Phenotypic Screening for Small Molecules that Protect ß-Cells from Glucolipotoxicity.
ACS Chem Biol
; 17(5): 1131-1142, 2022 05 20.
Article
en En
| MEDLINE
| ID: mdl-35439415
ABSTRACT
Type 2 diabetes is marked by progressive ß-cell failure, leading to loss of ß-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to ß-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of ß-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting ß-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 ß-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 ß-cell viability in the face of glucolipotoxicity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos