Objective To investigate the blood glucose lowering and weight loss effects of glucagon like peptide-1 receptor (GLP-1 R) and glucagon receptor (GCGR) double target agonist Qingmulutide in normal and model animals.

Methods The high-fat diet induced obesity (DIO) model mice were divided into a model control group, Qingmulutide 3, 10, 30 nmol/kg groups, and liraglutide 30 nmol/kg group, and a normal control group was established at the same time; the mice were subcutaneously administered daily for 30 consecutive days; the body mass of mice was observed every day, and fasting blood glucose, food intake, and postprandial blood glucose were measured weekly.The normal cynomolgus monkeys were divided into a normal control group and Qingmulutide 9, 27, 82 nmol/kg groups, and subcutaneously administered daily for 30 consecutive days; the levels of insulin and glucagon before administration and 1-2 hours after meal on day 1 and day 30 of administration, body mass, food intake, fasting blood glucose, and postprandial blood glucose were observed.

Results Qingmulutide at the doses of 3, 10, 30 nmol/kg could reduce fasting blood glucose on day 6-23 of administration, and postprandial blood glucose on day 23 of administration in DIO mice (P < 0.05 to P < 0.01);while the effect of 30 nmol/kg liraglutide on fasting blood glucose was less than that of 30 nmol/kg Qingmulutide, and the effect on postprandial blood glucose was basically the same.One hour after the first administration, Qingmulutide at doses of 9, 27, 82 nmol/kg significantly reduced the blood glucose levels of cynomolgus monkeys (P < 0.01).At the ninth and tenth hours of the first administration, the insulin levels in the 27, 82 nmol/kg Qingmulutide groups were significantly decreased (P < 0.01), and the glucagon level only increased at the ninth hour in the 82 nmol/kg Qingmulutide group (P < 0.01).Both 27 nmol/kg and 82 nmol/kg Qingmulutide could reduce the glucagon level at the ninth hour on day 30 of administration (P < 0.05 and P < 0.01).From day 4 of administration, 30 nmol/kg Qingmulutide reduced the body mass of DIO mice (P < 0.05), by day 8 of administration, the body mass of DIO mice returned to the normal level (P>0.05), and the weight loss effect was better than that of liraglutide 30 nmol/kg.On day 5-30 of administration, 82 nmol/kg Qingmulutide reduced the body mass of cynomolgus monkeys (P < 0.05).Both Qingmulutide and liraglutide at the same dose 30 nmol/kg significantly reduced the food intake of DIO mice from day 1 of administration, and the effect of liraglutide lasted until day 5 of administration (P < 0.05 to P < 0.01), which was superior to that of Qingmulutide.At week 1-3 of administration, 27 nmol/kg and 82 nmol/kg of Qingmulutide reduced the food intake of cynomolgus monkeys (P < 0.05 to P < 0.01), while 9 nmol/kg Qingmulutide could only reduce the food intake of cynomolgus monkeys at week 1 of administration (P < 0.05).

Conclusions Qingmulutide is a potent GLP-1R/GCGR double agonist, can significantly reduce abnormally elevated blood glucose levels, and has no significant effect on normal blood glucose levels.It also has a powerful weight loss effect by reducing food intake and increasing energy expenditure, and its weight loss effect is superior to that of liraglutide.