KD025 Is a Casein Kinase 2 Inhibitor That Protects Against Glucolipotoxicity in β-Cells.

Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on β-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protect β-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil-containing kinase isoform 2 (ROCK2), as a GLT-protective compound in INS-1E cells and dissociated human islets. To further understand the mechanism of action of KD025, we found that pharmacological and genetic inhibition of ROCK2 was not responsible for the protective effects of KD025 against GLT.

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

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.