Kleckner N W, Kizaki Z, Thurman R G
Department of Pharmacology, University of North Carolina, Chapel Hill 27514.
Biochem J. 1987 Sep 1;246(2):417-23. doi: 10.1042/bj2460417.
Diabetes was induced by treating rats with alloxan, and was confirmed by blood glucose values greater than 250 mg/dl. In perfused livers from both normal and diabetic rats, basal rates of O2 uptake were similar (120-130 mumol/h per g). In livers from diabetic rats, basal rates of glucose output of 60 mumol/h per g declined to around 20 mumol/h per g during 1 h of perfusion. Basal glucose production was abolished by pretreatment with an inhibitor of glycogen synthesis, galactosamine (1.5 g/kg), injected 3 h before perfusion. The subsequent infusion of lactate (2 mM) increased O2 uptake and glucose production about 40-50 mumol/h per g in both groups; however, the average maximal increase in glucose output was nearly twice as high in livers from normal (33 mumol/h per g) as from diabetic (18 mumol/h per g) rats. Rates of lactate uptake were also about 50% lower in livers from diabetic than from normal rats, yet rates of ketone-body formation were similar. Miniature O2 electrodes placed on periportal and pericentral regions of the liver lobule were employed to measure local rates of O2 uptake before, during and after infusion of lactate by stopping the flow of perfusate through the liver and measuring the decrease in local [O2]. Local rates of glucose production were calculated from the extra O2 consumed and the known stoichiometry between O2 uptake and glucose production from lactate. In livers from normal rats, glucose was synthesized predominantly in periportal regions of the liver lobule; however, glucose was produced exclusively in periportal regions in livers from diabetic rats. In pericentral regions, O2 uptake increased slightly in livers from normal rats, but declined significantly by 10 mumol/h per g in livers from diabetic rats. These data are consistent with the hypothesis that gluconeogenesis from lactate occurs exclusively in periportal regions of the liver lobule in livers from diabetic rats. A portion of this glucose is metabolized back to lactate in pericentral areas, leading to increased rates of glycolytic ATP production, thereby decreasing the demands for O2. This production of glucose from lactate in periportal regions, followed by conversion of glucose back into lactate in pericentral areas, raises the possibility of intercellular futile cycling, stimulated by diabetes.
通过用四氧嘧啶处理大鼠诱导糖尿病，并通过血糖值大于250mg/dl来确认。在正常和糖尿病大鼠的灌注肝脏中，基础氧摄取率相似（每克120 - 130μmol/h）。在糖尿病大鼠的肝脏中，基础葡萄糖输出率为每克60μmol/h，在灌注1小时期间降至约每克20μmol/h。在灌注前3小时注射糖原合成抑制剂半乳糖胺（1.5g/kg）进行预处理可消除基础葡萄糖生成。随后输注乳酸（2mM）使两组的氧摄取和葡萄糖生成增加约每克40 - 50μmol/h；然而，正常大鼠肝脏（每克33μmol/h）的葡萄糖输出平均最大增加量几乎是糖尿病大鼠肝脏（每克18μmol/h）的两倍。糖尿病大鼠肝脏的乳酸摄取率也比正常大鼠肝脏低约50%，但酮体生成率相似。通过在肝小叶的门静脉周围和中央周围区域放置微型氧电极，在灌注乳酸之前、期间和之后，通过停止灌注液流经肝脏并测量局部[O2]的下降来测量局部氧摄取率。根据额外消耗的氧以及氧摄取与乳酸生成葡萄糖之间已知的化学计量关系计算局部葡萄糖生成率。在正常大鼠的肝脏中，葡萄糖主要在肝小叶的门静脉周围区域合成；然而，糖尿病大鼠肝脏中的葡萄糖仅在门静脉周围区域产生。在中央周围区域，正常大鼠肝脏的氧摄取略有增加，但糖尿病大鼠肝脏的氧摄取显著下降，每克下降10μmol/h。这些数据与以下假设一致：糖尿病大鼠肝脏中乳酸的糖异生仅发生在肝小叶的门静脉周围区域。一部分葡萄糖在中央周围区域又代谢回乳酸，导致糖酵解ATP生成率增加，从而降低了对氧的需求。门静脉周围区域由乳酸生成葡萄糖，随后在中央周围区域葡萄糖又转化回乳酸，这增加了糖尿病刺激的细胞间无效循环的可能性。
