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首页> 外文期刊>Cell metabolism >High-Throughput Luminescent Reporter of Insulin Secretion for Discovering Regulators of Pancreatic Beta-Cell Function
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High-Throughput Luminescent Reporter of Insulin Secretion for Discovering Regulators of Pancreatic Beta-Cell Function

机译：胰岛素分泌的高通量发光记者发现胰腺β细胞功能调节剂。

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摘要

Defects in insulin secretion play a central role in the pathogenesis of type 2 diabetes, yet the mechanisms driving beta-cell dysfunction remain poorly understood, and therapies to preserve glucose-dependent insulin release are inadequate. We report a luminescent insulin secretion assay that enables large-scale investigations of beta-cell function, created by inserting Gaussia luciferase into the C-peptide portion of proinsulin. Beta-cell lines expressing this construct cosecrete luciferase and insulin in close correlation, under both standard conditions or when stressed by cytokines, fatty acids, or ER toxins. We adapted the reporter for high-throughput assays and performed a 1,600-compound pilot screen, which identified several classes of drugs inhibiting secretion, as well as glucose-potentiated secretagogues that were confirmed to have activity in primary human islets. Requiring 40-fold less time and expense than the traditional ELISA, this assay may accelerate the identification of pathways governing insulin secretion and compounds that safely augment beta-cell function in diabetes.
机译：胰岛素分泌的缺陷在2型糖尿病的发病机理中起着核心作用，但是驱动β细胞功能障碍的机制仍然知之甚少，并且维持葡萄糖依赖性胰岛素释放的疗法还不够。我们报告了一种发光胰岛素分泌测定法，该测定法可通过将高斯荧光素酶插入胰岛素原的C肽部分中来进行大规模的β细胞功能研究。在标准条件下或在细胞因子，脂肪酸或ER毒素的压力下，表达此构建体的β细胞系均紧密相关地分泌荧光素酶和胰岛素。我们使报道分子适应高通量测定，并进行了1600种化合物的中试筛选，确定了抑制分泌的几类药物以及已证实在原代人胰岛中具有活性的葡萄糖增强促分泌剂。与传统的ELISA相比，该方法所需的时间和费用少40倍，可以加快识别控制胰岛素分泌的途径和安全增强糖尿病患者β细胞功能的化合物的鉴定。

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