288-LB: CHIP Haplodeficiency Exacerbates Experimental Type 1 Diabetes via the Regulation of DNA Damage Response and Apoptosis

Type 1 diabetes is a disease characterized by hyperglycemia resulting from defects in insulin secretion. Streptozotocin (STZ)-induced pancreatic β-cell damage is commonly used as causing hyperglycemia of type 1 diabetes model. It has been established that the carboxyl terminus of heat shock protein 70-interacting protein (CHIP) contributes to the pathogeneses of diabetic complications. However, the mechanisms linking type 1 diabetes and CHIP-dependent antidiabetic signaling pathway remain to be addressed. Here we utilized STZ-induced murine model of type 1 diabetes to examine DNA damage responses (DDR) during pancreatic β-cell apoptosis. This study was undertaken to explore the mechanism whereby CHIP instigates pancreatic β-cell apoptosis via DDR-dependent signaling pathway. Wild type and CHIP haplodeficient mice were i.p. injected with 50 or 100 mg/kg STZ in order to induce experimental mouse model of type I diabetes. STZ-induced hyperglycemia, glucose intolerance, and inflammatory responses were exacerbated in CHIP haplodeficient mice compared to Wild type. In addition, immunoblotting data revealed that depletion of CHIP with siRNA against rat stub1 enhanced STZ-induced apoptosis and DDR pathway in INS-1 cells, a rat insulinoma cell line. Notably, CHIP inhibition deteriorates STZ-induced cell cycle arrest and oxidative stress in INS-1 cells. In addition to in vitro study, immunohistochemical and immunoblotting study showed that CHIP haplodeficiency exacerbates DDR in pancreas from an experimental mouse model of type I diabetes. These results suggest that CHIP protects against STZ-induced pancreatic β-cell apoptosis and hyperglycemia by interrupting the DDR-mediated apoptotic pathway. Key words: diabetes, CHIP, DNA damage response, apoptosis, β-cell