Phenotypic Screening for Small Molecules that Protect β‑Cells from Glucolipotoxicity
datasetposted on 19.04.2022, 23:43 by Jonnell C. Small, Aidan Joblin-Mills, Kaycee Carbone, Maria Kost-Alimova, Kumiko Ayukawa, Carol Khodier, Vlado Dancik, Paul A. Clemons, Andrew B. Munkacsi, Bridget K. Wagner
Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.
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specific families includingknown biological targetsincreased calcium fluxcdk ), piprotective small moleculesfound 312 glucolipotoxicityassociated kinase 216 kinase inhibitorssmall moleculeskinase inhibitorsjak ),increased levels3 kinasepi3k inhibitorsvalidation studiesthroughput screentherapeutic optionsrock2 ).results providerestoring insreduced glucolipotoxicityphenotypic screeningobesity leadmitochondrial depolarizationhit rateelevated glucosedependent kinasescirculating glucosecell viabilitycell masscell glucolipotoxicitycell failurecell death876 compounds