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.