Metformin Impairs Intestinal Fructose Metabolism

Objective To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo . Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin’s effects on sugar metabolism are pleiotropic. Highlights Metformin decreases intestinal fructose absorption, metabolism, and fructose delivery to the liver. Metformin reduces intestinal glucose production from fructose-derived metabolites. Metformin reduces protein levels of multiple metabolic enzymes involved in fructose and glucose metabolism in intestinal tissue.