New Cucurbitane triterpenoids from bitter melon with potent antidiabetic properties associated with activation of AMPK
A targeted approach was conducted to investigate the antidiabetic principles of bitter melon (Momordica charantia), a popular medicinal vegetable with reported hypoglycaemic effects. Four new cucurbitane glycosides, momordicosides Q, R, S, T, and karaviloside XI were isolated, and absolute configurations of these compounds were established. These compounds and their aglycones exhibited a strong efficacy (EC50: ˜1nM and maximum: 10–100nM) comparable to insulin (100nM) and AICAR (2mM) in stimulating GLUT4 translocation to the cell membrane in both L6 myotubes and 3T3L1 adipocytes. This effect was associated with increased phosphorylation (T172) of AMPK and acetyl-CoA carboxylase (S79) in analogous to the well-known AMPK activator AICAR. Consistent with these in vitro effects, administration of momordicoside S (100mg/kg, sc) into C57BL/6J mice significant enhanced glucose disposal (12.5±1.2at 30min vs. 16.9±0.6mM in controls, P<0.01, ipGTT at 3g/kg) and promoted fatty acid oxidation (decreased RER over 6 hrs, P<0.01). Further studies in insulin resistant high fat fed mice showed that momordicoside T (10mg/kg, ip) significantly improved glucose tolerance in an ipGTT (2g/kg). This study indicates that cucurbitane triterpenoids are likely to be major contributors to the anti-diabetic effects of bitter melon, and may provide novel leads as a new class of therapeutics for diabetes and obesity .
References: 1. Tan, M.J. et al. (2008) Chem. Biol. 15: 263–273.