Rationale: To study nutritional transitions and diet-induced insulin resistance (IR), time-course exploration of metabolome, associated with targeted metabolites net fluxes at the splanchnic and peripheral levels in a minipig model, open new perspectives and understanding of the adaptive mechanisms occurring during IR development induced by a western diet (WD). Methods: Pigs were equipped with catheters in aorta, portal and hepatic veins. They were fed a WD over 60 days (4-fold more energy supply as lipids than regular diet). Before (D0) and after 1 (D1), 7 (D7), 14 (D14) and 60 (D60) days of adaptation to WD, blood and urine samples were taken pre and postprandially. Plasma metabolites were determined by classical biochemistry and urinary metabolome by UPLC-QToF. Metabolomic data were analysed by multivariate OPLS-DA and plasma metabolites by one-way ANOVA. Results: From D14 up to the end of the trial, minipigs presented fasting hyperglycemia and hyperinsulinemia, along with an increased HOMA-IR index, confirming the early installation of IR. Urinary metabolome follows a 2 steps pattern: a 1st phase of immediate adaptation to the diet (within the 1st 7 days) followed by a 2nd progressive step (D7 to D60) linked to alterations of endogenous metabolome. This is consistent with a rapid shift of arterial plasma metabolites levels and net splanchnic utilization of nutrients within the D0-D14 period: +34% arterial lactate (P<0.09) amplified at J60 (+50%, P<0.05), +15% glucose and +192% cholesterol, D0 vs D7 (P<0.05). Conclusion: These preliminary data show that a combination of urinary metabolome and targeted plasma metabolites determination at various sampling sites and times can highlight adaptive mechanisms involved in the development of WD-induced IR.