Oral L-Serine and D-Serine acutely suppress postprandial hyperglycemia through inhibition of intestinal glucose absorption in healthy mice.

D-Serine (D-Ser), an enantiomer of L-Serine (L-Ser), has been reported to exert unique physiological effects distinct from those of L-Ser. Chronic oral administration of L-Ser has been reported to improve glucose tolerance in diabetic model mice. In this study, we compared the acute effects of oral administration of L-Ser and D-Ser on postprandial blood glucose regulation and the underlying mechanisms in healthy mice. Oral glucose tolerance tests were performed in C57BL/6J mice administered L-Ser or D-Ser (2.0 g/kg BW) simultaneously with glucose loading. Both L-Ser and D-Ser significantly suppressed postprandial hyperglycemia compared with the control group. However, neither L-Ser nor D-Ser significantly affected serum insulin levels after glucose loading or insulin sensitivity during insulin tolerance tests, suggesting that their glucose-lowering effects were independent of insulin secretion and insulin sensitivity. In addition, intraperitoneal glucose tolerance tests showed no significant changes in postprandial hyperglycemia after administration of either L-Ser or D-Ser. In intestinal glucose absorption assays using everted intestine, both L-Ser and D-Ser significantly suppressed glucose absorption. Furthermore, Western blotting analysis demonstrated that L-Ser reduced GLUT2 expression in the brush border membrane, whereas D-Ser reduced both SGLT1 and GLUT2 expression. These findings demonstrate that single oral administration of l-/D-Ser acutely suppresses postprandial hyperglycemia independently of insulin secretion and insulin sensitivity by inhibiting intestinal glucose absorption. In addition, the underlying mechanisms may differ between L-Ser and D-Ser, as reflected by their distinct effects on intestinal glucose transporters, suggesting stereospecific regulation of intestinal glucose metabolism.