Bandsma R H J, Grefhorst A, van Dijk T H, van der Sluijs F H, Hammer A, Reijngoud D-J, Kuipers F
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.
Diabetologia. 2004 Nov;47(11):2022-31. doi: 10.1007/s00125-004-1571-8. Epub 2004 Dec 1.
AIMS/HYPOTHESIS: Leptin-deficient ob/ob mice are hyperinsulinaemic and hyperglycaemic; however, the cause of hyperglycaemia remains largely unknown.
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.
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/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.
目的/假设：瘦素缺乏的ob/ob小鼠存在高胰岛素血症和高血糖症；然而，高血糖症的病因在很大程度上仍不清楚。
通过输注[U-(13)C]-葡萄糖、[2-(13)C]-甘油、[1-(2)H]-半乳糖和对乙酰氨基酚6小时，并对血糖和尿中对乙酰氨基酚-葡萄糖醛酸苷进行质量同位素异构体分布分析，研究9小时禁食的ob/ob小鼠和瘦的同窝小鼠的体内葡萄糖代谢。
以体重为基础计算，ob/ob小鼠的内源性葡萄糖生成（肥胖小鼠与瘦小鼠相比，分别为109±23对152±27微摩尔·千克(-1)·分钟(-1)，p<0.01）和葡萄糖-6-磷酸的从头合成（肥胖小鼠与瘦小鼠相比，分别为122±13对160±6微摩尔·千克(-1)·分钟(-1)，p<0.001）低于瘦的同窝小鼠。相反，肥胖小鼠的葡萄糖循环显著增加（肥胖小鼠与瘦小鼠相比，分别为56±13对26±4微摩尔·千克(-1)·分钟(-1)，p<0.001）。结果，肝脏葡萄糖总输出量未受影响（肥胖小鼠与瘦小鼠相比，分别为165±31对178±28微摩尔·千克(-1)·分钟(-1)，无显著性差异）。肥胖小鼠的葡萄糖代谢清除率显著降低（肥胖小鼠与瘦小鼠相比，分别为8±2对18±2毫升·千克(-1)·分钟(-1)，p<o.001）。ob/ob小鼠中编码葡萄糖激酶和丙酮酸激酶的基因的肝脏mRNA水平显著升高。
结论/解读：在高胰岛素血症情况下肝脏葡萄糖总输出量未受影响，这反映了ob/ob小鼠存在肝脏胰岛素抵抗，这与葡萄糖循环速率显著增加有关。ob/ob小鼠的高血糖症主要是由葡萄糖代谢清除率降低所致。
