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This Article Full Text Full Text (PDF) Corrigendum All Versions of this Article: 296/6/E1251    most recent 90619.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Masson, E. Articles by Fantus, I. G. PubMed PubMed Citation Articles by Masson, E. Articles by Fantus, I. G.

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

Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute, Banting and Best Diabetes Centre, University Health Network and Department of Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 9 July 2008 ; accepted in final form 10 February 2009

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 β-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 β-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 β-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 β-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-1β, 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 β-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 β-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced β-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.

thioredoxin interacting protein; pancreatic β-cell; apoptosis; insulin secretion