Kjems L L, Kirby B M, Welsh E M, Veldhuis J D, Straume M, McIntyre S S, Yang D, Lefèbvre P, Butler P C
Diabetes Research Unit and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, Scotland.
Diabetes. 2001 Sep;50(9):2001-12. doi: 10.2337/diabetes.50.9.2001.
Most insulin is secreted in discrete pulses at an interval of approximately 6 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 approximately 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 pg/ml; 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.
大多数胰岛素以约6分钟的间隔呈离散脉冲式分泌。餐后胰岛素分泌增加是通过脉冲量放大机制实现的。相反，在2型糖尿病中，由于胰岛素脉冲量减少，胰岛素分泌受损。据报道，2型糖尿病患者的β细胞量不足。我们检验了β细胞量减少导致胰岛素脉冲量减少这一假说。在猪模型中，通过单次注射四氧嘧啶使β细胞量减少约60%前后，对胰岛素分泌进行了检测。注射四氧嘧啶导致稳定的糖尿病状态（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量选择性降低（分别降低54%、60%和90%），而脉冲频率无变化。节律分析显示，空腹状态下给予四氧嘧啶后，规则振荡的周期性无变化，但在肠内或静脉注射葡萄糖刺激后无法可靠检测到稳定的节律。给予四氧嘧啶后，胰岛素分泌和胰岛素脉冲量（而非胰岛素脉冲间隔）与β细胞量相关而降低。然而，脉冲量降低（以及输送到肝脏的脉冲幅度）与肝脏胰岛素清除率降低有关，这部分抵消了胰岛素分泌的减少。尽管存在高血糖，但给予四氧嘧啶后餐后胰高血糖素浓度仍升高（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细胞量选择性减少通过减弱胰岛素脉冲量导致胰岛素分泌不足，而后者与肝脏胰岛素清除率降低和相对胰高血糖素血症有关，从而模拟了2型糖尿病中观察到的胰岛功能障碍模式。
