The Inhibitory Effects of NCT503 and Exogenous Serine on High-Selenium Induced Insulin Resistance in Mice

Objective: This study aims to identify whether the development of Insulin resistance (IR) induced by high selenium (Se) is related to serine deficiency via the inhibition of the de novo serine synthesis pathway (SSP) by the administrations of 3-phosphoglycerate dehydrogenase (PHGDH) inhibitor (NCT503) or exogenous serine in mice.

Method: forty-eight male C57BL/6J mice were randomly divided into four groups: adequate-Se (0.1 mgSe/kg), high-Se (0.8 mgSe/kg), high-Se +serine (240 mg/kg/day), and high-Se +NCT503 (30 mg/kg, twice a week) for 5 months. The glucose tolerance test (GTT) and Insulin tolerance test (ITT) were used to confirm the development of IR in mice with high-Se intake, and fasting blood glucose levels were measured monthly. The Se contents in plasma and tissues were detected by ICP-MS. The levels of Insulin (INS), homocysteine (HCY), and serine in plasma were tested by ELISA. Western blot analyses were conducted to evaluate the protein expressions of Glutathione Peroxidase 1 (GPX1), selenoprotein P (SELENOP) and PHGDH, the PI3K-AKT-mTOR pathway, folate cycle (SHMT1, MTHFR), and methionine cycle (MS).

Results: An IR model was developed in mice from the high-Se group with elevated fasting blood glucose and INS levels, impaired glucose tolerance, and reduced Insulin sensitivity, but not in both the high-Se +serine group and the high-Se +NCT503 group. Compared with the high-Se and high-Se +serine groups, the expressions of GPX1 and SELENOP significantly decreased for the high-Se +NCT503 group in the liver, muscle, and pancreas tissues. The expression of PHGDH of high-Se group was significantly higher than that of the adequate-Se group in the liver (p < 0.05) and pancreas (p < 0.001). Also, the expected high expression of PHGDH was effectively inhibited in mice from the high-Se +serine group but not from the high-Se +NCT503 group. The expression of p-AKT (Ser-473) for the high-Se group was significantly lower than that of the adequate-Se group in the liver, muscle, and pancreas.

Conclusions: The IR induced by high-Se intake in the body has been confirmed to be partially due to serine deficiency, which led to the initiation of SSP to produce endogenous serine. The supplementations of exogenous serine or inhibitors of PHGDH in this metabolic pathway could be used for the intervention.

IR; PHGDH inhibitor; SSP; high-Se; serine.