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-C-13]-glucose, [2-C-13]-glycerol, [1-H-2]-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 mumol.kg(-1).min(-1), obese versus lean mice, p<0.01) and de novo synthesis of glucose-6-phosphate (122 +/- 13 vs 160 +/- 6 mu mol.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 mumol.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 mu mol.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(-l).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.