Anti-diabetic potential of naturally-occurring cinnamates

Caffeic acid (CA) and ferulic acid (FA) are phenolics found in the seeds of many plants such as coffee, wheat and oat. They are reported to be anti-oxidant, anti-carcinogenic, anti-inflammatory, and immunomodulatory [1]. There is growing interest in the anti-diabetic activity of derivatives of these molecules. Whereas CA and FA have no effect on cellular glucose uptake, a derivative of CA, caffeic acid phenethyl ester (CAPE), can increase glucose uptake in cultured skeletal muscle cells by more than 2-fold at low micromolar concentrations [2], and has been shown to have anti-diabetic effects in STZ-diabetic animals [3]. However, this activity may be accompanied by high potential for toxicity. The purpose of the present study is to identify other cinnamates with excellent anti-hyperglycemic potential but reduced potential for toxicity, while elucidating mechanisms of action as well as structural properties responsible for activity. In this study, we have screened several derivatives of CA and FA at 100µM using the skeletal muscle glucose uptake assay and have identified two CA derivatives with high activity, and four FA derivatives with moderate activity. Western immunoblot experiments of muscle cells treated with these active compounds reveal that activity is not due to stimulation of insulin signalling pathway, but rather to stimulation of the AMP-activated protein kinase pathway. Additionally, our results indicate that activity is correlated with lipophilicity and with absence of carboxyl groups. Decreased lipophilicity compared to CAPE may translate into reduced potential for toxicity. In conclusion, we report cinnamates with heretofore unknown activity and good therapeutic potential against hyperglycemia.

References: 1. Shin, KM et al. (2004) Biochem. Pharmacol. 68 2327–2336.

2. Lee, E.S. et al. (2007) Biochem. Biophys.. Res. Com. 361: 854–858.

3 Okutan, H. et al. (2005) Clin. Biochem. 38: 191–196.