Ferrannini E, Barrett E J, Bevilacqua S, DeFronzo R A
J Clin Invest. 1983 Nov;72(5):1737-47. doi: 10.1172/JCI111133.
Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at approximately 100 microU/ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at approximately 50 microU/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min X kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 mumol/ml. With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3 +/- 1.3 vs. 7.4 +/- 0.6 mg/min X kg, P less than 0.02). Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2 +/- 1.1 vs. 9.8 +/- 1.9 mg/min X kg, P less than 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of glucose uptake (r = 0.69, P less than 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/min X kg) but markedly stimulated endogenous glucose production (1.4 +/- 0.5 vs. 0.5 +/- 0.4 mg/min X kg, P less than 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5 +/- 0.5 vs. 0.7 +/- 0.6 mg/min X kg, P less than 0.05). We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.
自最初提出葡萄糖脂肪酸循环以来，关于其在体内的生理意义已引发了相当多的争议。在本研究中，我们在三种受控实验条件下，检测了正常受试者体内游离脂肪酸（FFA）浓度急性生理性升高对葡萄糖生成和摄取的影响。在A组中，通过胰岛素输注使血浆胰岛素水平升高并维持在比基线高约100微单位/毫升，同时通过可变葡萄糖输注使血浆葡萄糖维持在空腹水平。在B组中，血浆葡萄糖浓度升高125毫克/100毫升，通过生长抑素和胰岛素联合输注使血浆胰岛素钳制在约50微单位/毫升。在C组中，血浆葡萄糖比空腹水平升高200毫克/100毫升，同时用生长抑素抑制胰岛素分泌，并用胰高血糖素输注（1纳克/分钟×千克）替代外周胰高血糖素水平。每个方案都在同一受试者中重复进行，并联合脂质 - 肝素输注，以使血浆FFA水平升高1.5 - 2.0微摩尔/毫升。在正常血糖高胰岛素血症（研究A）时，脂质输注导致总葡萄糖摄取显著抑制（6.3±1.3对7.4±0.6毫克/分钟×千克，P＜0.02）。无论是否进行脂质输注，内源性葡萄糖生成（通过[3 - 3H]葡萄糖技术估算）均被完全抑制。在高血糖高胰岛素血症（研究B）时，脂质输注也导致葡萄糖利用显著受损（6.2±1.1对9.8±1.9毫克/分钟×千克，P＜0.05）；尽管FFA浓度升高，但内源性葡萄糖生成再次被完全抑制。在这两种情况下（A和B），FFA对葡萄糖摄取的抑制百分比与葡萄糖摄取总速率呈正相关（r = 0.69，P＜0.01）。相反，当高血糖与相对胰岛素缺乏和高胰高血糖素血症相关（研究C），从而模拟糖尿病状态时，脂质输注对葡萄糖摄取无影响（2.9±0.2对2.6±0.2毫克/分钟×千克），但显著刺激内源性葡萄糖生成（1.4±0.5对0.5±0.4毫克/分钟×千克，P＜0.005）。在与研究C相同的条件下，输注甘油使血浆甘油水平与脂质 - 肝素所达到的水平相似，增强了内源性葡萄糖生成（1.5±0.5对0.7±0.6毫克/分钟×千克，P＜0.05）。我们得出结论，在胰岛素水平良好的状态下，升高的FFA水平有效地与葡萄糖竞争外周组织摄取，无论是否存在高血糖。另一方面，当胰岛素缺乏时，脂解速率升高可能导致高血糖，不是通过竞争燃料利用，而是通过增强内源性葡萄糖输出。
