Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans
Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans
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DOI：
10.2337/diabetes.54.6.1649
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发表时间：
2005-06-01
期刊：
影响因子：
7.7
通讯作者：
Butler, PC
中科院分区：
文献类型：
--
作者：
Meier, JJ;Veldhuis, JD;Butler, PC
在健康状态下，胰岛素以离散脉冲的形式分泌到门静脉中，胰岛素分泌速率的调节是通过调节胰岛素脉冲质量来实现的。多项证据表明，胰腺的胰岛素输送模式决定了肝脏的胰岛素清除率。在之前的大型动物研究中，胰岛素脉冲的幅度与胰岛素清除的程度有关。在人类（和大型动物）中，门静脉中的胰岛素振荡幅度比体循环中的胰岛素振荡幅度高出 100 倍，尽管稀释度仅为五倍，这意味着胰岛素脉冲优先由肝脏提取。在本研究中，通过对健康人进行直接肝静脉取样，我们试图确定首过肝脏胰岛素提取的程度，并确定胰岛素分泌模式（胰岛素脉冲质量和振幅）是否决定肝脏胰岛素清除率，从而将胰岛素输送到肝外胰岛素反应组织。五名非糖尿病受试者（两名男性和三名女性，平均年龄 32 岁 [范围 25-39]，BMI 24.9 kg/m(2) [21.2-27.1]）参与。通过从肝静脉和动脉静脉同时采样并直接估计内脏血流量，在基础过夜禁食状态下和在 2 mg 中心点 kg(-1) 中心点 min(-1) 葡萄糖输注期间测量内脏床的胰岛素和 C 肽输送。根据 C 肽和肝脏胰岛素输送率之间的差异计算胰岛素提取率。分别通过反卷积和聚类分析来分析胰岛素浓度和肝脏胰岛素清除率的时间模式。使用互相关分析来关联C肽分泌和胰岛素清除率。葡萄糖输注使外周葡萄糖浓度从 5.4 +/- 0.1 增加到 6.4 +/- 0.4 mmol/l (P < 0.05)。同样，葡萄糖输注期间胰岛素和 C 肽浓度增加 (P < 0.05)。肝脏胰岛素清除率随葡萄糖输注而增加（1.06 +/- 0.18 vs. 2.55 +/- 0.38 pmol center dot kg(-1)center dot min(-1)；P < 0.01），但部分肝脏胰岛素清除率稳定（分别为 78.2 +/- 4.4 vs. 84 0. +/- 3.9%；P = 0.18）。葡萄糖输注期间胰岛素分泌爆发量增加（P < 0.05），而爆发间期保持不变（4.4 +/- 0.2 vs. 4.5 +/- 0.3 分钟；P = 0.36）。聚类分析确定了胰岛素清除率的振荡模式，大约每 5 分钟出现一次峰值。肝前 C 肽分泌与肝脏胰岛素清除率之间的互相关分析表明，存在显着的正相关关系，且没有可检测到的（< 1 分钟）时间滞后。胰岛素分泌爆发质量强烈预测胰岛素清除率（r = 0.81，P = 0.0043）。总之，在人类中，大约 80% 的胰岛素是在第一次肝脏通过期间提取的。肝脏对胰岛素分泌的波动迅速做出反应，优先提取以脉冲形式输送的胰岛素。穿过肝脏的胰岛素脉冲的质量（以及振幅）是肝脏胰岛素清除率的主要决定因素。因此，通过这种方式，胰岛素释放的脉冲质量决定了肝脏（直接）和肝外（间接）的胰岛素输送。这些发现强调了肝脏和胰腺的双重作用以及它们在调节全身胰岛素输送的数量和模式中通过胰岛素脉冲质量的大小介导的关系。
In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is similar to 100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25-39], BMI 24.9 kg/m(2) [21.2-27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg center dot kg(-1) center dot min(-1) by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 +/- 0.1 to 6.4 +/- 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 +/- 0.18 vs. 2.55 +/- 0.38 pmol center dot kg(-1)center dot min(-1); P < 0.01), but fractional hepatic insulin clearance was stable (78.2 +/- 4.4 vs. 84 0. +/- 3.9% , respectively; P = 0.18). Insulin secretory-burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 +/- 0.2 vs. 4.5 +/- 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (< 1 min) time lag. Insulin secretory-burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, similar to 80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery.These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic isulin delivery.