Muscelli Elza, Mari Andrea, Natali Andrea, Astiarraga Brenno D, Camastra Stefania, Frascerra Silvia, Holst Jens J, Ferrannini Ele
Dept. of Internal Medicine, University of Pisa, 56122 Pisa, Italy.
Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1144-50. doi: 10.1152/ajpendo.00571.2005. Epub 2006 Feb 14.
The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate beta-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 +/- 0.18, P = 0.004] amounted to 18 +/- 2 nmol/m(2) (32 +/- 4% of oral response), and its time course matched that of total insulin secretion. The beta-cell glucose sensitivity (OGTT/IV ratio = 1.52 +/- 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 +/- 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, beta-cell glucose sensitivity (75 +/- 14 vs. 156 +/- 28 pmol.min(-1).m(-2).mM(-1) of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity. In IGT, beta-cell function is inherently impaired, whereas the incretin effect is only partially affected.
肠胰岛轴影响β细胞功能的机制尚未得到详细研究。我们对正常糖耐量（NGT；n = 11）或糖耐量受损（IGT；n = 10）的受试者进行了口服和等血糖静脉注射（IV）葡萄糖试验，使用C肽反卷积计算胰岛素分泌率，并通过数学建模对β细胞功能进行定量分析。肠促胰岛素效应以口服与静脉注射反应的比值来衡量。在NGT中，肠促胰岛素介导的胰岛素释放[口服葡萄糖耐量试验（OGTT）/IV比值 = 1.59 ± 0.18，P = 0.004]达18 ± 2 nmol/m²（占口服反应的32 ± 4%），其时间进程与总胰岛素分泌的时间进程相符。β细胞对葡萄糖的敏感性（OGTT/IV比值 = 1.52 ± 0.26，P = 0.02）、速率敏感性（对葡萄糖变化速率的反应，OGTT/IV比值 = 2.22 ± 0.37，P = 0.06）以及葡萄糖非依赖性增强作用在口服葡萄糖时均明显高于静脉注射葡萄糖。在IGT中，β细胞对葡萄糖的敏感性（75 ± 14与NGT的156 ± 28 pmol·min⁻¹·m⁻²·mM⁻¹相比，P = 0.01）和增强作用在OGTT中受损。就血浆胰高血糖素样肽1和葡萄糖依赖性促胰岛素多肽反应、总胰岛素分泌以及β细胞对葡萄糖敏感性的增强（OGTT/IV比值 = 1.73 ± 0.24，与NGT相比P = 无显著差异）而言，肠促胰岛素效应与NGT无显著差异。然而，肠促胰岛素介导的胰岛素分泌和增强作用的时间进程发生了改变，葡萄糖诱导的刺激作用占主导地位，而非肠促胰岛素介导的刺激作用。我们得出结论，在生理情况下，肠促胰岛素介导的胰岛素分泌刺激源于β细胞功能所有动态方面的增强，尤其是β细胞对葡萄糖的敏感性。在IGT中，β细胞功能本身受损，而肠促胰岛素效应仅受到部分影响。
