II型糖尿病(T2D)的进展特征是β细胞质量的复杂和高度可变的损失,导致胰岛素分泌受损。已经使用有限的β细胞系和原代啮齿动物/人胰岛开发了旨在发现可以保护或恢复β细胞质量和功能的分子的许多T2D药物发现努力。各种高通量筛选方法已用于药物发现的背景下,包括基于荧光素酶的报告分析,葡萄糖刺激的胰岛素分泌,和高含量的筛选。在这种情况下,小分子发现的基石是使用永生化的啮齿动物β细胞系。虽然有见地,这种用法使人们对啮齿动物β细胞增殖途径有了更全面的了解,而不是对人类的了解.与单层培养物相比,三维(3D)原代胰岛和假胰岛提供了增强生理相关性的优势,但是这些方法仅限于在低通量实验中使用。新兴方法,例如高通量3D胰岛成像与机器学习相结合,旨在提高将3D显微组织结构整合到高通量筛选中的可行性。这篇综述探讨了目前用于高通量筛选β细胞质量和功能的小分子调节剂的方法。糖尿病药物发现的潜在关键策略。
The progression of type II diabetes (T2D) is characterized by a complex and highly variable loss of beta-cell mass, resulting in impaired insulin secretion. Many T2D drug discovery efforts aimed at discovering molecules that can protect or restore beta-cell mass and function have been developed using limited beta-cell lines and primary rodent/human pancreatic islets. Various high-throughput screening methods have been used in the context of drug discovery, including luciferase-based reporter assays, glucose-stimulated insulin secretion, and high-content screening. In this context, a cornerstone of small molecule discovery has been the use of immortalized rodent beta-cell lines. Although insightful, this usage has led to a more comprehensive understanding of rodent beta-cell proliferation pathways rather than their human counterparts. Advantages gained in enhanced physiological relevance are offered by three-dimensional (3D) primary islets and pseudoislets in contrast to monolayer cultures, but these approaches have been limited to use in low-throughput experiments. Emerging methods, such as high-throughput 3D islet imaging coupled with machine learning, aim to increase the feasibility of integrating 3D microtissue structures into high-throughput screening. This review explores the current methods used in high-throughput screening for small molecule modulators of beta-cell mass and function, a potentially pivotal strategy for diabetes drug discovery.