BACKGROUND: Previous studies showed that early after Roux-en-Y gastric bypass (RYGB), there is a remarkable improvement in type 2 diabetes, which is characterized by insulin resistance. This study aims to gain insight into the underlying mechanisms of this effect. We determined the acute effects of RYGB on hepatic and peripheral insulin sensitivity. METHODS: A rat model of type 2 diabetes was established using high-fat diet combined with streptozotocin (30 mg/kg, ip). Animals were divided into four groups: diabetic, diabetic RYGB, diabetic RYGB sham, and control rats. Hyperinsulinemic-euglycemic clamps with tracer infusion were completed at 2 weeks postoperatively to assess insulin sensitivity. Triglyceride concentration in liver and muscle tissues was determined. Protein kinase C (PKC) membrane translocation, protein expression of phospho-c-Jun NH2-terminal kinase (JNK), and phospho-IκB kinase β (IKKβ) were assessed with western blot. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities in the liver were also measured. RESULTS: RYGB surgery significantly improved hepatic insulin sensitivity index and decreased hepatic triglyceride concentration (P < 0.05), without an improvement in peripheral insulin sensitivity. Membrane translocation of PKC-ε, PKC-δ, and PKC-θ; the ratio of MDA to SOD; and the expression of p-JNK and p-IKKβ in the liver were lower in the diabetic RYGB group than in the diabetic group. CONCLUSIONS: Diabetes remission was induced at short term after RYGB. The improvement of hepatic tissue lipotoxicity decreased the activation of certain PKC isoforms, the activity of JNK and IKK inflammatory signaling pathways, and the degree of oxidative stress. Furthermore, the hepatic insulin sensitivity was ameliorated, which is possibly a mechanism for early diabetes remission.