4640 Background: Diabetes mellitus type 2 (DM2) is well-known to be associated with increased risk as well as adverse outcome of pancreatic cancer. Only limited studies focused on translating this knowledge into potential clinical interventions that could modify the risk or outcome of diabetic pancreatic cancer patients. Methods: We investigated the impact of two interacting factors that changes at various stages of the DM2 disease process (hyperglycemia and hyperinsulinemia) on the proliferation of pancreatic cancer cells and examined whether some anti-diabetic drugs, namely metformin, rosiglitazone and exenatide, have direct inhibitory effects on MiaPaCa2 cells in vitro. Results: Our data demonstrated that insulin promoted the proliferation of MiaPaCa2 pancreatic cancer cells, but the growth promoting effect of glucose was dependent on insulin and was observed only at high insulin concentrations. Both insulin and glucose contributed to the chemoresistance of pancreatic cancer cells to gemcitabine. Treatment with metformin or rosiglitazone suppressed MiaPaCa2 cell growth via inactivation of Akt pathway, leading to apoptosis. Metformin activated AMPK and rosiglitazone increased the protein level of PTEN. The inhibitory effects of these 2 drugs were observed regardless of the various combinations of glucose and insulin concentrations mimicking different stages in the natural history of DM2. Both metformin and rosiglitazone resulted in further inhibition of MiaPaCa2 cell growth and increase in apoptosis when combined with gemcitabine in all the combinations of glucose and insulin concentrations. Exenatide did not have any inhibitory effects on MiaPaCa2 cells. Conclusions: Our results showed that either culture conditions mimicking hyperinsulinemia and hyperglycemia stimulated pancreatic cancer cell proliferation and conferred chemoresistance to gemcitabine. Two antidiabetic drugs, metformin and rosiglitazone, had direct effects on MiaPaCa2 cells and added to the inhibitory effect of gemcitabine. These results have significant therapeutic implications in terms of the choice of pharmacotherapy for DM2 in the context of diabetic pancreatic cancer patients. No significant financial relationships to disclose.