Natali A, Gastaldelli A, Camastra S, Sironi A M, Toschi E, Masoni A, Ferrannini E, Mari A
Metabolism Unit of the Consiglio Nazionale delle Ricerche Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa, 56126 Pisa, Italy.
Am J Physiol Endocrinol Metab. 2000 May;278(5):E794-801. doi: 10.1152/ajpendo.2000.278.5.E794.
The traditional methods for the assessment of insulin sensitivity yield only a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clearance (Cl(max)) and an insulin concentration at half-maximal response (EC(50)). We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous insulin administration (two steps of 20 and 200 mU x min(-1) x m(-2), 100 min each). The effect of insulin on plasma glucose clearance was calculated from non-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Michaelis-Menten function of insulin concentration with a delay (t(1/2)). In seven nondiabetic subjects, the model predicted adequately the tracer concentration: the model residuals were unbiased, and their coefficient of variation was similar to the expected measurement error (approximately 3%), indicating that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min) and maximal responses (Cl(max) = 705 +/- 46 vs. 668 +/- 259 ml x min(-1) x m(-2), respectively), whereas EC(50) was 240 +/- 84 microU/ml in the lean vs. 364 +/- 229 microU/ml in the obese (P < 0.04). EC(50) and the insulin sensitivity index (ISI, initial slope of the dose-response curve), but not Cl(max), were related to body adiposity and fat distribution with r of 0.6-0.8 (P < 0.05). Thus, despite the small number of study subjects, we were able to reproduce information consistent with the literature. In addition, among the lean individuals, t(1/2) was positively related to the ISI (r = 0.72, P < 0.02). We conclude that the test here presented, based on a more elaborate representation of glucose kinetics and insulin action, allows a reliable quantitation of the insulin dose-response curve for whole body glucose utilization in a single session of relatively short duration.
传统的胰岛素敏感性评估方法只能得出单一指标，而非完整的剂量反应曲线信息。该曲线通常由最大胰岛素刺激的葡萄糖清除率（Cl(max)）和半数最大反应时的胰岛素浓度（EC(50)）来表征。我们开发了一种方法，基于使用示踪葡萄糖和外源性胰岛素给药（两个步骤，分别为20和200 mU·min(-1)·m(-2)，各持续100分钟），通过单次体内试验来估计完整的剂量反应曲线。胰岛素对血浆葡萄糖清除率的影响通过非稳态数据，利用葡萄糖动力学循环模型和胰岛素作用模型来计算，其中葡萄糖清除率表示为具有延迟（t(1/2)）的胰岛素浓度的米氏函数。在7名非糖尿病受试者中，该模型对示踪剂浓度的预测较为准确：模型残差无偏，其变异系数与预期测量误差相似（约3%），表明该模型未引入显著的系统误差。瘦体型（n = 4）和肥胖体型（n = 3）受试者的胰岛素作用半衰期（t(1/2) = 25 ± 9分钟对25 ± 8分钟）和最大反应（Cl(max)分别为705 ± 46 ml·min(-1)·m(-2)对668 ± 259 ml·min(-1)·m(-2)）相似，而瘦体型受试者的EC(50)为240 ± 84 μU/ml，肥胖体型受试者为364 ± 229 μU/ml（P < 0.04）。EC(50)和胰岛素敏感性指数（ISI，剂量反应曲线的初始斜率），而非Cl(max)，与身体肥胖程度和脂肪分布相关，r值为0.6 - 0.8（P < 0.05）。因此，尽管研究对象数量较少，但我们能够重现与文献一致的信息。此外，在瘦体型个体中，t(1/2)与ISI呈正相关（r = 0.72，P < 0.02）。我们得出结论，这里介绍的试验基于对葡萄糖动力学和胰岛素作用更精细的描述，能够在单次相对较短时间的试验中对全身葡萄糖利用的胰岛素剂量反应曲线进行可靠定量。
