Department of Information Engineering, University of Padova, Padua, Italy.
Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1115-21. doi: 10.1152/ajpendo.00705.2009. Epub 2010 Feb 23.
Glucagon-like peptide-1 (GLP-1)-based therapies for diabetes have aroused interest because of their effects on insulin secretion and glycemic control. However, a mechanistic model enabling quantitation of pancreatic response to GLP-1 has never been developed. To develop such a model we studied 88 healthy individuals (age 26.3 +/- 0.6 yr, BMI 24.9 +/- 0.4 kg/m(2)) by use of a hyperglycemic clamp. A variable infusion maintained glucose concentrations at 150 mg/dl for 240 min. At 120 min, an intravenous infusion of GLP-1 was started (0.75 pmol kg(-1) min(-1) from 120-180 min, 1.5 pmol kg(-1) min(-1) from 181-240 min). Consequently, plasma C-peptide concentration rose from 1,852.0 +/- 62.8 pmol/l at 120 min to 4,272.2 +/- 176.4 pmol/l at 180 min and to 6,995.8 +/- 323.5 pmol/l at 240 min. Four models of GLP-1 action on insulin secretion were considered. All models share the common assumption that insulin secretion is made up of two components, one proportional to glucose rate of change through dynamic responsivity, Phi(d), and one proportional to glucose through static responsivity, Phi(s), but differing by modality of GLP-1 control. The model that best fit C-peptide data assumes that above-basal insulin secretion depends linearly on GLP-1 concentration and its rate of change. An index (Pi) measuring the percentage increase of secretion due to GLP-1 is derived. Before GLP-1 infusion, Phi(d) = 245.7 +/- 15.6 10(-9) and Phi(s) = 25.2 +/- 1.4 10(-9) min(-1). Under GLP-1 stimulus, Pi = 12.6 +/- 0.71% per pmol/l, meaning that an increase of 5 pmol/l in peripheral GLP-1 concentrations induces an approximately 60% increase in over-basal insulin secretion.
胰高血糖素样肽-1（GLP-1）为基础的治疗糖尿病的方法引起了人们的兴趣，因为它们对胰岛素分泌和血糖控制的影响。然而，一种能够定量测量 GLP-1 对胰腺反应的机制模型从未被开发出来。为了开发这样的模型，我们通过高血糖钳夹研究了 88 名健康个体（年龄 26.3 ± 0.6 岁，BMI 24.9 ± 0.4 kg/m2）。通过可变输注将葡萄糖浓度维持在 150 mg/dl 240 分钟。在 120 分钟时，开始静脉输注 GLP-1（从 120-180 分钟时为 0.75 pmol kg-1 min-1，从 181-240 分钟时为 1.5 pmol kg-1 min-1）。结果，血浆 C 肽浓度从 120 分钟时的 1852.0 ± 62.8 pmol/l 上升到 180 分钟时的 4272.2 ± 176.4 pmol/l，到 240 分钟时的 6995.8 ± 323.5 pmol/l。考虑了四种 GLP-1 作用于胰岛素分泌的模型。所有模型都有一个共同的假设，即胰岛素分泌由两部分组成，一部分与葡萄糖变化率通过动态反应性（Phi(d)）成比例，一部分与葡萄糖通过静态反应性（Phi(s)）成比例，但 GLP-1 控制方式不同。最适合 C 肽数据的模型假设基础胰岛素分泌量随 GLP-1 浓度及其变化率呈线性增加。由此得出一个测量由于 GLP-1 分泌增加的百分比的指数（Pi）。在 GLP-1 输注之前，Phi(d) = 245.7 ± 15.6 10-9 min-1，Phi(s) = 25.2 ± 1.4 10-9 min-1。在 GLP-1 刺激下，Pi = 12.6 ± 0.71%/pmol/l，这意味着外周 GLP-1 浓度增加 5 pmol/l 会导致基础胰岛素分泌增加约 60%。
