A human glucagon-like peptide-1-albumin recombinant protein with prolonged hypoglycemic effect provides efficient and beneficial control of glucose metabolism in diabetic mice

Abstract

GW002 is a recombinant protein engineered by fusing the C-terminal region of human glucagon-like peptide-1 (GLP-1) to the N-terminal region of human serum albumin (HSA) with a peptide linker. This study aims to evaluate its anti-diabetic effects both in vitro and vivo. The GLP-1 receptor-dependent luciferase reporter plasmid was transiently transfected in NIT-1 cells to calculate the half-maximal concentration (EC₅₀) for GLP-1 receptor activation, and normal ICR mice and diabetic KKAy mice were acutely injected with GW002 (1, 3 and 9 mg/kg) subcutaneously to evaluate the hypoglycemic action, while the diabetic KKAy and db/db mice were treated with GW002 once daily for 7 weeks to evaluate the effects on glucose metabolism. The results showed that GW002 activated GLP-1 receptor in NIT-1 cells with higher EC₅₀ versus exendin-4 (46.7 vs. 7.89 nM), and single subcutaneous injection of GW002 at doses of 1, 3 and 9 mg/kg efficiently restrained the glycemia variation after oral glucose loading in ICR mice for at least 4 days, as well as reducing the non-fasting blood glucose in KKAy mice for about 2 days, while repeated injections of GW002 significantly improved abnormal glycaemia, HbA1c levels, oral glucose intolerance and β-cell function in diabetic db/db mice. These results suggested that GW002 showed prolonged hypoglycemic action by activating its cognate receptor and provided efficient control of glucose metabolism. Thus GW002 may be a potential treatment for the management of type 2 diabetes.