Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model

Abstract

Elucidating the mechanisms of regulation of β cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β cell compensatory proliferation by subjecting wild-type (WT) and Txnip knockout (KO) mice to a high fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased β cell proliferation and enhanced β mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in β cell proliferation and cell cycle regulation. Txnip knockout in HFD mice also led to activated levels of p-P13K, p-AKT, p-mTOR and p-GSK3β, suggesting that Txnip may act via PI3K/AKT signaling to suppress β cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.

Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

“…Thioredoxins mainly act by reducing oxidized cysteine residues, with elevated levels of this enzyme linked to increased levels of circulating non-esterified fatty acids in patients with T2D[ 139 ]. Other findings indicate that elevated thioredoxin-interacting protein (TXNIP) levels correlate with increased β-cell apoptosis[ 140 ]; whereas TXNIP deficiency safeguards against T2D by promoting β-cell survival[ 141 ]. In fact, TXNIP is considered essential for the regulation of pancreatic β-cell function and other complications of T2D[ 142 , 143 ].…”