Absence of Thioredoxin Domain Containing 5 Improves Glucose Tolerance and Insulin Sensitivity in Male Mice

Thioredoxin domain-containing protein 5 (TXNDC5) plays a role in diseases related to oxidative stress, energy metabolism, and cellular inflammation. This protein has also been associated with diabetes and insulin folding. To gain insight into these relationships, glucose metabolism was characterized using Txndc5-deficient mice. The absence of TXNDC5 lowered glycemia, which was correlated with higher non-esterified fatty acid (NEFA) levels following an overnight fast on a chow diet in males. Several tolerance tests (pyruvate, glucose, and insulin) revealed no impairment in gluconeogenesis, but rather, higher insulin sensitivity. In vitro assays using an engineered hepatic cell line corroborated the results of increased glucose uptake. When a high-fat, high-sucrose diet was administered to induce a prediabetic state, the absence of TXNDC5 reproduced the lower glycemia and higher NEFA levels observed in mice consuming the chow diet. However, higher levels of plasma insulin were observed in Txndc5-deficient mice. The insulin receptor was increased in the hepatic plasma membranes. Increased hepatic gene expression of G6pc, Irs2, and Igfbp1 was also observed in the absence of TXNDC5. These results indicate that TXNDC5 plays a role in the hepatic sex-differential handling of glucose and lipids, and in retaining the insulin receptor on the plasma membrane.