Hcb-19/TxNIP-/- Mice are Resistant to Streptozotocin (STZ)-Induced Diabetes

[b]Results:[/b] TxNIP (Thioredoxin Interacting Protein) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. It has been found that diabetic mice exhibit increased expression of TxNIP in pancreatic islets and recent in vitro studies suggest that TxNIP is a proapoptotic factor in pancreatic β cells. In this study, we aimed to determine the influence of TxNIP deficiency on the development of diabetes in vivo. TxNIP deficient (Hcb-19/TxNIP-/-) and control (C3H) mice received 5 daily intraperitoneal injections of 50mg/kg STZ to induce insulin-deficient diabetes (AMDCC protocol). Six hour fasting blood glucose and insulin were measured 6 weeks later and the pancreas was harvested to assess total insulin content, β cell mass and apoptosis by immunohistochemistry. Untreated TxNIP-/- mice had lower glycemia than the C3H controls (5.8±1.1 vs 10.4±1.2 mmol/L). In contrast to the controls, they did not develop hyperglycemia in response to the STZ protocol (8.9±1.7 vs 24.5±7.9 mmol/L for the C3H) and required a 2nd set of injections to develop diabetes. Interestingly, untreated TxNIP-/- mice demonstrated higher insulinemia (1.2-fold), total pancreatic insulin content (1.3-fold) and β cell mass (1.2-fold) than C3H mice. After the 1st set of STZ injections, these parameters, although decreased, were still significantly higher than in controls and became similar only after the repeated STZ injections, correlating with similar hyperglycemic levels. Moreover, islet cells from TxNIP-/- mice exhibited a 2 to 3-fold lower rate of apoptosis in response to STZ exposure compared to C3H. Lastly, isolated pancreatic islets from untreated TxNIP-/- mice demonstrated a higher insulin content (51±14 vs 30±8 ng/islet) but a lower glucose-induced insulin secretion than the C3H, suggesting that insulin secretory capacity of individual islet was not implicated in the “resistance” to STZ-induced diabetes observed in TxNIP-/- mice. In summary: i) TxNIP participates in the development of insulin-deficient diabetes in vivo, ii) higher baseline insulin reserve in the TxNIP-/- mice is, at least in part, responsible for their “resistance” to STZ-induced diabetes, iii) STZ and/or high glucose-induced β cell apoptosis is decreased by TxNIP deficiency. In conclusion, our work supports the concept that oxidative stress targeting may be effective in preventing the loss of β cell mass and improving insulin reserve to maintain glucose homeostasis in diabetes.

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