High -cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice

Masson E, Koren S, Razik F, Goldberg H, Kwan EP, Sheu L, Gaisano HY, Fantus IG. High -cell mass prevents streptozotocininduced diabetes in thioredoxin-interacting protein-deficient mice. Am J Physiol Endocrinol Metab 296: E1251–E1261, 2009. First published February 17, 2009; doi:10.1152/ajpendo.90619.2008.— Thioredoxin-interacting protein (TxNIP) 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 that 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, and 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 with 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 small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1 , interferon, and tumor necrosis factor. 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 because of an increase in -cell mass. However, TxNIP deficiency is associated with sensitization to STZand cytokine-induced -cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.