241-LB: Inhibition of TXNIP-Thioredoxin Redox Switch Improves Insulin Sensitivity on a High-Fat Diet

Abstract

Thioredoxin interacting protein (TXNIP) is a regulator of glucose metabolism and oxidative stress. It is the only arrestin-domain protein known to bind to reduced thioredoxin (Trx) at a C247 residue. This binding site is conserved in mammals, but its specific purpose is unclear. Here, we studied TXNIP's metabolic roles through the binding of Trx in vivo. We hypothesized that the TXNIP-Trx interaction may regulate a High-Fat Diet (HFD) induced insulin resistance triggered by redox stress. To abolish this interaction, we generated a new mouse model with a single C247S amino acid substitution in the txnip gene using CRISPR-Cas9. Over 8 weeks, we fed male C57BL/6J WT, C247S, and TXNIP KO mice (n=10/group) chow and HFD and performed insulin and glucose tolerance tests. Notably, C247S mice on HFD exhibited improved insulin sensitivity compared to WT, but this was not observed on a chow diet (Figure 1). Additionally, these mice had lower glucose tolerance on a chow diet and higher glucose tolerance on a HFD compared to WT. Moreover, KO mice were hypoglycemic and hypersensitive to insulin compared to C247S and WT mice in both diets. Our data reveals that inhibiting the TXNIP-Trx interaction on a HFD (stressed condition) can improve insulin sensitivity, suggesting a protective effect against insulin resistance. Future studies are needed to unravel this relationship between redox and arrestin biology in regulating metabolism. Disclosure M. F. Hoang: None. S. Dagdeviren: None. V. Meier: None. J. Benoit: None. V. Y. Melnik: None. R. Lee: Advisory Panel; Elevian, Inc., Research Support; BlueRock Therapeutics. Funding National Institutes of Health (1F32DK126289, R01DK126688)