Aims/hypothesis: PTEN may play a reversible role in TNF alpha induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNF alpha, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to beta-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNF alpha treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNF alpha treatment. PTEN siRNA markedly inhibited the TNF alpha-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNF alpha-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNF alpha treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. Published by Elsevier Inc.