Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2.
Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2.
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Insr 和 Irs2 联合突变小鼠的代偿性 β 细胞反应分析。
DOI：
10.1152/ajpendo.00430.2006
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Accili,Domenico
中科院分区：
文献类型：
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作者：
Kim,JaneJ;Kido,Yoshiaki;Scherer,PhilippE;White,MorrisF;Accili,Domenico
2型糖尿病是由胰岛素作用受损和β细胞功能障碍引起的。β细胞功能障碍至少有两个因素：胰岛素分泌受损和β细胞质量减少。为了分析这两个变量如何导致糖尿病患者代谢控制的进行性恶化，我们询问了由于IRS2消融而导致β细胞生长受损的小鼠是否能够在单倍体功能不全导致的胰岛素抵抗的背景下产生代偿反应。正如之前报道的那样，由于∼细胞质量显著减少，70%的携带InsrandIrs2联合突变的小鼠患上了糖尿病。在疾病的最初阶段，我们观察到循环中胰岛素水平的强劲上升，即使β细胞质量逐渐下降，这表明复制缺陷的β细胞通过增加胰岛素分泌来补偿胰岛素抵抗。这些数据为β细胞对胰岛素抵抗的异质性反应提供了进一步的证据，在这种反应中，当质量有限时，可以通过增加功能暂时实现补偿。代偿性胰岛素分泌的最终失败表明，对2型糖尿病β细胞功能障碍的综合治疗应该对β细胞生理学的两个方面都有积极的影响。
Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused byInsrhaploinsufficiency. As previously reported, ∼70% of mice with combinedInsrandIrs2mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.