FAILURE OF SUBSTRATE-INDUCED GLUCONEOGENESIS TO INCREASE OVERALL GLUCOSE APPEARANCE IN NORMAL HUMANS - DEMONSTRATION OF HEPATIC AUTOREGULATION WITHOUT A CHANGE IN PLASMA-GLUCOSE CONCENTRATION
FAILURE OF SUBSTRATE-INDUCED GLUCONEOGENESIS TO INCREASE OVERALL GLUCOSE APPEARANCE IN NORMAL HUMANS - DEMONSTRATION OF HEPATIC AUTOREGULATION WITHOUT A CHANGE IN PLASMA-GLUCOSE CONCENTRATION
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DOI：
10.1172/jci114735
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发表时间：
1990-08-01
影响因子：
15.9
通讯作者：
GERICH, JE
中科院分区：
文献类型：
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作者：
JENSSEN, T;NURJHAN, N;GERICH, JE
糖异生前体供应的增加可能是导致非胰岛素依赖型糖尿病(NIDDM)患者空腹高血糖的主要原因。因此，为了验证这样一种假设，即增加糖异生底物供应本身可以增加肝脏葡萄糖输出量，足以导致空腹高血糖，我们给正常志愿者注射乳酸钠的速度大约是NIDDM患者观察到的出现率的两倍，同时将血浆胰岛素、胰高血糖素和生长激素控制在基础水平。在对照实验中，以等摩尔率注入碳酸氢钠，而不是乳酸钠。在这两个实验中，注入[6-13H]-葡萄糖来测量葡萄糖的外观，并注入[U-14C]乳酸或[U-14C]丙氨酸来测量这些底物的外观和转化为血糖的速率。对照组和乳酸输注实验的血浆胰岛素、胰升糖素、生长激素、C-肽和甘油浓度以及血碳酸氢盐和pH值无显著差异。输注乳酸可使血浆乳酸和丙氨酸升高至4.48+-。3 mm和610。+-。33微米，分别来自1.6+-的基准值。0.2 mm和4317。+-。28微米，P<；0.01；乳酸和丙氨酸出现率增加到38。+-。1.0和8.0。+-。0.3微克分子/公斤每分钟(P<；0.01对基础速率14.4+-.0.4和5.0。+-。分别为每分钟0.5微克分子/公斤)。经过克雷布斯循环碳交换校正后，血糖中的乳酸掺入增加了近三倍，达到每分钟10.4微克分子/公斤，约占总血糖的50%。丙氨酸掺入血糖中的量增加了两倍多。尽管糖异生显著增加，但总的肝脏葡萄糖输出量和血浆葡萄糖都没有增加，而且它们都与对照实验中观察到的值没有显著差异(10.8±-)。0.5比10.8。+-。每分钟0.5µmol/kg和5.4.+-。0.4比5.3。+-0.3 mm)。因此，我们得出结论，在正常人中，存在一个独立于血糖和糖调节激素浓度变化的自我调节过程，该过程防止底物诱导的糖异生增加增加总的肝脏葡萄糖输出量；由于这一过程不能以抑制其他底物的糖异生来解释，它可能涉及糖原分解的减少。这一过程中的缺陷可以至少部分解释NIDDM患者肝脏葡萄糖输出增加的原因。
It has been proposed that increased supply of gluconeogenic precursors may be largely responsible for the increased gluconeogenesis which contributes to fasting hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). Therefore, to test the hypothesis that an increase in gluconeogenic substrate supply per se could increase hepatic glucose output sufficiently to cause fasting hyperglycemia, we infused normal volunteers with sodium lactate at a rate approximately double the rate of appearance observed in NIDDM while clamping plasma insulin, glucagon, and growth hormone at basal levels. In control experiments, sodium bicarbonate was infused instead of sodium lactate at equimolar rates. In both experiments, [6-13H]-glucose was infused to measure glucose appearance and either [U-14C]lactate or [U-14C]alanine was infused to measure the rates of appearance and conversion of these substrates into plasma glucose. Plasma insulin, glucagon, growth hormone, C-peptide, and glycerol concentrations, and blood bicarbonate and pH in control and lactate infusion experiments were not significantly different. Infusion of lactate increased plasma lactate and alanine to 4.48 .+-. 3 mM and 610 .+-. 33 .mu.M, respectively, from baseline values of 1.6 .+-. 0.2 mM and 431 7.+-. 28 .mu.M, both P < 0.01; lactate and alanine rates of appearance increased to 38 .+-. 1.0 and 8.0 .+-. 0.3 .mu.mol/kg per min (P < 0.01 versus basal rates of 14.4 .+-. 0.4 and 5.0 .+-. 0.5 .mu.mol/kg per min, respectively). With correction for Krebs cycle carbon exchange, lactate incorporation into plasma glucose increased nearly threefold to 10.4 .mu.mol/kg per min and accounted for about 50% of overall glucose appearance. Alanine incorporation into plasma glucose increased more than twofold. Despite this marked increase in gluconeogenesis, neither overall hepatic glucose output nor plasma glucose increased and each was not significantly different from values observed in control experiments (10.8 .+-. 0.5 vs. 10.8 .+-. 0.5 .mu.mol/kg per min and 5.4 .+-. 0.4 vs. 5.3 .+-. 0.3 mM, respectively). We, therefore, conclude that in normal humans there is an autoregulatory process independent of changes in plasma glucose and glucoregulatory hormone concentrations which prevents a substrate-induced increase in gluconeogenesis from increasing overall hepatic glucose output; since this process cannot be explained on the basis of inhibition of gluconeogenesis from other substrates, it probably involves diminution of glycogenolysis. A defect in this process could explain at least in part the increased hepatic glucose output found in NIDDM.