Serine Supplementation Attenuates High-Selenium-Induced Insulin Resistance via Feedback Inhibition of PHGDH in Mice

In previous studies, we first reported that insulin resistancetogether with 3-phosphoglycerate dehydrogenase (PHGDH) overexpression, a key enzyme involved in de novo synthesis of endogenous serine (Ser), was observed in mice with a high selenium (Se) diet. This study aimed to investigate the effect of exogenous Ser on high-Se induced insulin resistance (IR) in mice. Thirty mice were randomized into three groups fed: (1) 0.1 mg/kg Se (non-IR control group), (2) 0.8 mg/kg Se (IR control group); and (3) 0.8 mg/kg Se with Ser supplement (IR Ser-intervention group). After IR was confirmed in mice both in two groups fed with a high-Se diet for 4 months, mice in the intervention group were administered with Ser (215 mg/kg body weight daily) whilst mice in the other two groups with saline by gavage for another month. Then, body weight, fasting blood glucose, plasma constituents (insulin, Se, Ser, homocysteine (HCY)), plasma lipid profiles (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TCHO), triglycerides (TG)), tissue Se levels, glucose tolerance test (GTT) and insulin tolerance test (ITT) were measured in all mice before and after Ser intervention. Furthermore, the expression profiles of key enzymes participating in Ser synthesis and metabolism in the liver, skeletal muscle, and pancreas were also analyzed. Ser supplementation significantly improved insulin sensitivity in IR mice, evidenced by a 19.34% reduction in ITT area under the curve (AUC) compared to IR controls (P < 0.05). Compared to the IR control group, lower liver, skeletal muscle, and pancreas PHGDH expression as well as lower skeletal muscle glutathione peroxidase 1 (GPX1) expression were found in mice from the IR Ser-intervention group (P < 0.01). Plasma Ser levels increased by 13.91% (P < 0.05), while plasma HCY levels decreased by 18.4% (P < 0.001) after Ser intervention. Plasma lipid profiles improved significantly with reductions of 15.35% in HDL-C, 25.64% in LDL-C, 16.08% in TCHO, and 25.64% in TG versus IR controls (P < 0.05). Oral supplementation with Ser effectively alleviates insulin resistance and lipid metabolic disturbances in mice fed a high-Se diet via feedback inhibition of PHGDH enzyme gene overexpression. These findings highlight the potential translational value of Ser as a dietary intervention to mitigate metabolic dysfunction associated with high Se conditions.