Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset
Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset
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DOI：
10.2337/db15-1718
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发表时间：
2016-09-01
期刊：
影响因子：
7.7
通讯作者：
Speier, Stephan
中科院分区：
文献类型：
--
作者：
Chen, Chunguang;Chmelova, Helena;Speier, Stephan
新出现的胰岛素抵抗通常可以通过增加胰岛β细胞的胰岛素生成来补偿，从而维持正常的血糖。然而，目前还不清楚这是通过适应β细胞功能、质量还是两者兼而有之。最重要的是，当2型糖尿病发展时，这些适应性机制中的哪一种失败了仍是未知的。我们对移植的朗格汉斯胰岛的β细胞钙动力学和胰岛质量进行了体内纵向成像，研究了饮食诱导的从正常血糖稳态到胰岛素抵抗代偿到糖尿病前期的进展。结果表明，胰岛素抵抗的补偿以胰岛细胞功能的改变为主，而胰岛质量只是逐渐扩大。因此，功能适应是通过钙效应的增加来介导的，这涉及到EPAC信号转导。在糖尿病前期，β细胞功能表现为刺激钙动力学降低，而胰岛质量在糖尿病前期持续增加。因此，我们的数据揭示了胰岛功能在糖尿病发病前的体内过程中具有触发和放大途径的显著作用。这些发现支持将保护和恢复β细胞功能作为糖尿病预防和治疗的主要目标，并为潜在的治疗靶点提供了洞察。
Emerging insulin resistance is normally compensated by increased insulin production of pancreatic beta-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of beta-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of beta-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of beta-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, beta-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of beta-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.