUT-4. In summary, as a hypoglycemic drug for long-term treatment, mFGF21 has the potential to be an ideal drug candidate for the therapy of type 2 diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: In this study, we compared the long-acting hypoglycemic effect of PEGylated FGF21 (PEG-FGF21) with insulin glargine in mice with STZ-induced type 1 diabetes., Methods: PEG-FGF21 and insulin glargine were administered once daily for two months, and blood glucose was measured prior to the next administration. Real-time PCR was used to measure mRNA expression of glucokinase (GK), glucose 6-phosphatase (G6pase), phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 1 (GLUT1) and glucose transporter 4 (GLUT4)., Results: During long-term treatment, the blood glucose of untreated mice remained at 25.0 to 28.0mmol/L for the whole experiment, and the blood glucose of mice treated with insulin glargine remained at 16.5 to 18.0mmol/L. However, mice treated with PEG-FGF21 had lower blood glucose levels of 8.0 to 9.0mmol/L on day 10 and maintained this level until the end of the experiment. qRT-PCR showed that PEG-FGF21 up-regulated mRNA expression of GK and GLUT1, and down-regulated mRNA expression of G6Pase and PEPCK. Insulin glargine up-regulated mRNA expression of GLUT4, but had no effect on GK, G6Pase, PEPCK or GLUT1., Conclusions: PEG-FGF21 has a better long-acting efficacy than insulin glargine. PEG-FGF21 achieves glucose clearance by accelerating glycolysis by up-regulating expression of GK and GLUT1 and inhibiting gluconeogenesis via down-regulation of G6Pase and PEPCK expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)