Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice

Aims/hypothesis. Leptin-deficient ob/ob mice are hyperinsulinaemic and hyperglycaemic; however, the cause of hyperglycaemia remains largely unknown. Methods. Glucose metabolism in vivo in 9-h fasted ob/ob mice and lean littermates was studied by infusing [U-¹³C]-glucose, [2- ¹³C]-glycerol, [1-²H]-galactose and paracetamol for 6 h, applying mass isotopomer distribution analysis on blood glucose and urinary paracetamol-glucuronide. Results. When expressed on the basis of body weight, endogenous glucose production (109±23 vs 152±27 μmol·kg^-1·min^-1, obese versus lean mice, p<0.01) and de novo synthesis of glucose-6-phosphate (122±13 vs 160±6 μmol·kg^-1·min^-1, obese versus lean mice, p<0.001) were lower in ob/ob mice than in lean littermates. In contrast, glucose cycling was greatly increased in obese mice (56±13 vs 26±4 μmol·kg^-1·min^-1, obese versus lean mice, p<0.001). As a result, total hepatic glucose output remained unaffected (165±31 vs 178±28 μmol·kg ^-1·min^-1, obese vs lean mice, NS). The metabolic clearance rate of glucose was significantly lower in obese mice (8±2 vs 18±2 ml·kg^-1·min^-1, obese versus lean mice, p<0.001). Hepatic mRNA levels of genes encoding for glucokinase and pyruvate kinase were markedly increased in ob/ob mice. Conclusions/ interpretation. Unaffected total hepatic glucose output in the presence of hyperinsulinaemia reflects hepatic insulin resistance in ob/ob mice, which is associated with markedly increased rates of glucose cycling. Hyperglycaemia in ob/ob mice primarily results from a decreased metabolic clearance rate of glucose.