Mechanism Guided Discovery of New Therapeutics Agents for Type 2 Diabetes from Berberine

Berberine (BBR) is commonly used as a nonprescription oral drug in China to treat gut infections and diarrhea with few side effects and its therapeutic potential for the treatment of diabetes and dyslipidemia in humans has also been reported [1,2]. These beneficial effects are related in part to the ability of BBR to activate AMPK.

By further investigation, we have found BBR activates AMPK via inhibition of respiratory complex I of the mitochondrion. Despite its potent stimulation of AMPK in cell-based assay, an important issue arising from our previous work is that a considerably large oral dose (560mg/kg/day) of BBR was required for beneficial metabolic effects in rodents. Aiming to improve its therapeutic efficacy, we designed a number of BBR derivatives with improving their bioavalability and found two types of BBR derivatives, dihydroberberine and 8,8-disubstituted dihydroberberine derivatives, have markedly improved in vivo efficacy in the treatment of insulin-resistant rodents.

Figure 1. Optimization of BBR

References: [1] Hu L-H, et al. (2010) Bioorganic & Medicinal Chemistry, 18: 5915–5924. [2] Hu L-H, et al. (2008) Diabetes, 57(5): 1414–1418.