Protein tyrosine phosphatases (PTPases) such as PTP1B can play a role in regulating a wide variety of cellular responses such as insulin signaling. Substituted thiophene compounds such as, for example, 2-carboxyl, 3-carboxymethoxy, 5-aryl substituted thiophenes, can inhibit PTP1B and thereby induce greater insulin sensitivity. Accordingly, PTP1B inhibition can provide an alternate treatment for PTPase-mediated disorders such as diabetes.