Thioredoxin-Interacting Protein (TXNIP) in Gestational Diabetes Mellitus

Abstract

Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this protein in other molecular pathways involving inflammation, apoptosis, and glucose metabolism. Methods: This review aims to highlight the importance of TXNIP in diabetes-related pathophysiology and explore the existing evidence regarding TXNIP's role in GDM-associated pathogenetic mechanisms, revealing common regulatory pathways. Results: Among other complex diseases, TXNIP has been found upregulated in diabetic pancreatic beta cells, thus contributing to diabetes pathogenesis and its related complications. In addition, depletion of TXNIP has been shown to decrease the negative consequences of excessive stress in various cellular systems and diseases, pointing towards a potential therapeutic target. In line with these findings, TXNIP has been investigated in the pathogenesis of Gestational Diabetes Mellitus (GDM), a common pregnancy complication affecting the mother and the neonate. Overexpression of TXNIP has been found in GDM placentas or trophoblast cell lines mimicking GDM conditions and has been associated with key dysregulated mechanisms of GDM pathophysiology, like oxidative stress, inflammation, apoptosis, impaired autophagy, altered trophoblast behavior, and placental morphology. Interestingly, TXNIP has been found upregulated in GDM maternal serum and downregulated in umbilical cord blood, indicating potential compensatory protective mechanisms to GDM-related oxidative stress. Conclusions: Due to its contribution to the regulation of critical cellular processes such as inflammation, metabolism, and apoptosis, TXNIP finds its place in the pathophysiology of gestational diabetes through a currently limited number of scientific reports.

Keywords: GDM pregnancy; TXNIP; inflammation; oxidative stress; placental dysfunction.

Figure 1

Schematic representation of the human TXNIP structure. (a) TXNIP contains two arrestin-like domains (N-ARR and C-ARR). In the N-ARR domain, SH3-binding PxxP motifs are present, facilitating protein–protein interactions. The C-ARR domain contains critical cysteine residues (Cys63, Cys247), as well as ITIM and CRM1 binding regions. The C-terminal tail includes two PPxY motifs, an LL motif, and additional SH3-binding PxxP motifs. (b) The 3D structure of TXNIP, as predicted by the AlphaFold database (UniProt ID: Q9H3M7). N-ARR: N-arrestin like domain; C-ARR: C-arrestin like domain; SH3: Src homology 3; ITIM: immunoreceptor tyrosine-based inhibitory; CRM1: chromosome maintenance region 1; LL: dileucine; GLUTs: Glucose Transporters; HIF1-α: hypoxia-inducible factor-1α; pVHL: von Hippel–Lindau ubiquitin ligase; Trx: Thioredoxin; ASK1; apoptosis signal-regulating kinase 1.

Figure 2

A schematic representation of TRX regulation by TXNIP under (a) oxidative and (b) nitrosative stress conditions. TRX alternates between its oxidized (inactivated) and reduced (activated) form, through the catalytic action of NADPH-dependent TrxR, thus regulating cellular redox homeostasis. Under excessive ROS production, a disulfide bond between TXNIP Cys247 and TRX Cys32 is formed, leading to the formation of redoxisome complex and inactivation of TRX. Under high RNS levels, TXNIP is downregulated, facilitating TRX-mediated denitrosylation, a critical process for maintaining cellular redox balance. ROS: reactive oxygen species; RNS: reactive nitrogen species; TrxR: thioredoxin reductase; Trx: Thioredoxin. Created in © 2025 BioRender. Kokkinopoulou, I. (2025) https://BioRender.com/5tmi5uq (accessed on 13 May 2025).

Figure 3

The role of TXNIP dysregulation in GDM-associated pathophysiological mechanisms. GDM-associated hyperglycemia, ROS generation, and ER stress induce TXNIP upregulation through modulation of TXNIP methylation status and/or upregulation of miRNAs targeting TXNIP. Hyperglycemia-induced TXNIP upregulation promotes oxidative stress and mitochondrial dysfunction through increased ROS generation, enhances apoptosis through ASK1 activation, induces inflammation through NLRP3 inflammasome activation, inhibits autophagy, and impairs trophoblast morphology and behavior through dysregulation of STAT-3 and Vimentin-related mechanisms, ultimately contributing to GDM-related maternal and fetal complications. Created in © 2025 BioRender. Kokkinopoulou, I. (2025) https://BioRender.com/cettpq6 (accessed on 30 March 2025).