Targeting Cellular Calcium Homeostasis to Prevent Beta-Cell Death in Type 1 Diabetes

Cytokines are important mediators of beta cell death leading to type 1 diabetes (T1DM). The mechanism of cytokine-mediated beta cell death has been previously shown to involve alterations in beta cell calcium homeostasis and increases in endoplasmic reticulum (ER) stress. Our group has previously established that pharmacologic modulation of cellular calcium levels with dantrolene and sitagliptin can significantly decrease cytokine and ER stress-mediated activation of the calpain and thioredoxin interacting protein pro-apoptotic pathways and suppress cell death in vitro using INS-1E rat insulinoma cells. The current study was designed to determine if dantrolene and sitagliptin can prevent beta cell death and diabetes in the low dose streptozotocin (STZ) model of T1DM. Male C57Bl/6 mice were treated with 5 doses of STZ (50 mg/kg) daily by 10 days of intraperitoneal (IP) injections of placebo, dantrolene, or sitagliptin. Blood sugar was monitored via tail vein blood using a glucometer. Blood glucose and insulin levels in response to 2g/kg IP dextrose injection were obtained on day 10. Unmethylated insulin DNA was also measured from plasma drawn on day 0, 8 and 15 to monitor beta cell death. Sitagliptin treated mice were resistant to low dose STZ induced diabetes as indicated by lower random blood glucose levels and normalization of blood glucose and insulin levels in response to IP dextrose infusion compared to placebo treated animals. In addition, sitagliptin treated animals had significantly lower levels of circulating unmethylated insulin DNA suggesting lower incidence of beta cell death as compared to placebo treated animals. In summary, in the low dose STZ model of diabetes, sitagliptin lowered random blood sugar, normalized blood glucose and insulin response to IP glucose tolerance testing and significantly decreased STZ mediated beta cell death. This study supports further study on the effect of sitagliptin and DPP-4 inhibition on beta cell function and survival in T1DM. Disclosure A.L. Clark: None. D. Abreu: None. C.M. Brown: None. F. Urano: Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; CytRx.