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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 296; no. 6; pp. E1251 - E1261
• Main Authors: Masson, Elodie, Koren, Shlomit, Razik, Fathima, Goldberg, Howard, Kwan, Edwin P, Sheu, Laura, Gaisano, Herbert Y, Fantus, I George
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2009
• Subjects: Animal biology; Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis - physiology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cytokines - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Dose-Response Relationship, Drug; Food and Nutrition; Glucose - pharmacology; In Situ Nick-End Labeling; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - physiology; Life Sciences; Male; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Rats; Streptozocin - pharmacology; Thioredoxins - genetics; Thioredoxins - metabolism; pancreatic β-cell; thioredoxin interacting protein; apoptosis; insulin secretion
• ISSN: 0193-1849; 1522-1555
• 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 beta-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 beta-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 beta-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 beta-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-1beta, interferon-gamma, and tumor necrosis factor-alpha. 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 beta-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 beta-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced beta-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.