2134-P: Protection of Beta-Cell Mass from Diabetogenic Condition-Induced Apoptosis by the Inhibition of Mammalian STE20-Like Protein Kinase 1 (MST1)

Impaired insulin secretion, a characteristic of type 2 diabetes (T2D) is partly attributed to decreased β-cell mass due to apoptotic cell death under diabetogenic conditions. Current therapies for diabetes do not address apoptotic cell death mediated β-cell deterioration. Mammalian STE20-like protein kinase 1 (MST1) is reported as one of the critical regulators of β-cell apoptosis under diabetogenic conditions, and therefore, inhibition of MST1 in β-cells may offer β-cell protection and preserve β-cell mass under diabetogenic conditions. We carried out an investigation of MST1 modulation, apoptotic signaling in islet samples from healthy controls, T2D patients and in pancreatic cell lines using MST1 specific siRNAs, and a small molecule inhibitor of MST1 (XMU-MP-1, IC50 ∼100 nM) under diabetogenic conditions. Elevated levels of phospho-MST1, cleaved MST1, and pro-apoptotic markers such as cleaved caspase-3 and BIM were observed in islet samples from T2D patients as compared to healthy control, suggesting the activation of MST1 mediated apoptotic pathway under diabetogenic conditions. Similar findings were observed when pancreatic samples from ob/ob mice and control mice were used. siRNA against MST1 and XMU-MP-1 rescued high glucose (25 mM)/high palmitate (500 µM) induced apoptosis in Min6 and INS-1E cells. The rescue of MIN6 and INS-1E cells were associated with the lowering of phospho-MST1, cleaved MST1 and pro-apoptotic markers such as cleaved caspase-3, phospho-H2B, and BIM. Further, once daily (1 mg/kg) dosing of XMU-MP-1 protected the β-cells in an acute streptozotocin-induced diabetic animal model. Increased numbers of insulin-stained pancreatic islets were observed in XMU-MP-1 treated group compared to disease control. Our data suggest that inhibition of MST1 can protect β-cell mass under diabetogenic conditions. Identification and development of specific small molecule inhibitors of MST1 are underway.