Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin

To better define the modifications of liver gluconeogenesis and citric acid cycle, or Krebs' cycle, activity induced by insulin deficiency and the eff ects of metformin on these abnormalities, we infused livers isolated from p ostabsorptive or starved normal and streptozotocin-induced diabetic rats wi th pyruvate and lactate (labeled with [3-C-13]lactate) with or without the simultaneous infusion of metformin. Lactate and pyruvate uptake and glucose production were calculated. The C-13-labeling pattern of liver glutamate w as used to calculate, according to Magnusson's model, the relative fluxes t hrough Krebs' cycle and gluconeogenesis. These relative fluxes were convert ed into absolute values using substrate balances. In normal rats, starvatio n increased gluconeogenesis, the flux through pyruvate carboxylase-phosphoe nolpyruvate carboxykinase (PC-PEPCK), and the ratio of PC to pyruvate dehyd rogenase (PDH) flux (P < 0.05); metformin induced only a moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes resembled those of starved control livers, with increased gluconeogenesis and flux th rough PC-PEPCK. Starvation induced no further modifications in the diabetic group. Metformin decreased glucose output from the liver of starved diabet ic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were decreased (P < 0.05) by metformin in both groups of diabetic rats. In conc lusion, insulin deficiency increased in this model of diabetes gluconeogene sis through enhanced uptake of substrate and increased flux through PC-PEPC K; metformin decreased glucose production by reducing the flux through PC-P EPCK.