Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice.
OBJECTIVE
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-(13)C]-glucose, [2-(13)C]-glycerol, [1-(2)H]-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 micromol.kg(-1).min(-1), obese versus lean mice, p<0.01) and de novo synthesis of glucose-6-phosphate (122+/-13 vs 160+/-6 micromol.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 micromol.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 micromol.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
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.
Bandsma
R H J
RH
The Centre for Liver, Digestive and Metabolic Diseases, Research Laboratory of Paediatrics, CMC IV/2, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Grefhorst
A
A
van Dijk
T H
TH
van der Sluijs
F H
FH
Hammer
A
A
Reijngoud
D-J
DJ
Kuipers
F
F
D000818:Animals; D002247:Carbon Isotopes; D005260:Female; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000096:biosynthesis*; D005990:Glycerol / Q000378:metabolism; D006706:Homeostasis; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D013851:Thinness / Q000378:metabolism
D002247:Carbon Isotopes; D008112:Liver Glycogen; D019298:Glucose-6-Phosphate; D005947:Glucose; D005990:Glycerol