You are here

ACS Chem Biol DOI:10.1021/acschembio.2c00052

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity.

Publication TypeJournal Article
Year of Publication2022
AuthorsSmall, JC, Joblin-Mills, A, Carbone, K, Kost-Alimova, M, Ayukawa, K, Khodier, C, Dančík, V, Clemons, PA, Munkacsi, AB, Wagner, BK
JournalACS Chem Biol
Date Published2022 Apr 19
ISSN1554-8937
Abstract

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.

DOI10.1021/acschembio.2c00052
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35439415?dopt=Abstract

Alternate JournalACS Chem Biol
PubMed ID35439415