The purpose of this study was to evaluate hepatic glucose metabolism of diabetic induced rats after a daily oral load of insulin nanoparticles over 2 weeks. After the 2-week treatment, an oral glucose tolerance test was performed with [U-C-13] glucose and (H2O)-H-2. Plasma glucose H-2 and C-13 enrichments were quantified and the contribution of glycogenolysis and gluconeogenesis to overall glucose production were estimated. Animals with the insulin nanoparticles displayed the lowest glycemia before the oral glucose tolerance test. In all animals, 75% of the total glucose production was from gluconeogenesis and glycogen synthesis was only detected in some animals. Gluconeogenic pathway was an active contributor to hepatic glucose production and the treatment with oral delivered insulin nanoparticles did not alter this contribution, suggesting that under this treatment, protocol hepatic glucose metabolism is not the most relevant target of insulin action but instead a more generalised effect in peripheral tissues.