Adiponectin and its receptors are involved in various physiological regulations including glucose homeostasis and fatty acid oxidation, and adiponectin deficiency is closely related to chronic metabolic diseases.
A novel peptide agonist to AdipoR1, BHD1028, was designed and evaluated both in vitro and in vivo systems.
BHD1028 facilitated AMPK activation in C2C12 myotube and significantly enhanced glucose uptake (p<0.05) in insulin resistance-induced C2C12 cells.
A glucose lowering profile after single dose of s.c. injecting 50, 100 and 200 μg/Kg of pegylated BHD1028 (PEG-BHD1028) in db/db mice showed significantly lower than that of control animals during a 12-hour period without causing hypoglycemia. Besides, an OGTT was performed in db/db mice following a 1g/Kg of glucose oral load. The treated animals (s.c. injection, 1 and 50 μg/Kg) showed significantly lower glucose (p<0.05) and insulin (p<0.01) levels than control group, indicating an effective glucose homeostasis of PEG-BHD1028 by ameliorating the insulin resistance.
Subchronic effect of the drug following daily s.c. injection of 1, 5, 25, 50 and 200 μg/Kg in db/db mice for 3 weeks showed a significant plasma glucose lowering effect in the group received 50 and 200 μg/Kg from day 16, the weight loss in the range of 6-8% (p<0.01) on day 21 in the animals received 5, 25 and 50 μg/Kg. HbA1c levels of all treated groups were significantly lower than control animals (p<0.05) on day 21.
These results indicate that PEG-BHD1028 could be a potential therapeutic agent for type 2 diabetes, obesity, NASH, and other metabolic diseases.