Thioredoxin-interacting protein (TXNIP) is a key player in the endocrine pancreas; it induces beta cell apoptosis, such that TXNIP deficiency promotes beta cell survival. To study its function in more detail, we generated transgenic mice with ubiquitous overexpression of TXNIP. CBATXNIP/+ mice were investigated under basal conditions and after being challenged in diet-induced obesity (DIO) and streptozotocin-induced type 1 diabetes mellitus (T1DM) models. TXNIP overexpression caused no effect in the DIO model, contrasting to the already reported TXNIP-deficient mice. However, in the T1DM background, CBATXNIP/+ animals showed significantly enhanced blood glucose and increased glucose levels in a glucose tolerance test. Finally, the beta cell mass of CBATXNIP/+ transgenic animals in the T1DM model was significantly reduced compared to control littermates. Our study demonstrates that overexpression of TXNIP doesn't affect blood glucose parameters under basal conditions. However, overexpression of TXNIP in a T1DM model enhances the severity of the disease.