Diabetes mellitus, which includes both type 1 and type 2 diabetes mellitus (T2DM), is a major disease that threatens human health worldwide. Protein tyrosine phosphatase 1B (PTP1B) is a promising molecular-level therapeutic target that is effective in the management of T2DM. Natural products with various skeletons and diverse bioactivities offer opportunities for the development of new drugs and lead compounds with potent inhibitory activity against PTP1B in vitro and in vivo. Recently, a number of potent PTP1B inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis, and they exhibit potential for the treatment of T2DM. In this review, we discuss the development of potent natural and semisynthetic PTP1B inhibitors with IC50 values under 10 μM over the past six years (2009–2014), including their structural features, biological features, structure–activity relationships (SARs). We also discuss strategies for identifying potent PTP1B inhibitors from natural products to provide useful information for use by medicinal chemists in developing potent PTP1B inhibitors as T2DM treatments.
