TxNIP (thioredoxin-interacting protein) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets and recent studies suggest that TxNIP is a proapoptotic factor in -cells, which may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic -cell mass and/or insulin secretion. TxNIP deficient (Hcb-19/TxNIP^-/-) mice had lower baseline glycemia, higher circulating insulin concentrations, higher total pancreatic insulin content and -cell mass than control mice (C3H). Hcb-19/TxNIP^-/- did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although -cell mass remained higher in Hcb-19/TxNIP^-/- mice compared to C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with SiRNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines IL-1, IFN, and TNF. Furthermore, when corrected for insulin content, isolated pancreatic islets from TxNIP^-/- mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of -cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be due to an increase in -cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced -cell death indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.