Decrease in β-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig
Decrease in β-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig
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DOI：
10.2337/diabetes.50.9.2001
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发表时间：
2001-09-01
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：
Kjems, LL;Kirby, BM;Butler, PC
大多数胰岛素是以间隔约6分钟的离散脉冲分泌的。餐后胰岛素分泌的增加是通过脉冲群的放大机制实现的。相反，在2型糖尿病中，由于胰岛素脉冲质量减少，胰岛素分泌受损。据报道，2型糖尿病患者的β细胞质量不足。我们检验了β细胞量减少导致胰岛素脉冲量减少的假设。在猪模型中通过单次注射四氧嘧啶实现β-细胞质量减少60%之前和之后检查胰岛素分泌。四氧嘧啶注射导致糖尿病稳定（空腹血糖7.4 +/- 1.1 vs 4.4 +/- 0.1 mmol/l; P < 0.01），空腹和进食状态以及高血糖钳夹期间胰岛素分泌受损（分别降低54%、80%和90%）。去卷积分析显示胰岛素脉冲质量选择性降低（54、60和90%），脉冲频率无变化。节律分析显示，在禁食状态下给予四氧嘧啶后，规则振荡的周期性没有变化，但在肠内或静脉内葡萄糖刺激后，无法可靠地检测到稳定的节律。四氧嘧啶给药后，胰岛素分泌和胰岛素脉冲质量（但不是胰岛素脉冲间隔）相对于β细胞质量降低。然而，脉冲质量（和输送至肝脏的脉冲幅度）降低与肝脏胰岛素清除率降低相关，这部分抵消了胰岛素分泌减少。尽管高血糖，但四氧嘧啶给药后餐后胰高血糖素浓度增加（103.4 +/- 6.3 vs. 92.2 +/- 2.5 pg/ml; P < 0.01）。我们得出结论，四氧嘧啶诱导的β细胞质量的选择性减少通过减弱胰岛素脉冲质量导致胰岛素分泌不足，并且后者与肝脏胰岛素清除率降低和相对高胰高血糖素血症相关，从而模拟在2型糖尿病中观察到的胰岛功能障碍的模式。
Most insulin is secreted in discrete pulses at an interval of similar to6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. beta -cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased beta -cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an similar to 60% decrease in beta -cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 +/- 1.1 vs. 4.4 +/- 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90%) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to beta -cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 +/- 6.3 vs. 92.2 +/- 2.5 pgtml; P < 0.01). We conclude that an alloxan-induced selective decrease in beta -cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes.